The National Heart, Lung, and Blood Institute convened a Working Group of investigators on June 14 -15, 2004, in Bethesda, Maryland to identify the opportunities for scientific advancement, including basic and clinical research, in lung transplantation. The Working Group participants first discussed clinical issues related to donor organ procurement, how to increase the donor pool by using lung grafts from non-heart-beating donors, increasing public awareness and acceptance of donor status, and initiating treatment to minimize lung ischemia and reperfusion injury. These presentations underscored that better standardization of organ procurement protocols, improved ways to assess the functional quality of the donor organ, and a more uniform patient database were needed.
As there are several new treatment protocols to improve the host's acceptance or tolerance of the allograft lung, these were reviewed in the context of ameliorating acute rejection and later development of bronchiolitis obliterans syndrome (BOS) which usually causes graft failure from chronic rejection. Non-immunlogic strategies to improve allograft tolerance were presented which included therapy with statins and macrolide antibiotics, and preventing gastro-esophageal reflux.
Presentations and discussions next delved into basic science mechanisms of manipulating the lung graft and host with immune inductions to improve tolerance. Dissecting the immunopathogenesis of BOS underlies basic research that probes affected tissue and cells injured by rejection. Thus, an update about deranged or overstimulated innate immunity was given in terms of chemokine profiles, proteomics and regulatory T-cells that impact on endothelial and epithelial surfaces of the transplanted lung.
After the Working Group reviewed the current status of lung transplantation, further discussion provided the Institute with recommendations for new research opportunities to improve preserving and creating a more functional graft, better accuracy of clinical prognosis, and investigating host rejection mechanisms.
The general recommendations of the Working Group are to:
- Establish a multi-center collaborative network to enhance the standards of clinical protocols, to understand the disease of BOS, including a lung tissue repository to assist in the characterization of the disease, and to conduct clinical trials.
- Increase use of the present donor pool of lung organs (utilization in US is about 15% versus 30-40% in European countries). Public policy issues should increase awareness of organ donation.
- Develop methods to better assess quality of donor lungs before transplantation.
- Assess new strategies for creating tolerance in the recipient and optimizing immunosuppression with pharmcogenomic methods and
- Identify better biomarkers and other proteomic tests to assess histologic onset of BOS before patient symptoms develop.
- Investigate methods to ameliorate ischemia/reperfusion injury in the allograft lung.
- Target research into the whole spectrum of graft dysfunction: primary failure, acute rejection and BOS. This would focus on innate and adaptive immunity and the emerging awareness that autoimmunity is involved in the rejection response.
- Continue to assess and develop relevant animal models that reflect the immulogic changes that occur in acute and chronic phases of huma allograft rejection.
Working Group Members
Co-chair: Thomas M. Egan, M.D., The University of North Carolina at Chapel Hill
Co-chair: David S. Wilkes, M.D., Indiana University School of Medicine
- William M. Baldwin, M.D., Johns Hopkins Medical Institutes
- William Burlingham, Ph.D., University of Wisconsin
- Steven R. Duncan, M.D., University of Pittsburgh
- Robert L. Fairchild, Ph.D., Cleveland Clinic Foundation
- Jay A. Fishman, M.D., Massachusetts General Hospital
- David A. Flockhart, M.D., Ph.D., Indiana University School of Medicine
- Joe G. N. Garcia, M.D., Johns Hopkins University School of Medicine
- Marshall I. Hertz, M.D., University of Minnesota
- Shaf Keshavjee, M.D., University of Toronto
- Sadis Matalon, Ph.D., University of Alabama at Birmingham
- Kenneth R. McCurry, M.D., University of Pittsburgh
- Scott M. Palmer, M.D., Duke University Medical Center
- G. Alexander Patterson, M.D., Washington University School of Medicine
- David J. Pinsky, M.D., University of Michigan
- Jonathan B. Orens, M.D., The John Hopkins Hospital
- Dirk E. M. Van Raemdonck, M.D., Ph.D., University of Gasthuisberg, Belgium
- Stig Steen, M.D., University Hospital of Lund, Sweden
- Robert M. Strieter, M.D., University of California, Los Angeles
- Adriana Zeevi, Ph.D., University of Pittsburgh
- Herbert Reynolds, M.D., Division of Lung Diseases