Mechanistic studies on Listeria infection and inhibition of allograft tolerance

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DESCRIPTION (provided by applicant): Transplanted organs such as the skin, lung and small bowel are more immunogenic and more resistant to tolerance induction than the heart and kidney. We reasoned that transplantation of the former organs would more likely result in the concurrent exposure of the immune system to bacteria and alloantigens than would transplantation of the latter. Based on that, we hypothesized that the concomitant exposure to bacteria enhances the immune response to the allograft and prevents allograft tolerance. As a proof of principle, we tested the effect of a model bacterial infection on the development and maintenance of allograft tolerance. Our preliminary observations indicate that Listeria monocytogenes (LM) infection at the time of heart transplantation prevented the development of tolerance in mice receiving anti-CD154 monoclonal antibodies (anti-CD154) ¿ donor-specific transfusion (DST). The rejection in LM-infected and anti-CD154 ¿ DST- treated recipients was associated with the production of allo-IgG and primed, alloreactive IFN?-producing cells in the spleen. The effect of LM was observed in either CD4- or CD8-deficient mice, suggesting that LM infection independently facilitated the priming of alloreactive CD4+ and CD8+ cells. We also observed that LM infection on days 60-90 post-transplantation reversed allograft tolerance induced by anti-CD154 ¿ DST. However, the rejection of long-term surviving allografts was not associated with the production of allo-IgG or the presence of primed, alloreactive IFN?-producing cells in the spleen. These observations led us to hypothesize that the mechanisms by which LM infection reverses established tolerance differ from the mechanisms by which LM prevents the induction of tolerance. This proposal aims at further defining the mechanisms by which LM infection antagonizes the development and maintenance of allograft tolerance. We have proposed two aims: 1: Delineate the mechanisms by which LM infection prevents anti-CD154-mediated induction of tolerance. 2: Delineate the mechanisms by which LM infection precipitates the rejection of tolerant allografts. While these investigations use LM as a model bacterial pathogen and anti-CD154 as the model agent for inducing tolerance, we believe that the insights gained from these studies will likely be applicable to other pathogens and models of allograft tolerance. The long-term goal of these investigations is to use the information gained from these studies to develop new approaches for reducing the immunogenicity of transplanted organs, and for facilitating the induction and maintenance of allograft tolerance.