Pulmonary transplantation is often an effective therapy for otherwise intractable cardiopulmonary disorders. Despite recent technical advances, however, allograft rejection continues to be a frequent cause of morbidity and mortality among lung transplant recipients. The candidate for this award has clinical experience in the care and management of these patients and is now seeking the necessary expertise to continue fundamental investigations of rejection phenomena. The projects described herein will investigate mechanisms of respiratory tract alloreactivity and explore the feasibilities of new modalities to obviate or ameliorate lung transplant rejection. Furthermore, these experiments are formulated to capitalize on the unique expertise available in this laboratory and institution. T cell antigen receptor (TCR) gene expression among graft-infiltrating lymphocytes (GIL) and peripheral blood lymphocytes (PBL) of human lung allograft recipients have been extensively characterized by a sensitive and quantitative RNase assay developed in this laboratory. These data show that T cell repertoires of patients with chronic lung rejection are often highly biased and, in some, the abnormal TCR VP are due to oligoclonal (or monoclonal) proliferations and/or sequestrations. The findings suggest that the severe lung injury of chronic rejection is mediated by a limited number of T cell clones with unique, and readily identifiable, cell surface markers that could be exploited by novel therapies. Longitudinal studies of selected patients will additionally establish whether expansions or contractions of T cell clonotypes are useful indicators of changing clinical conditions (i.e., rejection or infection). We have also successfully induced allotolerance in a murine model of respiratory tract transplantation using intrathymic injections of donor antigen-presenting cells. Ongoing investigations will explore mechanisms and establish the duration of this allotolerance. Finally we will begin a series of studies to develop recombinant gene therapy methodologies that will ultimately result in intrathymic expression of allogeneic (donor) major histocompatibility complex (MHC) antigens. The ability to effect expression of donor MHC in the thymuses of recipients, particularly after intravenous administration, could enable widespread utilization of allotolerance induction in adult humans by minimally invasive means.
