Immunological Ignorance as an Adjunct to Tolerance

Yale University, New Haven CT

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Abstract

Immunological ignorance occurs if an antigen remains outside secondary lymphoid tissues, the site where[unreadable] mature antigen presenting cells (ARC) activate naive T and B lymphocytes. Although ignorance is an[unreadable] important mechanism by which autoreactive T cells avoid self-antigens, ignorance of transplanted organs is[unreadable] seldom observed. Even allografts that are allowed to recover from the surgical procedure continue to[unreadable] present antigen in the draining lymphoid tissue and undergo either acute or chronic rejection when[unreadable] immunosuppression is withdrawn or upon the transfer of exogenous naive or effector/memory T cells. This[unreadable] suggests that transplantation poses a barrier to immunologic ignorance even after long periods of stable[unreadable] allograft function. Exploring these barriers could provide new strategies that facilitate allograft acceptance[unreadable] and prevent chronic rejection. Therefore, we propose in this component of the PPG to investigate why the[unreadable] immune system does not ignore a 'healed' allograft. The specific aims will focus on two hypotheses that[unreadable] integrate with Projects 1 and 2 of the PPG, respectively: (1) Innate immune activation persists in a "healed"[unreadable] allograft leading to APC maturation, naive T cell activation, and enhanced entry of effector/memory T cells[unreadable] into the graft; and (2) lymphodepletion that often accompanies tolerance-inducing regimens is responsible for[unreadable] continuous recognition of the graft by naive T cells that undergo lymphopenia-induced proliferation (LIP) and[unreadable] transform into memory-like lymphocytes. In specific aim 1, we will investigate what perpetuates the innate[unreadable] immune response to a 'healed' allograft, with emphasis on innate lymphocytes (NK and iNKT cells),[unreadable] neutrophils, the complement system, and direct activation of APCs via TLR-signaling pathways. In specific[unreadable] aim 2, we will investigate the mechanisms responsible for regulating lymphophenia-induced proliferation of[unreadable] naTve T cells, with emphasis on CTLA-4 and TGFb. Understanding these mechanisms would allow us to[unreadable] develop ignorance-based strategies that facilitate allograft acceptance and prevent chronic rejection. This[unreadable] Project is critically dependent on the Histopathology Core for processing and analysis of cardiac[unreadable] allograft samples, quantitating allograft vasculopathy, and phenotyping dendritic cells.