Mechanistic studies on Listeria infection and inhibition of allograft tolerance

描述（申请人提供）：与心脏和肾脏相比，皮肤、肺和小肠等移植器官具有更强的免疫原性和更强的耐受性诱导。我们推断，移植前一种器官比移植后一种器官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会增强对同种异体移植物的免疫反应，并阻止同种异体移植物的耐受性。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。我们的初步观察表明，心脏移植时单核增生李斯特菌（LM）感染阻止了接受抗cd154单克隆抗体（anti-CD154）和供者特异性输血（DST）的小鼠产生耐受性。lm感染和抗cd154 - DST治疗的受体的排斥反应与同种异体igg和引发的同种异体反应性IFN的产生有关。脾脏中产生-的细胞在CD4-或CD8缺陷小鼠中观察到LM的作用，表明LM感染单独促进了同种异体反应性CD4+和CD8+细胞的启动。我们还观察到移植后60-90天LM感染逆转了抗cd154¿DST诱导的同种异体移植耐受。然而，长期存活的同种异体移植物的排斥反应与同种异体igg的产生或引发的同种异体反应性IFN的存在无关。脾脏中产生-的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与LM阻止诱导耐受性的机制不同。本研究旨在进一步明确LM感染拮抗同种异体移植物耐受性发展和维持的机制。我们提出了两个目标：1：描述LM感染阻止抗cd154介导的耐受诱导的机制。描述LM感染引发耐受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cd154作为诱导耐受性的模型剂，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性模型。这些研究的长期目标是利用从这些研究中获得的信息来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.