Mechanistic studies on Listeria infection and inhibition of allograft tolerance

描述（由申请方提供）：与心脏和肾脏相比，皮肤、肺和小肠等移植器官的免疫原性更强，对耐受诱导的抗性更强。我们推断，前一种器官的移植比后一种器官的移植更可能导致免疫系统同时暴露于细菌和同种异体抗原。基于此，我们假设，同时暴露于细菌增强了对同种异体移植物的免疫反应，并防止了同种异体移植物耐受。作为原理的证明，我们测试了模型细菌感染对同种异体移植物耐受性的发展和维持的影响。我们的初步观察结果表明，单核细胞增生李斯特菌（LM）感染时，心脏移植防止耐受性的发展，在小鼠接受抗CD 154单克隆抗体（抗CD 154）供体特异性输血（DST）。在LM感染和抗CD 154 <$DST治疗的受者中，排斥反应与异源IgG和致敏同种异体反应性IFN？在脾脏中产生细胞。在CD 4-或CD 8-缺陷小鼠中观察到LM的作用，表明LM感染独立地促进同种异体反应性CD 4+和CD 8+细胞的引发。我们还观察到移植后60-90天的LM感染逆转了抗CD 154 <$DST诱导的同种异体移植物耐受。然而，长期存活的同种异体移植物的排斥反应与异源IgG的产生或致敏的同种异体反应性IFN？在脾脏中产生细胞。这些观察结果使我们假设LM感染逆转已建立的耐受性的机制不同于LM阻止诱导耐受性的机制。该建议旨在进一步确定LM感染拮抗同种异体移植耐受的发展和维持的机制。我们提出了两个目标：1：阐明LM感染阻止抗CD 154介导的耐受诱导的机制。2：阐明LM感染加速耐受同种异体移植物排斥反应的机制。虽然这些研究使用LM作为模型细菌病原体和抗CD 154作为诱导耐受的模型药物，但我们相信从这些研究中获得的见解可能适用于其他病原体和同种异体移植物耐受模型。这些研究的长期目标是利用从这些研究中获得的信息开发新的方法来降低移植器官的免疫原性，并促进诱导和维持同种异体移植耐受。

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.