Lung Transplant - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

LUNG

TRANSPLANT A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Lung Transplant: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00686-3 1. Lung Transplant-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on lung transplant. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON LUNG TRANSPLANT.................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Lung Transplant ........................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 43 The National Library of Medicine: PubMed ................................................................................ 44 CHAPTER 2. NUTRITION AND LUNG TRANSPLANT ........................................................................ 93 Overview...................................................................................................................................... 93 Finding Nutrition Studies on Lung Transplant.......................................................................... 93 Federal Resources on Nutrition ................................................................................................... 96 Additional Web Resources ........................................................................................................... 97 CHAPTER 3. ALTERNATIVE MEDICINE AND LUNG TRANSPLANT ................................................. 99 Overview...................................................................................................................................... 99 National Center for Complementary and Alternative Medicine.................................................. 99 Additional Web Resources ......................................................................................................... 105 General References ..................................................................................................................... 106 CHAPTER 4. PATENTS ON LUNG TRANSPLANT ............................................................................ 107 Overview.................................................................................................................................... 107 Patent Applications on Lung Transplant .................................................................................. 107 Keeping Current ........................................................................................................................ 111 CHAPTER 5. BOOKS ON LUNG TRANSPLANT ................................................................................ 113 Overview.................................................................................................................................... 113 Book Summaries: Federal Agencies............................................................................................ 113 Chapters on Lung Transplant.................................................................................................... 114 CHAPTER 6. PERIODICALS AND NEWS ON LUNG TRANSPLANT .................................................. 115 Overview.................................................................................................................................... 115 News Services and Press Releases.............................................................................................. 115 Newsletter Articles .................................................................................................................... 118 Academic Periodicals covering Lung Transplant ...................................................................... 118 CHAPTER 7. RESEARCHING MEDICATIONS .................................................................................. 121 Overview.................................................................................................................................... 121 U.S. Pharmacopeia..................................................................................................................... 121 Commercial Databases ............................................................................................................... 122 Researching Orphan Drugs ....................................................................................................... 122 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 127 Overview.................................................................................................................................... 127 NIH Guidelines.......................................................................................................................... 127 NIH Databases........................................................................................................................... 129 Other Commercial Databases..................................................................................................... 131 APPENDIX B. PATIENT RESOURCES ............................................................................................... 133 Overview.................................................................................................................................... 133 Patient Guideline Sources.......................................................................................................... 133 Associations and Lung Transplant ............................................................................................ 135 Finding Associations.................................................................................................................. 136 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 139 Overview.................................................................................................................................... 139 Preparation................................................................................................................................. 139 Finding a Local Medical Library................................................................................................ 139 Medical Libraries in the U.S. and Canada ................................................................................. 139

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ONLINE GLOSSARIES................................................................................................................ 145 Online Dictionary Directories ................................................................................................... 146 LUNG TRANSPLANT DICTIONARY ...................................................................................... 147 INDEX .............................................................................................................................................. 203

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with lung transplant is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about lung transplant, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to lung transplant, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on lung transplant. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to lung transplant, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on lung transplant. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON LUNG TRANSPLANT Overview In this chapter, we will show you how to locate peer-reviewed references and studies on lung transplant.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and lung transplant, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “lung transplant” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Tacrolimus (FK 506): A Review Source: UNOS Update. 11(3): 13-18. March 1995. Contact: Available from UNOS. 1100 Boulders Parkway, Suite 500, P.O. Box 13770, Richmond, VA 23225-8770. (804) 330-8500. Summary: In this article, the author provides readers with an update on tacrolimus (FK 506), an immunosuppressive agent approved by the FDA in 1994. Topics include the discovery and early studies of the drug; early animal transplant experiments; the use of FK506 therapy in liver transplantation, both as primary therapy and as rescue therapy; multicenter randomized liver transplantation studies; human kidney transplant studies; human heart and lung transplant studies; human small intestine transplant studies; the mechanism of action of tacrolimus; its pharmacology in humans; and the toxicity of

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tacrolimus. The author notes that tacrolimus has a unique ability to reverse ongoing graft rejection occurring under cyclosporine immunosuppression. 1 figure. 54 references.

Federally Funded Research on Lung Transplant The U.S. Government supports a variety of research studies relating to lung transplant. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to lung transplant. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore lung transplant. The following is typical of the type of information found when searching the CRISP database for lung transplant: •

Project Title: APPLIED GENOMICS IN CARDIOPULMONARY DISEASE Principal Investigator & Institution: Haponik, Edward F.; Professor of Internal Medicine; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: The Clinical Core will serve as the coordinating center for patient recruitment, specimen procurement and data base management. It is the mission of this Core to identify and provide disease-specific candidate genes from patients with such clinical disorders as acute lung injury, COPD, cystic fibrosis, asthma, pulmonary hypertension, pulmonary fibrosis, ischemic heart failure and both lung and cardiac transplant rejection. This core will also be responsible for the establishment of a Cardiopulmonary Tissue Repository that will maintain an archive of cryopreserved tissues and maintain an accurate data base of patient demographic and clinical data for correlation with biological end points produced by cDNA microarray. Following patient consent and registration, tissue samples and peripheral blood are delivered to the Core laboratory. The freezing facility will also serve as a repository for cyropreserved human lung and cardiac specimens. The Core Investigators will meet regularly to review all diagnostic materials on each specimen procured including histochemical stains and biopsies in order to determine a precise diagnosis and relevant demographic and clinical data for entry into the Project's data base which will include critical variables for the analysis of the biological data obtained. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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Project Title: APPROACHES TO THE GENETICS OF COPD Principal Investigator & Institution: Silverman, Edwin K.; Assistant Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 16-AUG-1999; Project End 30-JUN-2004 Summary: Cigarette smoking is the major environmental risk factor for the development of chronic obstructive pulmonary disease (COPD); however, only a subset of smokers develop clinically significant COPD. In addition to the risk from smoking, subjects with severe alpha 1-antitrypsin deficiency have a major genetic predisposition to COPD; other genetic determinants of COPD have not been proven. The frequent development of COPD in individuals with alpha 1-antitrypsin deficiency has provided a foundation for the protease-antiprotease hypothesis for the pathogenesis of COPD. However, many subjects with severe, early-onset COPD are not alpha 1-antitrypsin deficient. To define the mechanisms responsible for the development of severe, early-onset COPD unrelated to alpha 1-antitrypsin deficiency, we propose a multidisciplinary study that combines field, laboratory, and analytical approaches. We will assemble a group of 140 pedigrees ascertained through probands with severe, early-onset COPD (without severe alpha 1antitrypsin deficiency) who are referred for lung transplant or lung volume reduction surgery evaluations. We will assess these probands and their relatives with spirometry (including bronchodilator response) and a questionnaire. We will obtain genotyping with highly polymorphic short tandem repeat (STR) markers at 10 cM intervals throughout the genome from the NHLBI Mammalian Genotyping Service; these genotypes will be used to assess for genetic linkage to phenotypes including FEV1, FEV1/FVC, chronic bronchitis, and bronchodilator responsiveness. In chromosomal regions with suggestive linkage from the genome screen, additional STR markers will be tested at 1 cM intervals; multipoint linkage analysis, family-based association studies, and haplotype analysis will be used to narrow the regions likely to contain genetic determinants of COPD-related phenotypes. mRNA levels of genes within these regions narrowed by fine mapping will be compared in lung tissue from early-onset COPD probands and control subjects. The results of this study could identify specific regions of the genome which are likely to contain COPD susceptibility genes and provide candidate susceptibility genes for COPD. Identification of such genetic determinants could provide insight into the biochemical mechanisms causing the variable development of COPD at all ages, allow identification of highly susceptible individuals, and lead to new therapeutic interventions for COPD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIORAD ASPERGILLOSIS

GALACTOMANNAN

EIA

FOR

DIAGNOSIS

OF

Principal Investigator & Institution: Marr, Kieren A.; Assistant Member; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 29-FEB-2008 Summary: (provided by applicant): The Bio-Rad galactomannan enzyme immunoassay (GM EIA) will soon be submitted to the FDA for approval as an aid to diagnose aspergillosis, a frequent cause of infectious death in immunosuppressed patients. Our preliminary studies suggest that the assay may also be used as a screening test to enable early diagnoses; however, the optimal cut-offs for positivity have not been determined. Defining cut-offs to optimize performance is critical for patients who have different manifestations of infection (endobronchial vs. invasive), such as in solid organ transplant recipients, and in children, who appear to have frequent false-positive results.

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The studies proposed in this project will define parameters to use the GM EIA in multiple different patient populations, using clinical samples obtained from a large ongoing FHCRC longitudinal protocol in adult allogeneic hematopoietic stem cell transplant (HSCT) recipients, and samples obtained from multicenter trials sponsored by the NIH. Aim 1 will define parameters for use of the GM EIA as an early diagnostic test for aspergillosis in adult allogeneic HSCT patients. Studies will be performed to determine the lower limit of GM detection, identify clinical factors that impact levels of circulating GM, and to determine the role of GM EIA applied to non-blood fluids (bronchoalveolar lavage fluid and urine). Aim 2 will define appropriate cut-offs for positivity and characterize performance of the GM EIA as a diagnostic assay for aspergillosis in high-risk solid organ transplant recipients. To do this, longitudinal sample collection will be performed in a protocol conducted as a companion to an ongoing CDC-sponsored multicenter surveillance study. Aim 3 will define parameters for use of the GM EIA as an early diagnostic test for aspergillosis in neutropenic children. To determine the appropriate cut-offs for positivity in children, GM EIAs will be performed on serial sera obtained from children at high risk for aspergillosis after treatment with induction chemotherapy for AML, and after cord blood transplant. Companion protocols will be performed to collect sera as part of ongoing multicenter studies performed by the Children' s Oncology Group and the NHLBI Cord Blood Transplantation Study. Studies will be performed to determine if false-positivity of the GM EIA in children corresponds with gut translocation of GM during periods of mucositis, by measuring surrogate markers for GI integrity in a case-control study. This project is enabled by the cooperative activities of FHCRC investigators, Bio-Rad Laboratories, and several multicenter networks supported by the CDC, NIAID, and NHLBI. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CALCINEURIN INHIBITION: LUNG REPERFUSION INJURY Principal Investigator & Institution: Mulligan, Michael S.; Associate Professor of Surgery; Surgery; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAY-2007 Summary: (provided by applicant): Approximately 25 percent of lung transplant recipients and 15 percent of patients treated for chronic pulmonary embolic disease will develop post- operative lung ischemia reperfusion injury (IRI). Treatment is conservative and this problem continues to account for significant morbidity and mortality. Requirements for several proinflammatory mediators have been characterized. However, antagonism of a single mediator rarely produces dramatic protection. Clinical treatment with directed antibodies is likely therefore to be expensive, impractical and marginally effective. More effective interventions would block several mediators at once, potentially by acting at the transcriptional level. Inhibition of calcineurin mediated activation of NF-kB can reduce expression of a variety of proinflammatory mediators. Since cyclosporin (CSA) and tacrolimus (TAC) are calcineurin inhibitors that are already available clinically, it would be desirable to examine their effects in experimental lung IRI. CSA and TAC reduce IRI in other tissues and can consistently reduce NF-kB activation both in vitro and in vivo. In preliminary studies, we have reliably established an animal model of lung IRI and shown that NF-kB activation follows lung IRI and that activation is associated with the appearance of a number of inflammatory cytokines and chemokines. Our hypothesis, therefore, is that calcineurin mediates NF-kB activation with lung IRI which results in transcriptional upregulation of critical pro-inflammatory mediators and the ultimate development of

