Lung transplantation is the only definitive therapy for many forms of endstage lung disease, but chronic rejection remains the major impediment to the long term survival of the lung transplant recipient. Allthough anti-donor (allo-)T and B cell immunity is known to be involved in the rejection response, the co-POIs of this Program have reported that T cell-mediated autoimmunity to a minor collagen, type V collagen [col(V)], is the major risk factor for chronic rejection, known as obliterative bronchiolitis/bronchiolitis obliterans syndrome, which is the leading cause of death in lung transplant recipients. In addition, the co-PIs have reported that anti-col(V) humoral immunity is the major risk factor for primary graft dysfunction (PGD) which is the leading cause of early death post transplantation and a risk factor for acute rejection and OB/BOS. IL-17A produced by col(V)-reactive T cells and known to key roles in autoimmune disease, also has a key role in col(V)-reactive T cell-mediated OB and PGD. However, the role of IL-17A in stimulating anti-col(V) antibody responses, and the eptitopes recognized by these antibodies are unknown. In addition, the role of macrophages, reported to have a central role in IL-17A induction, is unknown. This application tests the hypothesis that IL-17A induced anti-col(V) humoral immunity contributes to the pathogenesis of acute rejection and OB by examining the following specific aims: 1. Determine the epitopes recognized by anti-col(V) producing B cells in patients post lung transplantation, as well as the pre-transplant conditions associated with this response.
Aim 2. Determine if anti-col(V) antibody production is 1L-17A dependent and if IL-17A facilitates anti-col(V) antibody mediated pathology in lung transplants.
Aim 3. Determine if macrophages are the antigen presenting cells responsible for stimulating anti-col(V) humoral immunity.
Aim 4. Determine if col(V)-induced tolerance will prevent 1L-17A production and anti-col(V) antibody synthesis.
This application will determine the role of antibodies to col(V), an autoantigen, in the pathogenesis of lung transplant rejection. In addition, these studies will provide greater understanding of the role of autoimmunity to col(V) in the rejection response. The objective of these studies is to identify potential targets for therapeutic intervention to prolong the life of the lung transplant patient.
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