Mechanistic studies on Listeria infection and inhibition of allograft tolerance

李斯特菌感染及抑制同种异体移植耐受的机制研究

• 批准号: 7913509
• 负责人: Anita S Chong
• 金额: $ 25.11万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913509
• 关键词: Alloantigen; Allograft Tolerance; Allografting; Bacteria; Bacterial Infections; Bacterial Model; CD8-Positive T-Lymphocytes; Cells; Development; Event; Exposure to; Goals; Graft Rejection; Guanine Nucleotide Dissociation Inhibitors; Heart; Heart Transplantation; Immune response; Immune system; Immunoglobulin G; Infection; Infection prevention; Investigation; Kidney; Listeria monocytogenes; Listeriosis; Lung; Maintenance; Mediating; Modeling; Monoclonal Antibodies; Mus; Organ; Organ Transplantation; Prevention; Production; Resistance; Role; Skin; Small Intestines; Spleen; T-Lymphocyte; Testing; Time; Transfusion; Transplantation; base; immunogenic; immunogenicity; insight; novel strategies; pathogen; prevent

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.

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诱导能力。我们推断，前者的器官移植比后者的移植更有可能导致免疫系统同时暴露在细菌和同种异体抗原之下。基于此，我们假设伴随的细菌暴露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的耐受。作为原理的证明，我们测试了一个模型细菌感染对同种异体移植耐受的发展和维持的影响。我们的初步观察表明，心脏移植时单核细胞增多性李斯特菌(Lm)感染阻止了接受抗CD154单抗(抗CD154)和供者特异性输血(DST)的小鼠的耐受性发展。Lm感染和抗CD154？DST治疗的受者的排斥反应与脾内产生allo-Ig G和预置的同种异体反应性干扰素？细胞有关。在CD4或CD8缺陷小鼠中观察到了LM的作用，这表明LM感染独立地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天的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异体免疫球蛋白的产生或脾中产生同种异体反应性干扰素的细胞的存在无关。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阻止耐受性诱导的机制不同。这项建议旨在进一步确定LM感染对抗同种异体移植耐受的形成和维持的机制。我们提出了两个目标：1：阐明LM感染阻止抗CD154介导的耐受诱导的机制。2：描述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作为模式细菌病原体，抗CD154作为诱导耐受的模式试剂，但我们相信，这些研究获得的见解可能适用于其他病原体和同种异体移植耐受模型。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。