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tissue injury. We will address this hypothesis systematically beginning with interventional studies in vivo and proceed to mechanistic analysis both in vivo and in vitro. We will pursue three related aims: Aim 1: To determine whether calcineurin inhibition is protective against the development of lung IRI. We will accomplish this using our animal model. Aim 2: To determine whether calcineurin inhibition results in transcriptional down-regulation of mediators involved in lung IRI through an NFkBdependent mechanism. We will measure protection offered by CSA/TAC and assess associated changes in cytokine production and NFkB in nuclear protein. Aim 3: To define the cellular sources of critical mediators of lung IRI and their dependence on calcineurin driven transcription and cell-cell interactions. We will accomplish this by culturing alveolar macrophages , type II pneumocytes and pulmonary artery endothelial cells (individually and in combination) and subject them to hypoxia and reoxygenation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CD40 AND TGFB IN HUMAN LUNG TRANSPLANT CHRONIC REJECTION Principal Investigator & Institution: Mckee, Charlotte M.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 16-JUL-2001; Project End 01-AUG-2002 Summary: Chronic rejection is the most important clinical problem in human lung transplantation. The underlying causes of this process (which is manifest as obliterative bronchiolitis (OB) in lung transplants) are not completely understood, but host antidonor cellular immunity has been shown to be a key factor. The CD40 costimulatory pathway is critical for optimal cellular immune responses, and evidence suggests that CD40 activity plays a major role in chronic rejection. However, the mechanism(s) by which CD40 facilitates chronic rejection are not known. CD40 signaling can induce the production of TGFbeta, a pro-fibrotic cytokine whose role in chronic rejection and organ fibrosis is well-established, in human B cells. We postulate that CD40-mediated induction of TGFbeta1 by alveolar macrophages (AM), which are important sources of this cytokine in pulmonary fibrosis, represents a mechanistic link between CD40 activity and chronic rejection. We therefore propose to study 1) indices of CD40 activity in tissues from lung transplant patients with OB and from patients with acute rejection (who are at increased risk of developing OB) and 2) the ability of CD40 signaling to induce TGFbeta1 in AM from lung transplant patients. The Principal Investigator has an extensive background in basic immunology and clinical lung transplantation. The research project outlined here will train her to integrate these elements of her background and to approach clinical problems such as chronic rejection with the combined tools of basic science and clinical research. This award will provide her with the training, resources and protected time she needs to establish a successful career as an independent investigator in lung transplant immunology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CENTER FOR GENE THERAPY OF CYSTIC FIBROSIS Principal Investigator & Institution: Engelhardt, John F.; Associate Professor; Anatomy and Cell Biology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 31-AUG-2003 Summary: Development of effective gene therapies for inherited disorders requires interdisciplinary programs which focus on disease gene identification, disease pathogenesis, and the development of technologies for gene transfer. The goal of this

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proposal is to establish a Center that will provide investigators with the opportunity to improve and/or expand their gene therapy-based research. The primary focus of this Center will be on the development of gene therapies for cystic fibrosis (CF), but will also include several other genetic diseases. Several mechanisms are proposed to meet the goals of this Center. 1) The Center will support pilot and feasibility studies directed at CF and other genetic diseases. This will bring new members and new expertise into the Center. It also provides established investigators with the opportunity to pursue novel, high risk strategies for gene therapy. 2) The Center will strengthen relevant existing Cores (Vector Core and Cell Culture Core), and develop two new Cores (Morphology Core and Animal Models Core). These Cores provide investigators with specialized vectors, primary cultures of airway epithelia, various transformed cell lines, resources, and new methods that allow them to test hypotheses that could not otherwise be evaluated. 3) The Center has formulated a Midwest Regional Consortium for the acquisition CF lung transplant tissue. This consortium will create a repository of CF and non-CF primary airway cells and tissue which are critical for the gatherings. This provides a forum for critical evaluation of research directed at the development of new approaches, model systems, and novel ideas. 5) The Center will allow expansion of gene transfer research to newly characterized genetic diseases. This will take advantage of opportunities to develop new treatments in many areas. Translation of the work to other systems will also benefit the CF research effort. 6) The Center will establish formal internal mechanisms and external consultants to review the Center, the Cores, and the pilot and feasibility projects, thereby ensuring a high level of excellence and the most appropriate utilization of the Center's resources. In summary, the Center for Gene Therapy of CF and Other Genetic Diseases will greatly strengthen existing gene therapybased research programs at the University of Iowa and will allow progression of the research in existing new directions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHEMOKINE BIOLOGY IN BRONCHIOLITIS OBLITERANS SYNDROME Principal Investigator & Institution: Belperio, John A.; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 15-MAR-2001; Project End 28-FEB-2006 Summary: (Adapted from applicant's abstract) Chronic lung allograft rejection, Bronchiolitis Obliterans Syndrome (BOS) is a chronic process that demonstrates features of dysregulated and aberrant repair of airways. This process of fibroproliferation and deposition of extracellular matrix that ultimately leads to fibro-obliteration of airways, and impaired lung function. In this proposal, the investigators hypothesize that the persistent expression of monocyte chemoattractant protein-1 (MCP-1) during an allogeneic response and recruitment and activation of mononuclear phagocytes expression CC chemokine receptor 2 (CCR2) is a pivotal event that promotes the continuum of acute to chronic lung allograft rejection. Specifically, MCP-1 production, and the recruitment and activation of CCR2 expressing mononuclear phagocytes occurs during acute rejection. Moreover, the persistent presence of MCP-1 in the allograft maintains recruitment and activation of specific populations of mononuclear phagocytes expressing CCR2. These cells have a unique pro- fibrogenic phenotype that promotes fibrogenesis of chronic allograft rejection, BOS. Understanding the interaction between MCP-1 and CCR2 during the continuum of acute to chronic lung allograft rejection, will lead to novel therapies in the treatment and prevention of BOS. This proposal ,will test this hypothesis by performing the following experiments: I) determine the time-course,

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magnitude of expression, and cellular sources of MCP-1, as correlated to the recruitment of monocular cells expression CCR2 in an orthotopic rat model of acute lung allograft rejection. II) determine the specific contribution of MCP-1 to the pathogenesis of acute lung allograft rejection by a strategy of depletion of MCP-1. III) determine the timecourse of MCP-1 expression, as correlated to the recruitment of mononuclear cells expression CCR2 in a murine model of BOS. B) determine the specific contribution of MCP-1/CCR2 biology to the pathogenesis of BOS by using genetic approaches for deletion of the bioactivity of MCP-1 and/or CCR2. IV) determine if CCR2 expression mononuclear phagocytes are phenotypically profibrogenic (i.e., produce higher levels of TGF-beta and PDGF) and promote fibrogenesis during the pathogenesis of BOS. By successfully completing these objectives, the applicants hope to have gained significant insight into the persistence of MCP-1/CCR2 biology that impacts on the continuum and transition of acute lung allograft rejection to BOS. The understanding of this pathobiology will lead to novel therapies in the treatment and prevention of chronic lung allograft rejection, BOS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHEMOKINES IN LUNG TRANSPLANTATION Principal Investigator & Institution: Medoff, Benjamin D.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 04-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): With the proposed Mentored Clinical Scientist Development Award the applicant will continue his investigations into basic mechanisms of lung inflammation. After two productive years in this laboratory the applicant remains firmly committed to a career in academic pulmonary medicine. The proposed research will allow the applicant to master a broad range of laboratory techniques in immunology, cell, and molecular biology. The research experience will be supplemented by a program of study of immunology and medical science. The project focuses on the development of inflammation and fibrosis following lung transplantation and the role of chemokines in these processes. After a lung is transplanted there may be several types of injury to the graft, including ischemiareperfusion injury, acute rejection, and chronic rejection. These immune mediated injuries contribute to the development of scarring of the airways, so called bronchiolitis obliterans (BO). Over 50% of all lung transplants will develop BO after transplantation, and this remains the major cause of morbidity and mortality after lung transplantation. Neutrophils have been shown to be a prominent component of ischemia-reperfusion injury while T lymphocytes are the primary mediators of both acute and chronic rejection. The proposed project will determine which chemokines are produced after transplantation and their contribution to the development of graft injury and subsequent BO. Further experiments will manipulate chemokine or chemokine receptor expression in animal models of lung transplantation to investigate their role in the development of graft injury and BO. The applicant specifically proposes to: (1) investigate the expression of chemokines and chemokine receptors in the lung following transplantation in patients with and without acute rejection and BO; (2) investigate the role of chemokines in the development of ischemia-reperfusion injury in the airways using the murine tracheal heterotopic model of lung transplantation; (3) investigate the role of chemokines in the development of acute airway rejection and the development of BO in the murine tracheal heterotopic model of lung transplantation; (4) develop a novel murine model of airway rejection and BO. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHRONIC LUNG ALLOGRAFT REJECTION IN MHC-DEFINED SWINE Principal Investigator & Institution: Allan, James S.; Assistant Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2006 Summary: Graft loss from chronic rejection, which affects all solid organs to varying degrees, has become the major obstacle to the long-term success of lung transplantation. We have established a large animal model of chronic lung rejection, which reproduces with fidelity and consistency, the pathological lesions seen in human lung transplant recipients suffering from chronic rejection. Based on preliminary data and human studies, we hypothesize that chronic lung rejection is an immunologically mediated process driven by T cell recognition of major and minor histocompatibility antigens. The corollary to this hypothesis is that protocols to downregulate the immune system or to induce immune tolerance will most effectively prevent, interrupt and/or reverse chronic lung rejection. The goal of this proposal is to test this hypothesis and, in doing so, investigate the immunologic mechanisms underlying the process of chronic lung rejection. Using MHC inbred miniature swine, synthetic polymorphic allopeptides, and monoclonal antibodies cross-reactive for swine T cells, we plan to (1) define the immunogenetic requirements of chronic lung allograft rejection and characterize the cellular and humoral mechanisms that mediate this disease, (2) examine the role and mechanisms of indirect allorecognition of donor MHC peptides in the development of chronic lung rejection in miniature swine, and (3) determine the role of costimulatory molecules in the pathogenesis of chronic lung rejection in miniature swine. These studies should lead to a better understanding of the cellular and molecular mechanisms of chronic lung rejection in a clinically relevant experimental model and may ultimately lead to the development of new strategies to prevent or treat this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMPLEMENT MEDIATED INJURY IN ALLOGRAFT REJECTION Principal Investigator & Institution: Baldwin, William M.; Associate Professor; Pathology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-AUG-1994; Project End 31-MAR-2008 Summary: (provided by applicant): This continuation application is based on our novel finding that a deficiency of C6, which prevents assembly of the membrane attack complex (MAC), can delay acute allograft rejection from 7-10 days to greater than 6 weeks. This finding is of potential importance for 4 reasons. First, it demonstrates that complement (C), which is not suppressed adequately by conventional immunosuppressive agents used clinically, can play a significant role in acute allograft rejection. Second, this does not appear to be a strain-specific or anecdotal effect, because acute rejection is inhibited in all of the high responder strains into which we have now bred the C6 deficiency. Third, the effects C6 deficiency are not limited to one type of vascularized allografts, but affects transplants of both heart and lung. Fourth, C6 deficiency delays both acute rejection and chronic graft vasculopathy. Preliminary data indicate that donor and recipient sources of C6 can contribute to graft injury and rejection. Our hypothesis is that C from donor and recipient sources contribute to early tissue injury initiated by physiological stress as well as antibody deposition. The specific aims are to test mechanisms that control C6 production and activation in allografts. We will use an interrelated series of in vivo experiments that take advantage of congenic C6 deficient rat strains that we have bred to determine: 1) the source of C6 in acute injury

