Collagen a 1 (v) Epitope-Specific TH17 Cells in Heart and Lung Transplantation

Indiana University Indianapolis, Indianapolis IN

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Abstract

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.