The principal investigator, David S. Wilkes, M.D., is an Assistant Professor of Medicine in the Division of Pulmonary and Critical Care Medicine at the Indiana University School of Medicine. His ultimate goal is to become a division chief of a research based pulmonary/critical care division at a major university medical center. He is currently acquiring the scientific skills to develop into an independent investigator. His research focus involves the immune mechanisms involved in lung allograft rejection. Dr. Wilkes has developed a murine model which will greatly facilitate these studies. Utilizing this murine model, the current proposal tests the hypothesis that allogeneic lung macrophages and/or 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 role of distinct accessory cells in the induction of lung allograft rejection, purified allogeneic lung macro-phages and dendritic cells will be instilled into recipient mouse lungs followed by the assessment of the cellular and humoral immune changes, and histology in recipient lungs.
Aim 2, to determine the role of direct and indirect allorecognition 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, purified lung macrophages and dendritic cells which do not express MHC-II or MHC-I antigens will be instilled into he lungs of recipient mice followed by an assessment of the cellular and humoral immune changes, and histology in recipient lungs.
Aim 4, to determine the role of ICAM-1 and B7 costimulatory molecules in the pathogenesis of lung allograft rejection, donor accessory cells and recipient animals lacking these molecules, will be utilized as recipients, and donors in a murine model which mimicks lung allograft rejection. The significance of this proposal is that it will determine whether allogeneic lung accessory cells mediate the histological and immunological changes associated with lung allograft rejection and the molecular mechanisms involved. Understanding the relative contribution of these accessory cells in the rejection response will facilitate the development of new approaches for therapeutic interventions in the care of lung allograft recipients. These studies will be conducted in the Division of Pulmonary and Critical Care, and Department of Immunology and Microbiology at the Indiana University School of Medicine has committed 80% protected time to Dr. Wilkes to conduct these studies.