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cardiac and lung transplants, 2) the source of C6 in chronic vasculopathy and obliterative bronchiolitis, and 3) the role of altered expression of membrane-associated C regulators. The experimental approach will utilize the novel C6 deficient strains of rats that we developed in the first funding period of this project for both in vivo cardiac transplant studies and as sources of C6 deficient cells for in vitro studies. Most importantly, we will use our extensive clinical material to verify the relevance of our experimental findings to humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORRELATION OF IMMUNE PARAMETERS WITH OUTCOME Principal Investigator & Institution: Reinsmoen, Nancy L.; Professor/Director; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002 Summary: In most transplant programs, long-term transplant recipients tend to be treated with similar immunosuppressive protocols. However, such uniform treatment may lead to complications from over immunosuppression in some and under immunosuppression in others. Previous studies of withdrawal of one drug have not been successful. An important question is whether an individual immune parameter test or a battery of these tests would best predict long-term graft outcome in stable patients. Retrospective data from individual laboratories has suggested the immune parameters (donor antigen-specific hyporeactivity, allogeneic microchimerism, and the absence of donor antigen-specific HLA antibodies) predict successful long- term outcome after solid organ transplantation. However, each of these parameters has only been applied individuals and only to a subpopulation of transplant recipients. This grant will focus on the use of these three immunologic parameters to predict long-term graft success in a broad transplant population. We will determine whether donor antigen-specific hyporeactivity of the CD4 helped pathway (Specific Aim 1), peripheral blood allogeneic microchimerism (Specific Aim 2), and a lack of development (or regulation of) donor antigen-specific HLA antibodies (Specific Aim 3) correlate with improved long-term graft outcome. We will perform a prospective study, testing all three parameters for lung and heart recipients and the first and third parameters for kidney recipients transplant at the University of Minnesota. The transplant program at the University of Minnesota has a long-established mechanisms for clinical follow-up and clinical data collection. We will determine whether one parameter can be used in lieu of another in an organ specific manner. We plan to use these immune parameters to determine if immunosuppression can be individualized, If so, by selectively lowing immunosuppression in some recipient by maintaining it in others, we will provide significant long- term savings (cost, morbidity and outcome improvement) for solid organ transplant recipients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DETERMINANTS OF EPITHELIAL SURVIVAL IN AIRWAY ALLOGRAFTS Principal Investigator & Institution: Neuringer, Isabel P.; Medicine; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 07-MAY-2001; Project End 30-APR-2006 Summary: (provided by applicant) Lung transplantation has become a viable option for the treatment of end-stage lung disease, as surgical techniques and immunosuppressive therapies have improved. The major cause of late mortality and morbidity post-

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transplant is obliterative bronchiolitis (0B), characterized by a progressive decline in lung function and small airway fibroobliteration. Recurrent acute rejection predisposes to 0B, but HLA mismatch, ischernic injury, and infection may contribute, resulting in irreversible injury to the airway epithelium. A mouse model of heterotopic airway transplantation reproduces the histopathological lesion of 0B, and has been employed to investigate the pathogenesis of this disorder. In this model, allograft epithelium regenerates and proliferates vigorously, yet undergoes rapid, irreversible injury, through augmented apoptotic pathways, leading to airway denudation and fibroobliteration. We hypothesize that the survival of the airway epithelium is critical to preventing the ingrowth of fibroproliferative matrix, and that pro-apoptotic mediators present in the alloirnmune environment alter the normal kinetics of airway epithelial cell cycle-regulated proliferation and repair. The overall objective of this proposal is to determine dominant pathways of airway epithelial death in OB as mediated through cell cycle regulators p2l and p53, and assess the role of TGFB-1, a potent inhibitor of airway epithelial cell growth, in modulating the expression of these proteins. Specifically, we will quantitatively assess epithelial cell proliferation and cell cycle regulatory proteins in heterotopic mouse airway grafts, test the role of TGFB-1 in promoting airway epithelial cell death using in-vitro cell culture and in-vivo animal models, and lastly evaluate the kinetics of airway epithelial cell growth and death in clinical specimens with active OB lesions. This project will involve intensive training in tissue culture of rodent and human airway epithelium, protein chemistry, immunology, molecular biology techniques, and pulmonary pathophysiology and pathology, in a unique environment that will facilitate the development of independent investigation in pulmonary diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DONOR BONE MARROW AND IMMUNOREGULATION IN LUNG TRANSPLA* Principal Investigator & Institution: Pham, Si M.; Professor; Surgery; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2004; Project Start 24-MAY-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Lung transplantation is currently the only effective treatment for end stage lung diseases. However, chronic rejection that manifests as obliterative bronehiolitis (OB) is a major cause of late death after transplantation. The incidence of OB ranges from 34% to 65% while the mortality due to OB ranges from 62% to 100%. It has been reported that a low level of bone marrow derived donor cells was present in the tissues of long-surviving recipients of solid organs. Microchimerism was associated with a decrease in OB in lung recipients. Recent clinical data show that donor bone marrow infusion augments microchimerism, and decreases the incidence of OB. The mechanism by which donor bone marrow attenuates the development of OB is unknown. Lack of such knowledge is an important problem because without it, it is unlikely that effective strategies to reduce OB and to improve the survival of lung recipients can be developed. The objective of this grant application is to determine how infusion of donor bone marrow at the time of lung transplant reduces the development of OB in lung recipients. The central hypothesis of this application is that marrowderived cells of donor origin down-regulate recipient's allo-immune response via infectious tolerance that involves T regulatory cells. We have formulated this hypothesis based on our own novel observation that bone marrow derived donor cells preferentially home to the lung graft. The rationale for the proposed research is that once we understand how recipient's immune response is modulated by donor bone

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marrow, better strategies to prevent OB can be developed. We plan to test our hypothesis by pursuing the following two specific aims. In Aim 1, we will demonstrate that donor bone marrow infusion at the time of lung transplantation modulates the recipient's alloimmune response by infectious tolerance that involves T-regulatory cells. In Aim 2 we will determine whether dendritic cells in the lung grafts, and recipient's peripheral lymphoid tissues of lung-bone marrow recipients are more tolerogeneic than those from lung-alone recipients. The proposed work is innovative, because it capitalizes on our novel findings that bone-marrow derived cells of donor origins preferentially home to the lung graft in recipients receiving donor bone marrow infusion, and that infusion of donor bone marrow reduces the incidence of obliterative bronehiolitis in humans. We expect that the results of the proposed studies will elucidate the mechanism by which microchimerism modulates the recipient's alloimmune. These results will be significant, because they may help designing therapeutic strategies to reduce OB and to prolong the survival of lung and other solid organ recipients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EARLY DIAGNOSIS OF ACUTE LUNG TRANSPLANT REJECTION Principal Investigator & Institution: Tryon, Victor V.; Source Precision Medicine 2425 N 55Th St, Ste 111 Boulder, Co 80301 Timing: Fiscal Year 2003; Project Start 08-SEP-2003; Project End 07-SEP-2004 Summary: (provided by applicant): Lung transplant recipients are at high risk for acute organ rejection, especially during the first three months post-surgery. Presymptomatic diagnosis of this condition is critical for early and effective therapeutic intervention; once overt clinical symptoms indicative of transplant rejection develop, the process is usually well under way and significant lung damage may have already occurred. Standard medical practice relies heavily on serial bronchoscopies and transbronchial biopsies, two highly invasive and uncomfortable procedures which must be performed many times during the course of follow-up care. What is needed is a minimally invasive diagnostic system that can identify acute rejection in its early stages. Source Precision Medicine has performed extensive work on gene expression profiles in normals and in patients with inflammation- and immune-related diseases and has developed a system for high-precision molecular analysis that can be performed in small quantities of whole blood. The objective of Phase I is to evaluate the specific diagnostic potential of a panel of candidate gene loci. The specific aims of the proposed research are to: 1.) Measure the expression of 88 inflammation-immune related genes in whole blood from patients who are about to initiate high-dose immunosuppressive therapy for the treatment of an episode of acute LTx rejection; 2.) compare these data to reference databases of normals and to the patients, themselves, prior to the onset of rejection; and 3.) select a subset of these 88 genes coupled with candidate biomedical algorithms for use in future studies designed to test the ability to predict and monitor acute LTx using the TheraTrax system. The overall objective of this research is to develop a commercial analytical tool for early detection and evaluation of acute organ rejection in lung transplant patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EMPHYSEMA: OUTCOMES AND TECHNOLOGY ASSESSMENT Principal Investigator & Institution: Yusen, Roger D.; Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 10-JAN-2000; Project End 30-NOV-2004

