Recent discoveries by this PPG research team in clinical lung transplantation, idiopathic pulmonary flbrosis and cardiac atherosclerosis suggest that THI 7 T cells specific for epitopes of the minor collagen type V [col(V)] may be a common feature of fibro-obliterative diseases of airways and vasculature. Neariy 80% of lung transplants and 50% of heart transplants will succumb to chronic fibro-obliterative disease [BOS and CAV] over a 10 year period. The goal of this project is to test the hypothesis that collagen V plays a central role in chronic rejection of both heart and lung transplants. We will identify its immunodominant T cell epitopes , analyze the mechanisms of immunopathology mediated by col(V)-specific IL17-producing T cells, and determine if suppression by donor HLA-specific or col(V)-specific Treg cells can halt the progression of an airway or vascular occlusive lesion. We propose 4 specific aims: first, we will identify which col (V) peptides drive the CD4 T cell response of col(V)-sensitized individuals in 3 different class II contexts: human HLA-DR1, and 17, and mouse IA. We will then use these peptides to create class ll-peptide tetramers that react specifically with cognate pMHC-specific CD4 T cells (Aim 1). T cell cloning, both conventional &tetramer-assisted, will be used to identify, and characterize antigen- specific CD4 T cells and to study their interaction with APC and fibrillar collagen. We will compare col (V)-specific THI7 and TT-specific THI cellular immune responses in mice and humans (Aim 2).
In Aim 3, MHC-I &MHC ll/peptide tetramers, DTH, ELISPOT, intracellular cytokine and multiplex cytokine arrays will be used to trace the emergence of allo-specific and col(V)-specific T cells in mouse heart allograft models of chronic allograft vasculopathy [CAV], using atherosclerosis-prone, APO-e deficient and wt B6 mice as recipients. We will also explore the natural history of a pathogenic col(V)-specific T cell response using epitope-specific probes in non-transplanted, high-fat diet-fed APO-e mice. To determine if overexpression ofthe ?1(V) chain is the driving force in TH17 -mediated flbro-obliterative disease, will also test ?2(V)-deflcient and epitope-modified ?1(V) Tg mice [generated in project 1] as heart transplant donors and recipients (Aim 3). Finally, we will investigate the role of Treg cells in blocking or reversing allo-to-auto/col(V) epitope spreading in a study of human heart and lung transplant recipients (Aim 4), and by tolerizing mice to col(V) prior to heart allografting (Aim 3). Our T cell studies will be bolstered by the serum col V -speciflc IgG analysis in project 3, and will make extensive use of transgenic and immunopatholgy cores.
The Studies proposed will advance our understanding of the T cells that cause blockage of vessels and airways in chronic rejection of organ transplants. The knowledge gained will be used to design strategies to prevent graft loss and promote transplant acceptance.
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