IMMUNE REGULATION IN LUNG TRANSPLANTATION
Principal Investigator: WILLIAM BURLINGHAM
Abstract: DESCRIPTION:(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.
Funding Period: 2000-09-30 - 2005-06-30
more information: NIH RePORT
- CMV-infected allogeneic endothelial cells initiate responder and bystander donor HLA class I release via the metalloproteinase cleavage pathwayLynn D Haynes
University of Wisconsin, Madison, WI 53792, USA
Hum Immunol 66:211-21. 2005....
- Human CD4+CD25low adaptive T regulatory cells suppress delayed-type hypersensitivity during transplant toleranceQingyong Xu
Department of Surgery, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792, USA
J Immunol 178:3983-95. 2007..Thus, adaptive T(R) cells suppressing T(E) cell responses to donor allopeptides in two tolerant patients appear to be functionally and phenotypically distinct from CD4(+)CD25(high)FoxP3(+) T cells...
- IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplantsWilliam J Burlingham
Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA
J Clin Invest 117:3498-506. 2007..These data suggest that while alloimmunity initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration...
- Th-17, monokines, collagen type V, and primary graft dysfunction in lung transplantationJoseph L Bobadilla
Microbiology and Immunology, Director, Center for Immunobiology, Indiana University School of Medicine, Van Nuys Medical Sciences Building MS224, 635 Barnhill Drive, Indianapolis, IN 46202 5120, USA
Am J Respir Crit Care Med 177:660-8. 2008..Human studies and rodent models have shown that collagen type V (col[V]), stimulates IL-17-dependent cellular immunity after lung transplantation...
- Anti-type V collagen humoral immunity in lung transplant primary graft dysfunctionTakekazu Iwata
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
J Immunol 181:5738-47. 2008..This study demonstrates a major role for anti-col(V) humoral immunity in PGD, and identifies the airway epithelium as a target in PGD...
- Analysis of indirect pathway CD4+ T cells in a patient with metastable tolerance to a kidney allograft: possible relevance to superior graft survival of HLA class II closely matched renal allograftsQingyong Xu
Department of Surgery, University of Wisconsin, Madison, Wisconsin 53792, United States
Transpl Immunol 20:203-8. 2009..This may favor the generation of a beneficial form of indirect pathway alloreactivity, i.e. allopeptide-specific CD4(+) T regulatory cells, in the context of long term DC microchimerism...