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Summary: This project seeks to improve outcomes in patients with emphysema. Therapies such as lung volume reduction surgery (LVRS) and lung transplantation (LTx) offer potential improvements in quality of life, but they impose substantial risks. Thus, decision making about the use of LVRS and LTx requires trade-offs. Rational analyses of these trade-offs require valid measurements of the benefits and harms to the patients in all relevant domains that effect duration and quality of life, including morbidity, functional status, symptoms, and satisfaction. We do not have an agreed upon standard of successful therapy, specifically in situations where duration of survival is not the only issue. The instruments we use to assess procedures may not fully capture the aspects of health and quality of life that are most important. New instruments and models for assessing outcomes are necessary to complement those that exist. The specific aims of this project are 1) to further develop methods to assess outcomes of patients with emphysema, and 2) to assess the effects of lung volume reduction surgery and lung transplant on outcomes of patients with emphysema. The effects of therapies on mortality and quality of life, measured as utilities, will be assessed. Patient demographics, co-morbidity, functional status, symptoms, and satisfaction, as well as intermediate physiologic outcomes, and utilization of resources will be measured. To achieve the specific aims, primary data collection will be performed in three ways: instrument validation, cross-sectional and (pre and postoperative) longitudinal studies. Models of the relationships among functional status, satisfaction, physiology, and quality of life in patients with emphysema will be developed and used to explain the relationships among the various outcomes. We will also develop operational definitions of successful and unsuccessful treatments among patients with emphysema undergoing LVRS or LTx that account for functional status, satisfaction, physiology, and quality of life, as well as mortality. Prediction rules for outcomes among patients with emphysema undergoing LVRS or LTx will be developed. This research plan promotes the development of methods for assessing and understanding the role of new technologies and therapeutic interventions in patients with emphysema. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SYNDROME

FIBROPROLIFERATION

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BRONCHIOLITIS

OBLITERANS

Principal Investigator & Institution: Lama, Vibha N.; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2004; Project Start 15-AUG-2004; Project End 31-JUL-2009 Summary: (provided by applicant): Bronchiolitis Obliterans Syndrome (BOS) is the major cause of mortality after lung transplantation. Failure of immunosuppressive or anti-inflammatory therapies to meaningfully prevent or attenuate the course of the disease has focused attention on the role of fibroproliferation in its pathogenesis. Such a paradigm might involve an imbalance favoring pro-fibrotic over anti-fibrotic mediators, leading to fibroblast recruitment, proliferation and change in phenotype to more aggressive myofibroblasts with a high capacity for collagen synthesis. We have made the novel observation that fibroblasts can be cultured from the bronchoalveolar lavage fluid (BALF) of lung transplant recipients and appear to display an activated phenotype in cases with BOS. We hypothesize that the development of a pro-fibrotic milieu (increased ratio of BALF levels of pro- to anti-fibrotic mediators) and phenotypic alteration in fibroblasts are pivotal events in the clinical development of BOS. To test this hypothesis we will first study the levels of relevant pro- and anti- fibrotic biomarkers and the phenotype of fibroblasts in a cohort of patients with BOS and

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compare them to non-BOS patients (case control study, Aim 1). Second, in order to study such associations over time and the temporal sequence of events, we will serially measure these biomarkers and study phenotypic characteristics of fibroblasts longitudinally in a population of patients following lung transplant (prospective cohort study, Aim 2). This award will provide an opportunity for the Principal investigator to develop a career as a clinical researcher with expertise in translational studies in lung transplantation. A K-23 would provide the additional experience, didactic training and mentorship necessary to develop the skills necessary to transition to an independently funded investigator. An integral component of the training plan will include advanced didactic training in missing data management, longitudinal data analysis, sequential monitoring of survival endpoints and nonparametric survival analysis. These modalities of data analysis will be utilized to carry out the specific aims, thus providing practical experience to the candidate. Furthermore, the candidate will be directly mentored by one on one sessions with the co-mentors, Fernando J. Martinez MD, MS and Marc Peters-Golden MD, both of whom are well-funded researchers with a long track record of mentoring. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE EXPRESSION MICROARRAYS IN LUNG REJECTION Principal Investigator & Institution: Hertz, Marshall I.; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002 Summary: (provided by applicant): The overall goal of Project 3 is to identify gene expression patterns associated with lung transplant rejection using a new laboratory approach: large scale gene expression microarray (>10,000 genes) technology. We are uniquely positioned to accomplish this by virtue of our active clinical lung transplant program, comprehensive Lung Transplant Database, and the advanced facilities and expertise of the University of Minnesota Biomedical Genomics Center. Acute rejection is common after lung transplantation, occurring in up to 50 per cent of recipients during the first post transplant year. Although it is almost never immediately life threatening, acute rejection is a major risk factor for the later development of chronic lung rejection, or OB, the most important threat to the long-term survival of lung transplant recipients. The statistical relationship between acute and CR exists despite the fact that, in most cases, the histologic findings of acute rejection resolve after treatment. Based on this observation, a fundamental assumption of the proposed research is that specific genes are activated during acute rejection, some of which remain persistently activated despite treatment, and contribute to the pathogenesis of OB. Thus, identification of these genes may serve to identify recipients at risk for CR. In this proposal we will complete two necessary steps toward this goal: 1) identification of specific patterns of gene expression in BAL cells and peripheral blood mononuclear cells that differentiate patients with and without acute lung rejection histology; and 2) identification of genes that are reliably and persistently expressed after treatment induced normalization of acute rejection histology. If successful, these studies will set the stage for additional studies to determine the predictive value of persistently expressed acute rejection associated genes for the subsequent development of CR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNE MECHANISMS OF REJECTION IN HUMAN LUNG ALLOGRAFTS Principal Investigator & Institution: Mohanakumar, Thalachallour; Professor; Surgery; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-AUG-1996; Project End 31-JUL-2004 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNE REGULATION IN LUNG TRANSPLANTATION Principal Investigator & Institution: Burlingham, William J.; Associate Professor; Surgery; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 30-JUN-2004 Summary: Adapted from Investigator's abstract): Rapamycin inhibits obliterative fibrosis in a rat tracheal transplant model and promotes tolerance induction in mouse heart transplant models. Because it can spare the use of calcineurin inhibitors, rapamycin also promises to help eliminate the numerous side effects of cyclosporine and FK506. An ongoing multi-center, prospective, randomized, double-blinded clinical trial including patients from the UW-Madison is underway to see if a form of rapamycin (RAD) can prevent bronchiolitis obliterans syndrome (BOS) while improving long-term outcome in lung transplants. The clinical trial sponsored by Novartis relies on biopsy histology and pulmonary function tests to determine the primary endpoints; no immune function tests are funded. This proposal addresses not only surrogate markers of disease and therapeutic effects, but also aims, for the first time, to provide useful surrogate markers for the dynamic process of development and maintenance of allograft tolerance. We believe that such markers are essential for rational adjustment of maintenance immune suppressive therapy in a given patient. We also believe that tolerance is the best solution to the long-term problem of allograft obliterative airway disease, a problem that currently affects virtually all lung transplants. Specifically we will: 1) monitor the development of both systemic and local immune regulation of delayed type hypersensitivity (DTH) responses in all UW/Madison lung transplant recipients, including those receiving RAD-based vs. conventional IS therapy; 2) monitor the systemic and local release of soluble forms of donor HLA antigen in lung transplant patients, determine which soluble donor HLA antigens can trigger regulation of DTH, and analyze the role of metalloproteinase therein; and 3) monitor the persistence of donor T cells (including CMV-specific CD8+ cells), and alveolar macrophages, using flow cytometry of BAL cells. This research project will be conducted in conjunction with the current clinical trial, but will not exclude any lung transplant patients not enrolled in the trial. Our study has a high likelihood of providing clinical correlation of outcomes (acute & chronic rejection, infection) with surrogate markers of tolerance, alloreactivity and pathogen reactivity. We will determine how the sensitivity, specificity, and predictive value of each test would be clinically useful in the management of lung transplant patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNE RESPONSES IN LUNG ALLOGRAFT REJECTION Principal Investigator & Institution: Wilkes, David S.; Calvin H. English Professor of Medicine; Medicine; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167

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Timing: Fiscal Year 2002; Project Start 15-MAR-1999; Project End 14-MAY-2003 Summary: Lung allograft is believed to be initiated between donor lung macrophages and dendritic cells leading to presentation of major histocompatibility complex (MHC) antigens that stimulate host lymphocytes. Direct or indirect allo-recognition of donor MHC antigens or proteins homologous to MHC antigens (MHC-"like") is believed to perpetuate the rejection process. Conversely, indirect allo-recognition of MHC or MHC"like" peptides in the pre-transplant period may prevent rejection activity. Although donor MHC antigens are usually the target of allo-immune responses. alpha-chains of type V and XI collagen, that may be homologous to MHC proteins, are also recognized as antigens during lung allograft rejection. Therefore, pre-transplant immunization with peptides of type V or VI collagen may modulate the rejection response. We have developed a murine model in which the instillation of allogeneic (C57BL/6,H-2,1-a/b) bronchoalveolar lavage cells (96% macrophages, 1-2% dendritic cells) into the lungs of recipient mice (BALB/c, H-2/d, 1-a/d) reproduce the histology and cellular and humoral immunology of acute lung allograft rejection observed in humans, as well as, immune responses to type V and XI collagen. Utilizing this unique model the current proposal tests the hypothesis that allogeneic lung macrophages and dendritic cells mediate lung allograft rejection, and examines the molecular mechanisms responsible for the rejection process by examining the following specific aims: Aim 1. To determine the interactions between donor lung macrophages and dendritic cells and the microenvironment of the lung that lead to up-regulated allo-immune responses in the allograft, soluble signals produced locally in response to the instillation of allogenic macrophages and dendritic cells in recipient lungs will be examined for their role in facilitating rejection. 2. To determine the role of direct and indirect allo- recognition in the pathogenesis of lung allograft rejection, the requirement for functional donor accessory cells or recipient accessory cells in graft destruction will be tested. Aim 3. To determine the role of MHC alloantigens, and CD4+ and CD8+ lymphocytes in the rejection process, lung accessory cells which do not express MHC II or MHC I or both antigens will be instilled into the lungs of recipient mice followed by an assessment of the cellular and humoral immune changes and histology in recipient lungs. Aim 4. To determine if indirect allo- recognition of peptides that may be homologous to MHC antigens prior to transplantation down regulates the rejection response, BALB/c mice will be immunized with peptides of type V and XI collagen prior to instilling C57BL/6 bronchoalveolar lavage cells into BALB/c mice followed by an assessment of the histology, and immunology of acute rejection. The goal of these studies is to discern the immune mechanisms of lung allograft rejection at a molecular level so targets may be identified for therapeutic intervention to prolong the survival of lung allograft recipients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOBIOLOGY OF TRANSPLANT OBLITERATIVE AIRWAYS DISEASE Principal Investigator & Institution: Mueller, Daniel L.; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002 Summary: (provided by applicant): Lung allotransplantation frequently fails due to the late development of OAD as a consequence of chronic immune graft rejection. Such failures continue to occur, in part, because our current understanding of the immunobiology responsible for the onset of the airway fibrosis is quite limited. Using heterotopic tracheal allotransplantation in mice, we have determined that directly

