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.
