This application is for a Mentored Patient-Oriented Research Career Development Award entitled, ?The impact of tissue resident memory T cells on chronic rejection after lung transplantation?, submitted by Dr. Mark Snyder, an Assistant Professor of Medicine and Immunology within the Division of Pulmonary, Allergy, and Critical Care Medicine at the University of Pittsburgh, and member of the Starzl Transplantation Institute. The short-term goals outlined in this submission are designed to help the applicant achieve his long-term objective of becoming an independent investigator and leader in the field of human lung immunology research. These short-term goals include (1) advancing knowledge base related to both adaptive and innate immunity, (2) expansion of both technical and analytic tools required to effectively perform translational immunology research, and (3) development of leadership skills required to run a productive human immunology laboratory. The central objective of this research proposal is to investigate the impact of allograft tissue resident memory T cell (TRM) persistence and generation on the risk of developing bronchiolitis obliterans syndrome, the major phenotypic presentation of chronic lung allograft dysfunction (CLAD). CLAD affects up to 50% of lung transplant survivors by 5 years after transplantation and is associated with early mortality and substantial morbidity. The mechanism of CLAD remains undefined but is believed to be a T cell-mediated process. Antecedent acute cellular rejection (ACR) and infection, both T cell mediated processes, are associated with the ultimate development of CLAD. The applicant?s prior work, recently published in Science Immunology, shows that donor TRM persistence and recipient TRM generation within the lung allograft are associated with both ACR and infections. Furthermore, unpublished preliminary data show a trend towards early development of CLAD in those patients with rapid allograft population of recipient TRM. With this proposal, the applicant expands on this prior work with the following specific aims (1) Define the relationship between recipient TRM generation in the lung allograft and the risk of early CLAD (within 2 years of transplantation), (2) Determine the alloreactive potential and pathogen specificity of recipient-derived allograft TRM, and (3) Identify the relationship between T cell receptor (TCR) clonal diversity and gene expression among recipient allograft TRM and CLAD. The primary hypothesize is that recipient TRM accumulation will be associated with early-onset CLAD and that recipient TRM will be composed of an expanded population of T cells with high allo-reactive potential. To accomplish these aims, the applicant will employ his previously published method of isolating donor and recipient TRM from the bronchoalveolar lavage of lung transplant recipients longitudinally. Cox-proportional hazard model, adjusting for known confounders will be performed to test the exposure (early proportional decline in donor TRM compared to recipient TRM) as it relates to our outcome of early CLAD. Mixed lymphocyte reactions and single-cell TCR sequencing will be performed to determine TRM alloreactivity and clonality.
Median survival after lung transplant is less than six years, largely due to a high incidence of chronic rejection affecting up to 50% of survivors by five years after transplantation. Donor tissue resident memory T cells (TRM) persist within the allograft after transplantation, and recipient TRM are generated; the ratio of these two populations is associated with short-term clinical outcomes. This proposal will test the relationship between donor TRM persistence and recipient TRM generation on the risk of premature chronic rejection after lung transplantation, with the goal of discovering new therapeutic targets in the pathogenesis of rejection.