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alloreactive CD8 T cells as well as self-MHC-restricted CD4 T cells responding against minor transplantation antigens cooperate in the induction of OAD. We now propose to take advantage of Tg mouse technology to investigate this pathological CD8 and CD4 T cell response against tracheal allografts. Using this technique, tracheal allograft reactive TCR Tg T cells can be tracked and lymphokine and activation molecule expression and function in these T cells can be determined during the development of OAD. Therefore, we specifically aim to: 1) Investigate the nature of the cooperativity that exists between direct class I alloreactive CD8 and minor antigen reactive CD4 T cells in the induction of OAD following airway allotransplantation, 2) examine the role of costimulatory signal depend T cell lymphokines and effector molecules in the development of OAD in tracheal allografts, and 3) test the capacity of clonal energy induction in alloreactive CD8 and CD4 T cells to inhibit the development of OAD following tracheal allograft transplantation. The further development and validation of this Tg mouse model system will provide the transplantation field with a tool that more accurately assesses the activities of those T cells responsible for promoting chronic lung allograft injury. In addition, the information obtained in these experiments should serve as important pre clinical data for the development of effective immunomodulatory approaches to the problem of alloantigen specific transplantation tolerance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOPATHOGENESIS OF CHRONIC ALLOGRAFT REJECTION Principal Investigator & Institution: Sayegh, Mohamed H.; Director, Transplantaion Research Center; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2002; Project Start 19-SEP-2001; Project End 30-JUN-2006 Summary: (provided by applicant): The most common cause of late Allograft failure, excluding death with a functioning graft in the case of kidney transplantation, is a clinicopathologic entity termed chronic rejection. Chronic rejection is common to all solid organ transplants, including kidney, heart, lung, pancreas and to a lesser extent, liver. Despite extensive research, the precise mechanisms responsible for the characteristic pathological and functional changes seen in chronic rejection remain unclear. The overall hypothesis of this Program Project is that the alloimmune response, and especially CD4+ T cell recognition of donor MHC peptides presented by self antigen-presenting cells (indirect allorecognition), is a central and key event that is responsible for the initiation and progression of chronic rejection. In addition, based on studies in small animals, alloantigen-independent mechanisms contribute to this process by promoting immune recognition and injury to the graft. Therefore, our goal is to study the contribution and mechanisms of the alloimmune response, along with interactions with key alloantigen-independent factors in the pathogenesis of chronic rejection in humans. In Project 1, Dr. Madsen and co-investigators will focus on studying the immunopathogenesis of chronic rejection using clinically relevant large animal (miniature swine) models of heart and lung transplantation. These models are unique in that they are the only large animal models with defined MHC systems and reproducible chronic rejection pathology. A major focus of Project 1 is to study immune responses to CMV and autoantigens in humans with chronic allograft rejection, as an extension of the studies in the miniature swine. In Project 2, Dr. Briscoe and colleagues plan to study the mechanisms of the interactions between donor endothelial cells and recipient antigen-presenting cells and T cells in promoting indirect alloimmune responses and chronic rejection. In Project 3, Dr. Sayegh's group will investigate the immunopathogenesis of chronic rejection with emphasis on the indirect alloimmune T cell and antibody response, and interactions with alloantigen-independent mechanisms

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in human renal transplant recipients. In the Scientific Core, Dr. Hancock will provide the infrastructure and technology to perform morphology, immunopathology and molecular analyses of tissue and peripheral blood mononuclear cells provided by the 3 Projects. Dr. Sayegh, along with Dr. Patricia Hibberd, Director of the Clinical Research Core Programs Office at Children's Hospital, will lead the Administrative and Data Management Core which will coordinate all administrative, statistical and data management issues of the Program Project. It is the collective results from our human studies in transplant recipients, our in vitro mechanistic experiments, and our large animal model that will provide a better understanding of the pathogenesis of chronic rejection. Our studies will yield clinically relevant information that will result in development of better assays to monitor and predict patients at risk for development of chronic rejection, as well as development of new therapeutic strategies to prevent this process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNORECOGNITION IN CHRONIC ALLOGRAFT REJECTION Principal Investigator & Institution: Madsen, Joren C.; Associate Professor of Surgery; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2002 Summary: (provided by applicant): Using an immunologically versatile herd of MHC inbred miniature swine, we have developed and validated the only large animal model of heart and lung transplantation in which vascular and bronchial lesions reproduce with fidelity and consistency those lesions seen in human heart and lung transplant recipients suffering from chronic rejection. The current proposal is designed to elucidate the cellular and molecular mechanisms underlying the pathogenesis of chronic rejection in this clinically relevant large animal model and then to corroborate these finding in human heart transplant recipients. Our hypotheses, based on emerging rodent and human studies, are 1) that chronic rejection is mediated by an immune process initiated by CD4+ T cells that recognize donor allopeptides via the indirect pathway of allorecognition, 2) that recognition of non l MHC peptides derived from either viral antigens (e.g., CMV) or self proteins (e.g., cardiac myosin) can interact with the immune response to MHC peptides, and 3) that these immune responses can ignite, amplify or recruit one another, thus augmenting the chronic rejection response. To establish whether chronic rejection in large animals and humans is the end-result of the immune recognition of allopeptides, and to determine if the recognition of non-MHC peptides contribute to this process, we will use synthetic MHC allopeptides, MHC-linked viral tetramer analyses, and cardiac myosin to interrogate indirect alloimmununity, anti-viral immunity, and organ-specific autoimmunity, respectively. We plan to 1) examine and compare the roles of MHC allopeptides and organ-specific autoimmunity to cardiac myosin and antiviral immunity in the pathogenesis of CHR in miniature swine, 2) examine and compare the roles of MHC allopeptides and anti-viral immunity in the development of CLR in miniature swine, and 3) determine the role of autoimmune responses to cardiac myosin and anti-viral immunity to CMV in development of chronic rejection in human heart recipients. These mechanistic studies are critical to the development of successful therapeutic strategies aimed at extinguishing the chronic rejection response at its inception. A strategy of early intervention (at the immune recognition phase) would have the best chance of avoiding the programmed sequela of tissue injury and inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMPACT TRANSPLANTATION

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CYCLOSPORINE

IN

LUNG

Principal Investigator & Institution: Zeevi, Adriana V.; Professor; Pathology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Our clinical program has recently been awarded a 4-year RO1 NIH grant HL59490: "Aerosol Cyclosporine for Prevention of Lung Rejection". The project deals with a prospective double-blind randomized clinical trial to evaluate the effectiveness of aerosol CsA (versus placebo) combined with standard immunosuppression given for prevention of acute rejection early after lung transplantation. The clinical grant relies on biopsy histology and pulmonary function test to determine the primary end-points; no immune function tests are funded. This research proposal deals with immune correlates of rejection in this cohort of lung transplant recipients. The human lung allograft presents a unique clinical model where we can directly measure the effect of local drug delivery on the immune intragraft events associated with rejection. This proposal addresses not only "surrogate markers of disease and therapeutic effects" but will also permit us to draw important inferences regarding the "mechanism of the allograft response" to the human lung transplant. 1) We will extend our understanding of the patterns of intragraft cytokines and other effector molecules (competitive RT-PCR) and their origins (intracellular cytokine staining) following lung transplantation. Their measurements will be evaluated in stable and rejecting allografts and quantitation will be interpreted not only in lieu of systemic (oral) vs. regional (aerosol) immunosuppression but also in consideration of cytokine gene polymorphism. 2) We will study humoral allo-immunization in lung transplant recipients by following serum antibody levels against donor HLA class I and II antigens using a direct and an antihuman globulin-augmented lymphocytotoxicity assays and by an HLA-specific ELISA assay. HLA class I and II alloantibodies will be followed sequentially and related to systemic vs. regional immunosuppression. 3) We will study indirect allo-presentation by following BAL and plasma soluble donor HLA (by ELISA) in attempt to better understand its relationship to acute and chronic obliterative bronchiolitis in lung transplant recipients. The impact of aerosol CsA on the persistence of donor-specific macrophages (by flow-cytometry) will be also determined. This research project will be conducted in conjunction with the clinical trial. The project considers both cellular and humoral immune responses and has a high likelihood of providing clinical correlation of potential surrogate markers of alloreactivity. We will correlate the clinical end-points for acute rejection, chronic rejection and infection with the above laboratory parameters and determined how the sensitivity, specificity and predictive value of each assay would be clinical useful in management of lung transplant recipients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPACT OF MIND-BODY INTERVENTIONS POST ORGAN TRANSPLANT Principal Investigator & Institution: Gross, Cynthia R.; Professor; Experimental College; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 30-APR-2008 Summary: (provided by applicant): Solid organ transplant recipients require life-long immunosuppressive therapy that leads to side effects, complications and chronic symptoms, and reduces health-related quality of life. Pharmacologic options for managing symptoms increase the risks of side effects and drug interactions, and may

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reduce adherence by complicating an already challenging medication regimen. In contrast, mind-body based complementary therapies, such as mindfulness-based stress reduction (MBSR), may be ideal to treat distressing symptoms and negative emotions after transplantation. Our long-range objective is to develop evidence-based recommendations for non-pharmacologic strategies that provide symptom relief to transplant recipients, and are safe, practical and cost-effective. The specific aims are to: 1) Test the effectiveness of a MBSR program on symptom management (as measured by well-validated, self-report scales for symptoms of depression, anxiety and sleep disturbance), objective sleep changes, health-related quality of life and overall quality of life in transplant recipients at 6- and 12-mos follow-up; and 2) Evaluate the impact of this MBSR program on health care utilization and costs at 6- and 12-mos follow-up. We will randomize patients (N=150) to: 1) a MBSR intervention arm (8 wks of group instruction in mindfulness meditation techniques followed by home practice combined with individualized telephone monitoring); or 2) a health education (HE) active control arm, delivered in a format to match MBSR for instructor attention and group support. The sample will consist of kidney, kidney/pancreas, pancreas, lung, liver, heart or heart-lung transplant recipients at least 6-mo after transplant surgery. A two-stage randomization scheme will form a temporary, Delayed-Intervention (DI) inactive control arm for internal validation. The DI group will be randomized to MBSR or HE after 26 weeks of observation. This is a low cost, low risk intervention that, if successful, could be replicated easily, and result in important reductions in health care costs while improving the well being of patients with organ transplants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INNATE BRONCHIOLITIS

IMMUNE

RESPONSES

IN

OBLITERATIVE

Principal Investigator & Institution: Palmer, Scott M.; Medicine; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 31-MAR-2007 Summary: (provided by applicant): Dr. Scott M. Palmer, currently on faculty in the Duke University Pulmonary Division as an Associate in Medicine, proposes a structured five-year career development plan in order to develop into an independent investigator in pulmonary medicine. The proposal involves rigorous research training under an experienced physician scientist mentor, Dr. David Schwartz, who has expertise in the immunogenetics of innate immunity. Further research training is proposed under the guidance of a co-mentor with expertise in statistical genetics, a collaborator with expertise in transplant immunology, and complemented by didactic graduate coursework. The overall goal of the proposed research is to understand how innate immune responses contribute to the development of posttransplant bronchiolitis obliterans syndrome (BOS). We hypothesize that genetic, physiological or biological differences in innate immune responsiveness will significantly alter the risk for the development of BOS after lung transplant. This novel hypothesis is clinically relevant based on the high rate of posttransplant death due to BOS, scientifically relevant because of the incomplete understanding of the pathophysiology of BOS, and supported by several basic and clinical observations. We and others have recently demonstrated that significant polymorphisms exist in innate immune receptor genes, and that these differences significantly alter subsequent inflammatory and immune responses. In order to test our hypothesis, we will characterize polymorphisms in donor and recipient tolllike receptor-2 (TLR2), TLR4, and CD14 genes, and phenotypically characterize the airway physiological and biological response to endotoxin in a cohort of 120 lung

22

Lung Transplant

transplant recipients. We will prospectively capture clinical information on the cohort and determine the predictive importance of innate genetic, physiological, or biological factors on the development or progression of BOS in a multivariate model. At the conclusion of the career development award, Dr. Palmer will have gained considerable expertise in study design, basic genetic analyses, transplant immunology, and statistical analyses. He will apply these skills to direct future investigations of patient oriented research problems in pulmonary medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IP-10 CHEMOKINE: ROLE IN T CELL RECRUITMENT AND DISEASE Principal Investigator & Institution: Luster, Andrew D.; Chief, Director, and Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2004; Project Start 01-MAR-1996; Project End 31-DEC-2008 Summary: (provided by applicant): The attraction of leukocytes to sites of inflammation and infection is an essential component of the host response to disease. This process is controlled by chemokines, which are chemotactic cytokines. IP-10 (CXCL 10) is a chemokine that specifically attracts effector T cells and "innate lymphocytes" by activating a seven transmembrane spanning G protein-coupled chemokine receptor, CXCR3, which is expressed on these cells. Chemokines also have activities on nonhematopoietic cells and may be important mediators that link inflammation to tissue repair processes. In this regard, IP-10 inhibits angiogenesis and fibrosis in vivo. The molecular mechanism of these later effects have not been clearly established. IP-10, like many other chemokines, is a basic protein that binds to proteoglycans and also has the ability to form higher order aggregates. The functional consequences of these interactions are not clear, although they likely play important roles in IP-10's biological activity in vivo, especially in cells such as endothelial cells and fibroblasts where CXCR3 expression has been difficult to demonstrate. In this renewal application, we propose to continue our studies on IP-10 to define the structural domains that mediate its biological activities in vivo, to determine the mechanisms that control the differential regulation and function of the three CXCR3 ligands -- IP-10, MIG and I-TAC -- in vivo, and to define the role of CXCR3 and its ligands in the trafficking of defined subsets of antigenspecific CD4 and CD8 cells in vivo. Specifically, we propose: (1) To determine the structural domains of IP-10 that mediate its binding to CXCR3 and proteoglycans and its tendency to oligomerize, and the biological consequences each of these interactions have for IP-10's ability to induce T cell recruitment and inhibit angiogenesis and fibrosis in vivo; (2) To determine the unique roles of IP-10 and MIG in allograft rejection in a model of lung transplantation, and to determine the cellular and molecular mechanisms regulating the differential expression of these two CXCR3 ligands in this model; (3) To determine the role of IP-10, MIG, I-TAC and CXCR3 in the generation and trafficking of defined subsets of antigen-specific of CD4 and CD8 T cells in vivo. Studies supported by this grant have contributed to our understanding of IP- 10 and have helped establish IP10 and CXCR3 as attractive candidates for modulating the immune response in clinically relevant diseases, such as solid organ transplantation, pulmonary fibrosis and cancer. The current proposal will extend and refine our knowledge of this important clinically relevant chemokine-chemokine receptor system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ISCHEMIC TRANSPLANT

INJURY

IN

CADAVER

DONORS

FOR

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LUNG

Principal Investigator & Institution: Egan, Thomas M.; Associate Professor of Surgery; Surgery; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 20-SEP-2001; Project End 31-JUL-2004 Summary: Clinical lung transplantation (LTX) is severely limited by a shortage of suitable donors. Thus, hundreds of Americans die annually waiting for LTX, and thousands more with end stage respiratory disease are denied the opportunity of improved health that LTX may afford them. The lung is unique among solid organs in that it does not rely on perfusion for cellular respiration. We hypothesize that lung tissue remains viable for hours after circulatory arrest and death, and thus the lung may be suitable for transplantation, even if retrieved at substantial intervals after circulatory arrest and death of a non-heart beating organ donor (NHBD). We have substantiated this hypothesis with animal LTX experiments, which demonstrate that lungs retrieved at intervals after circulatory arrest may function well, but are affected adversely by ischemia-reperfusion injury (IRI). There is evidence that the cyclic nucleotide cAMP and cGMP are important mediators of altered endothelial permeability in lung IRI. IRI is associated with upregulation of endothelial cellular adhesion molecules (CAM) which recruit polymorphonuclear leukocytes (PMN) to the lung that contribute to IRI. We hypothesize that cyclic nucleotides play a pivotal role in maintaining endothelial cytoskeletal integrity, which in turn plays a role in CAM upregulation. This proposal aims to: 1) Characterize events that occur in the NHBD lung during the period of normothermic ischemia after circulatory arrest but prior to reperfusion. 2) Determine the relationship between CAMP and cGMP in lung tissue and pulmonary endothelial permeability changes due to IRI after circulatory arrest. 3) Determine the relationship between CAM expression, PMN recruitment, and lung function in transplanted lungs from NHBDs. Utilizing a rat isolated lung perfusion model and a rat LTX model, this proposal intends to achieve a better understanding of the molecular events involved in IRI and develop strategies that minimize lung injury in the setting of retrieval from NHBDs. This will facilitate the introduction of lung retrieval for transplant from NHBDs, which has the potential to extend the lives of thousands of Americans suffering with a variety of lung diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: KIDNEY TRANSPLANT CARELINK Principal Investigator & Institution: Safran, Charles; Chief Executive Officer; Clinician Support Technology, Inc. Suite 201 Newton, Ma 02459 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2003 Summary: (provided by applicant): We propose Kidney Transplant CareLink, an Internet-based learning, communication, and care support application that will help kidney transplant recipients improve their self-management skills and their ability to maintain immunosuppressive regimens over time using learning and intervention strategies, including individualized teaching, reminders, interactive counseling, monitoring, and peer support and mentoring. We will use information gathered by patient self-report to tailor learning and communication interventions to patients? individual needs. Kidney Transplant CareLink will be a patient-centered Internet web site connecting patients directly to their own transplant center care team. It will be a "one-stop," 24/7 source of knowledge, individualized learning and care support, self-

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Lung Transplant

care functionality, and emotional support. Transplant recipients will get information they want, when they want it, and in a format they prefer, directly from their own transplant center providers. It will enable recipients and the transplant center care team to sustain a strong sense of connection, knowledge exchange, and collaboration over time, regardless of geography. Kidney Transplant CareLink will be used by kidney transplant centers and their patients, as well as health plans and payers. If successful, this Internet-based model will be applicable to large and growing populations of pancreas, liver, heart, and lung transplant recipients. PROPOSED COMMERCIAL APPLICATION: We believe that Kidney Transplant CareLink will effectively address significant problems that adversely affect patient outcomes in kidney transplantation. We believe there is currently no commercial application available to transplant centers and patients that addresses the range and specificity of needs and that has the potential to improve outcomes as our model does. Kidney Transplant CareLink addresses a significant unmet need in the marketplace. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS CAUSING PULMONARY XENOGRAFT INJURY Principal Investigator & Institution: Davis, R Duane.; Associate Professor; Surgery; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2005 Summary: Although primary transplantation has evolved into an effective therapy for end-stage lung disease, the balance between organ supply and demand greatly limits its applicability. Pulmonary xenotransplantation using swine lungs in humans could provide a solution to this problem. However, pulmonary xenografts are rapidly reflected by mechanisms distinct from those causing hyperacute rejection of the heart or kidney. The long-term objective of this project is to determine the mechanisms responsible for pulmonary xenograft injury, develop strategies which will prevent this injury and to enable the clinical application of pulmonary xenotransplantation. Although the mechanisms responsible for rejection of the cardiac xenograft are dependent upon the binding of xenoreactive antibody to the Gal(1-3)Ga1 epitope with subsequent complement activation, the importance of this interaction in lung xenografts is unclear. The aims of this proposal are as follows: (1) define the role of the pulmonary intravascular macrophage and other resident macrophage and other resident macrophages within the lung in inducing pulmonary vasoconstriction, endothelial cell activation and initiation of coagulation; (2) to define the role of classical complement pathway activation, particularly anaphylatoxins and xenoreactive antibody in pulmonary xenograft injury; and (3) characterize the role of tissue factor initiated coagulation and inadequate regulation of coagulation in pulmonary xenograft injury particularly with regards to endothelial cell activation and augmentation of inflammation. The experiments outlined in this proposal will (1) deplete resident macrophages, both the intravascular and alveolar macrophages; (2) use of anti-C5a monoclonal antibodies and other inhibitors of the complement system; (3) depletion of Gal antibody and to use lungs of the Gal epitope; and (4) blockers of tissue factor dependent coagulation, swine vWF platelet interaction and regulator of the coagulation system that are effective in a swine to primate model. It is anticipated that these studies will further delineate the mechanisms responsible for the early pulmonary xenograft injury and to begin to allow for examination of the mechanisms responsible for acute vascular rejection. Strategies developed from these studies should form the basis for the application of pulmonary xenotransplantation to the treatment of patients with pulmonary failure.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS GOVERNING HYPERACUTE REJECTION OF THE LUNG Principal Investigator & Institution: Pierson, Richard N.; Associate Professor of Surgery; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS ALLOGRAFTS

OF

MAST

CELL

APOPTOSIS

IN

LUNG

Principal Investigator & Institution: Fang, Kenneth C.; Cardiovascular Research Inst; University of California San Francisco 3333 California Street, Suite 315 San Francisco, Ca 941430962 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2004 Summary: Mast cells and their mediators play critical roles in homeostatic wound healing pathways. Therefore, the premature demise of the mast cell population via programmed cell death or apoptosis may permit uncontrolled tissue remodeling which progresses to fibrosis. Metalloproteinases and their inhibitors exert diverse influences on cellular functions by processing matrix proteins and by regulating the dynamic display of membrane- anchored receptors, adhesion molecules and growth factors at the cell surface. The overall hypothesis of this proposal is that metalloproteinase-dependent mechanisms regulate mast cell apoptosis during fibrinogenesis. Binding of c-kit ligand (stem cell factor) to kit receptor tyrosine kinase regulates mast cell proliferation and apoptosis, and also induces receptor down-regulation via an uncharacterized metalloproteinase-dependent cleavage of Kit's extracellular domain. The experimental design employs complementary approaches using a rat model of lung transplantassociated airway fibrosis to study the role of metalloproteinases in mast cell apoptosis in vivo, and cultured mast cells to investigate the role of metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs) in molecular mechanisms which regulate proteolytic shedding of the Kit ectodomain. Consistent features of mast cells in fibrotic lung disorders, including transplant-associated obliterative bronchiolitis are fluctuations in the size of their population and persistent degranulation of stored mediators. To address the overall hypothesis, the proposed studies will investigate metalloproteinasedependent induction of mast cell apoptosis and the role of mast cell mediators in regulating proteolytic processing of Kt receptor. Aim 1 will identify the role of metalloproteinases and mast cell apoptosis during the development of obliterative bronchiolitis in a rat lung allograft model. Aim 2 will clarify the metalloproteinasedependent Kit receptor shedding mechanism by investigating mast cell expression of metalloproteinases such as tumor necrosis. Factor-alpha converting enzyme (TACE), and by identifying the proteases and peptide sites cleaved in Kit ectodomain processing. Aim 3 will determine the role of mast cell proteases and oxygen radicals in proteolytic and non-proteolytic processing of TIMPs which not only inhibit metalloproteolytic sheddases, but also regulate apoptosis. These studies should provide valuable insights into the role of mast cells in the pathogenesis of fibrotic lung disorders and also clarify mechanisms responsible for the development of obliterative bronchiolitis, the major obstacle to improved outcome and survival in lung transplant patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF PULMONARY ALLOGRAFT REJECTION IN SWINE Principal Investigator & Institution: Johnston, Douglas R.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-FEB-2002 Summary: Using miniature swine inbred to homozygosity at the MHC loci, we have developed a large animal model of chronic lung allograft rejection that reproduces with fidelity those histologic lesions seen in patients suffering from chronic lung rejection. The current proposal is designed to elucidate the mechanisms of chronic lung allograft rejection in these swine, with particular attention to the role of indirect recognition of donor MHC peptides. We hypothesize that chronic lung rejection is an immunological process mediated by T cell recognition of alloantigens, and that indirect recognition of donor allopeptides may play a dominant role in this process. A recent clinical study demonstrated that allorecognition of HLA class I-derived peptides correlated with the development of chronic rejection in human lung transplant recipients. However, definitive experimental evidence linking indirect allorecognition and chronic rejection in the development of chronic lung rejection using synthetic class I MHC allopeptides Specifically, we will define which MHC peptides are recognized during chronic lung rejection and whether priming animals with immunogenic class I MHC peptides will induce or accelerate chronic lung rejection. Then, we will attempt to induce tolerance to the indirect pathway in lung transplant recipients using T cell co-stimulatory blockade combined with donor allopeptides. Our hypothesis would predict that this clinically relevant therapeutic strategy would prevent the development of chronic rejection. These preclinical studies will contribute substantially to our knowledge of the mechanisms and treatment of chronic lung rejection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MEDIATORS OF FIBROSIS IN SCLERODERMA SKIN AND LUNG Principal Investigator & Institution: Feghali, Carol A.; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology that affects mostly women and is associated with significant morbidity and mortality. No effective therapies or cures for SSc are yet available. One of the hallmarks of SSc is overproduction of extracellular matrix components such as collagen and fibronectin by fibroblasts in the skin and internal organs. We have made the novel observation of a 20-fold increase in the expression of insulin-like growth factor binding protein 5 (IGFBP-5) in fibroblasts from the clinically affected skin of SSc patients. IGFBP-5, as well as IGFBP-3, are produced by fibroblasts and modulate the actions of IGF-I, including fibroblast activation and overproduction of collagen. We hypothesize that the IGFBP/IGF-I axis contributes to the development and perpetuation of skin and lung fibrosis in SSc. Our studies will use two unique sample sets available to us--fibroblasts and tissues from monozygotic (MZ) and dizygotic (DZ) twins discordant for SSc and from lungs of SSc patients undergoing lung transplant surgery and unused donor lungs-and target two organs affected by SSc--skin and lung. These samples constitute a unique and valuable resource. Our aims are l) to determine the regulation of IGFBP-3 and IGFBP-5 in vitro and in vivo in skin an lung tissues of SSc patients and twin and non-twin controls; 2) to determine the function of IGFBPs on skin and lung fibroblasts and identify key molecules downstream of IGFBPs; 3) to determine the

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mechanism of IGFBP-mediated effects on fibroblasts, including whether the effect of IGFBPs is IGF-I-dependent or - independent, the identification of IGFBP binding partners, and the effect of suppressing IGFBP expression on the fibrotic phenotype. Our combined approach using lung and skin fibroblasts and tissues will allow us to identify the systemic mechanisms that underlie the skin and lung phenotype in SSc, while the use of samples from twins discordant for SSc will allow us to determine the importance of the inherited genetic background in the development of the 'scleroderma' phenotype. Our results will provide important insights into mechanisms of overproduction of extracellular matrix components by fibroblasts and thus the pathogenesis of fibrosis. Identifying key steps in the cascade of events culminating in fibrosis will facilitate the development of novel targeted therapies for scleroderma and for other fibrotic conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MICROCHANNEL ASSEMBLIES FOR ARTIFICIAL LUNGS Principal Investigator & Institution: Mockros, Lyle F.; Biomedical Engineering; Northwestern University 633 Clark Street Evanston, Il 602081110 Timing: Fiscal Year 2004; Project Start 06-FEB-2004; Project End 31-JAN-2007 Summary: (provided by applicant): The objective of the proposed research is to develop technology for producing prosthetic assemblies of microchannels that can be utilized in artificial organs. These microchannels, with diameters of 10 to 20 microns, are imbedded in a matrix material with nanoscale pores. The microchannel assemblies somewhat simulate physiologic capillary beds. Mass transfer to/from blood flowing in such assemblies will be greatly enhanced compared to that with current technology. Although possibly applicable to a variety of organ-function replacement devices, the overall specific aim of the current proposal is to develop the technology for artificial lungs. Effective artificial lungs could have a significant clinical impact as a bridge to lung transplantation, as a support device immediately post lung transplant, and as a rescue and/or supplement to mechanical ventilation during treatment of severe respiratory failure. Preliminary calculations suggest that a 250 ml volume artificial lung using 12 mu m microchannel wafers for gas exchange could process 4 I/min blood using air. The basic component of these microchannel assemblies for artificial lungs will be wafers of porous, biocompatible matrix containing microchannels. We propose to produce sample wafers of this basic component and conduct a series of gas transfer studies to determine the dependence of transport efficiency on blood flow rate, gas-side oxygen concentration, microchannel diameter and length, and wafer matrix material. We also propose to investigate methods to improve the production of these wafers using different fiber and matrix materials and by varying the preparation procedure. Our proposed technique involves (1) making an array of closely spaced fibers as template for the microchannels, (2) imbedding the fiber bundle in a porous matrix, (3) removing the fibers, thereby creating an array of microchannels within the porous matrix wafer, (4) machining the wafer to a desired shape, (5) coating the external faces with a thin but dense nonporous film, and (6) coating the microchannel walls and wafer surfaces with silicone rubber for biocompatibility. We have successfully demonstrated steps (1) to (3), and produced small samples of 12 mu m diameter channels in a wafer. The results of the proposed study will provide proof of concept that such microchannel devices are substantially superior to the conventional devices. Future work would include detailed blood compatibility tests and address scale-up issues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MODULATION TRANSPLANTATION

OF

INNATE

IMMUNITY

IN

LUNG

Principal Investigator & Institution: Matalon, Sadis; Acting Associate Provost for Research; Anesthesiology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): A multi-center clinical trial sponsored by Fujisawa Healthcare, Inc, was planned to compare the efficacy of treating lung transplant patients with tacrolimus and sirolimus versus tacrolimus and azathioprine in reducing the incidence of acute rejection during the first twelve months after lung transplantation. Infection is a secondary endpoint and is assessed throughout the trial (i.e. for 3 years after randomization). Presently the mechanisms by which these agents may modify lung innate immunity have not been identified. Herein, we are proposing to isolate SP-A and AMs from the bronchoalveolar lavage fluid (BALF) of patients participating in this clinical trial to identify differences in the ability of AMs to kill gram positive and gram-negative bacterial pathogens and to identify differences in quantity of SP-A and modifications thereof. These data will be correlated with incidences of infection and rejection in patients participating in the clinical trial. We are also proposing to identify basic mechanisms by which normal but not nitrated SP-A enhances phagocytosis. These goals will be accomplished by completing the set of measurements outlined in the following specific aims: (1) Measure levels of surfactant lipids and SP-A in bronchoalveolar lavage (BAL) samples from patients treated with tacrolimus and sirolimus vs. tacrolimus and azathioprine. Oxidative modification to SPA (oxidation and nitration) will be assessed by Western blotting, ELISA and mass spectrometry analysis using techniques already established in our laboratory; (2) Quantitate levels of inflammatory cytokines (TNFa, INFgamma, IL-6 and IL-lb), as well as levels of nitrate and nitrite, the stable end products of NO metabolism, and nitrotyrosine in the BAL of these patients; (3) Assess the extent of pathogen killing (Klebsiella pneumoniae, a gram negative bacterium and Staphylococcus aureus, a gram positive bacterium) by AMs isolated from the lungs of these patients in the presence of SP-A and surfactant lipids, and (4) Identify putative mechanisms responsible for decreased ability of oxidized or nitrated SP-A to mediate pathogen killing by AMs. We propose that SP-A binding to AM receptors leads to activation of phospholipase C (PLC) which releases 1,4,5 inositol triphosphate (IP3) resulting in Ca+2 release from the endoplasmic reticulum. SP-A nitration may lead to decreased binding, diminishing or abrogating intracellular Ca+2 changes. Our data may provide mechanistic insight into why some patients may develop clinical infection and acute and chronic rejection and thereby form the rationale basis for choosing between these two immunosuppressive regiments for the management of patients with lung transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NMR IMAGING OF INERT FLUORINATED GASES IN LUNGS Principal Investigator & Institution: Kuethe, Dean O.; Scientist; New Mexico Resonance 2301 Yale Blvd Se, Ste C1 Albuquerque, Nm 87106 Timing: Fiscal Year 2002; Project Start 01-APR-1997; Project End 31-JUL-2005 Summary: (provided by applicant): This project endeavors to provide safe non-invasive, but powerful imaging methods for studying pulmonary physiology and diagnosing and evaluating lung diseases. One aim is to develop a new method of imaging alveolar ventilation to blood perfusion ratios (VA/Qs). The spatial distribution of this ratio is of

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central diagnostic importance in obstructive lung disease and characterizes the lung's ability to exchange gas. An advantage of our new method over our prior one is that patients who regularly breath oxygen enriched air will not have to breath gas with normal oxygen concentrations, but can breath a mixture rich in oxygen the entire time. The method will be developed in laboratory rats. Specifically, it involves imaging the longitudinal nuclear magnetic relaxation time of an inert fluorinated gas, which we recently discovered is a monotonic function of VA/Q. Because it will quantify VA/Qs in the low range that cause poor arterial blood gases, it is not only potentially a diagnostic tool but also a tool for advancing the physiology of gas exchange in diseased and normal individuals. After development, both VA/Q imaging methods will be applied to a study of elastase induced emphysema in rats. A second aim is to systematically develop methods to detect magnetic particles in images of inert fluorinated gas. The methods will be applied to collaborative studies of the patterns of deposition of magnetically labeled aerosol particles in rat lungs and the invasion of transplanted rat lungs by magnetically labeled immune cells. Understanding of how and where aerosol particles deposit in lungs is important to advancing the toxicology of inhaled air pollution and can further the effectiveness of inhaled drugs. Imaging lung rejection is important to diagnosing acute rejection and studying the rejection process to develop improved immunosuppressive strategies. Specifically, we will tailor methods of detecting magnetic particles in gas images for use in our collaborator's animal models and laboratories by systematic exploitation of the frequency shift and diffusional signal loss contrast mechanisms. With this second aim, we will advance inert fluorinated gas imaging beyond a development and demonstration stage to a new research tool that provides previously unavailable data to medical research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PAL: PRE-CLINICAL FABRICATION & OUTCOMES STUDIES Principal Investigator & Institution: Zwischenberger, Joseph B.; Professor; Mc3, Inc. 3550 W Liberty Rd, Ste 3 Ann Arbor, Mi 48103 Timing: Fiscal Year 2003; Project Start 01-MAY-2001; Project End 30-JUN-2005 Summary: (provided by applicant): End-stage Lung Disease from all causes is the fourth leading cause of death in the US. Despite the success of lung transplantation, demand for donor lungs has steadily outgrown supply. Currently, the average wait is 2 years, with 30% wait-list mortality. Likewise, acute respiratory distress syndrome (ARDS) is a predominant cause of death in trauma and critically ill patients. A paracorporeal artificial lung (PAL) was redesigned and built by MC3 (Ann Arbor, MI) in Phase I. The current PAL prototype in a pulmonary artery-to-pulmonary artery (PA-PA) configuration supported gas exchange in normal sheep (N=8) for up to 7 days. Additionally, 7/8 sheep achieved total gas exchange (02 and CO2) for 3 days following a lethal (LD100) smoke/burn injury. Our central hypothesis is that total extracorporeal gas exchange with the Optional Assisted Compliance Chamber (OACC) PAL will allow long-term respiratory support to achieve lung recovery from ARDS or bridge to lung transplant in patients with or without pulmonary hypertension. PHASE II Specific Aim 1: Develop an OACC to provide timed mechanical assist to right heart ejection. Since most patients with pulmonary disease have some degree of associated pulmonary hypertension, (often transiently severe) PAL must be able to provide total gas exchange (02 and CO2) and circulatory augmentation (primarily to the right ventricle). Specifically, using tightly coupled experimental and mathematical models (as outlined in the application); we will optimize the design of the OACC and PAL. The PAL will be able to overcome up to a 4-fold increase in pulmonary vascular resistance. We will

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determine the volume, pressure and cardiac cycle timing to optimize right ventricular support for application of PAL for pulmonary hypertension or right heart failure. Specific Aim 2" Design and fabricate injection molds for the preclinical production of PAL. Specific Aim 3: Utilizing our recently developed, clinically relevant LD100 sheep model of lethal ARDS, determine outcomes and measure injury parameters in two prospective randomized groups (N=10) over 10 days: 1) low tidal volume (LTV) ventilator management versus 2) PAL. Specific Aim 4: Investigate PAL impact on the pathophysiology of a lethal (LD100) smoke/burn induced lung injury randomized to PAL (N=10) or LTV ventilator management (N=10) then sacrifice at 48 degrees for full pathologic study. The knowledge gained will provide unique insight into the pathophysiology of ARDS and yield outcomes data for final PAL preclinical development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENESIS TRANSPLANT

OF

CHRONIC

REJECTION

IN

LUNG

Principal Investigator & Institution: Fernandez, Felix G.; Surgery; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-JUL-2002 Summary: (provided by the applicant): The long term survival and function of transplanted lungs are limited by the development of bronciolitis obliterans syndrome (BOS), an unexplained often nonreversible condition unresponsive to therapy and in most cases fatal. Over the past two years, compelling evidence has been obtained that the development of anti-HLA antibodies against mismatched donor antigens and the detection of in vivo priming against mismatched donor HLA class I antigens defined by indirect antigen presentation assays have significant correlation with the development of BOS. The first specific aim of this proposal is to demonstrate increased frequencies of donor reactive T cells prior to the appearance of anti-HLA antibodies in lung transplant recipients. This will be done by testing recipient peripheral blood leukocytes with donor mismatched HLA class I and II peptides in the presence of autologous antigen presenting cells in a proliferation assay. Therefore, in vitro methods to detect in vivo priming against mismatched donor HLA class land II antigens may serve as a good measure of successful intervention by changes in immunotherapeutic protocols. The second specific aim of this proposal is to define the biology and biochemistry of this newly identified airway epithelial antigen and to correlate the development of antigen specific antibodies with the development of BOS. A panel of airway epithelial cells (AECs) and the AEC specific silo antibodies developed post transplant will be used to define the polymorphism of this antigenic system. Using internal labeling of AEC and immunoprecipitation analysis using alloantibodies specific for AEC antigen, the biochemistry of this antigen will also be defined. The overall goals of this proposal are to continue to define the cellular and molecular mechanisms contributing to the development of BOS subsequent to lung transplantation and to allow the institution of new therapeutic strategies which will prevent the development and consequences of BOS, a major limiting factor for the continued function of the transplanted organ. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POSTTRANSPLANT IMMUNE PARAMETERS AND DECREASED IMMUNOSUPPRESSION Principal Investigator & Institution: Matas, Arthur J.; Professor; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070

Studies

31

Timing: Fiscal Year 2002 Summary: The long-term objective of our Project is to determine whether posttransplant immune parameters can predict which solid organ transplant recipients will tolerate decreased immunosuppression. The specific aims for recipients developing donor antigen-specific hyporesponsiveness. 1. To determine, in a prospective randomized trial, whether kidney transplant recipients can be tapered off steroids without an increased incidence of late acute rejection or of chronic rejection. 2. To determine whether heart transplant recipients can be tapered off steroids without an increased incidence of acute rejection and without an increased risk of allograft vasculopathy. 3. To determine whether lung transplant recipients can be converted from oral to inhaled steroids without an increased incidence of acute rejection episodes and without an increased risk of obliterative bronchiolitis. It is well-recognized that posttransplant immunosuppression is associated with morbidity. And many immunosuppressive care protocols attempt to lower or withdraw some immunosuppressive agents. However, trials of immunosuppression drug withdrawal or dosage lowering, based on clinical criteria alone, have not been routinely successful. We have previously shown that patients who develop donor antigen-specific hyporesponsiveness have decreased incidence of late acute rejection episodes, decreased chronic rejections (biopsy proven in kidney transplant recipients, coronary artery disease on angiogram in heart transplant recipients, and of obliterative bronchiolitis in lung transplant recipients), and improved long term graft survival. The goal of the current study is to determine whether those who have developed donor antigen-specific hyporesponsiveness can have the same excellent long-term outcome after prednisone withdrawal ( in kidneys and heart recipients) or conversion to nebulized prednisone (in lung transplant recipients). Identification of a subpopulation of patients who can safely tolerate prednisone (in long transplant recipients). Identification of a subpopulation of patient who can safely tolerate prednisone withdrawal will allow potential for decreased morbidity for these, while simultaneously not withdrawing prednisone from those who would be at risk for rejection episodes, will similarly help preserve graft function and decrease morbidity (due to the antirejection treatment). Finally, for lung transplant recipients who remain responsive to donor antigens, we will also determine if the addition of inhaled steroids to their oral steroid regimen will decrease the risk of bronciolitis obliterans. Thus, this study has the potential for allowing selective immunosuppression for transplant recipients after the first year. The selective immunosuppression will help improve graft survival while potential decreasing posttransplant morbidity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREDICTING DEATH IN CF PATIENTS AWAITING LUNG TRANSPLANT Principal Investigator & Institution: Belkin, Richard A.; Pediatrics; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 24-JUL-2003; Project End 23-JUL-2005 Summary: (provided by applicant) The traditional referral guidelines for lung transplant in CF are largely based on a FEV