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Tolerance Blockade by Immune Memory

免疫记忆的耐受封锁

基本信息

批准号：
10207614
负责人：
Ronald G Gill
金额：
$ 38.88万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207614
关键词：
Address Alloantigen Allogenic Allograft Tolerance Allografting Animal Model Animals Antigens Autoimmunity B-Lymphocytes Cells Clinical Development Disease Donor person Exposure to Future Goals Hematopoietic Immune Immune Tolerance Immunity Immunologic Memory Impairment Individual Infection Inflammation Intervention Islets of Langerhans Transplantation Licensing Link MHC antigen Memory Modeling Monitor Organ Transplantation Pathway interactions Physiological Process Publishing Report (document)Resistance Route Source T memory cell T-Lymphocyte Testing Tissue Transplantation Translations Transplant Recipients Transplantation Transplantation Tolerance Vaccination Vaccines Virus allograft rejection clinically relevant cross reactivity design experience gammaherpesvirus genetic resistance in vivo isoimmunity mouse model pathogen response restraint

项目摘要

Abstract For many years, animal models have been greatly useful for dissecting basic mechanisms of allograft rejection and tolerance. However, the translation of basic studies to clinical intervention has been an arduous challenge. The majority of published small animal allograft studies utilize relatively young healthy animals, both as transplant donors and recipients. One can argue that these models often do not reflect several features of clinical transplantation that can impair the tolerance process. In response to this dilemma, many more recent studies have focused on identifying key rate-limiting, clinically relevant obstacles to allograft tolerance induction. This proposal focuses on identifying how a particular route of immune memory results in the disruption of tolerance in a mouse model of islet transplantation. The prevailing view of immune memory as a barrier to tolerance is that prior exposure to environmental antigens, pathogens, and vaccination antigens generates a burden of antigen-experienced T and B cells that can spontaneously cross react to allogeneic MHC molecules. However, our recently published studies indicate that vaccine-induced memory with little if any cross-reactivity to donor MHC can nevertheless disrupt tolerance if the donor cells express the vaccine-directed antigen. We refer to this type of reactivity as 'incognito' immune memory simply because it is not readily detected by pre-transplant host monitoring for anti-donor MHC reactivity. As such, this scenario models a common transplant setting in which the donor graft harbors non-MHC antigens that can be recognized by host immunity generated through prior exposure to pathogens, vaccinations, or pre-existing autoimmunity. We posit that this type of common host immunity can be disregarded and yet it can readily impair tolerance induction without any requirement for cross-reactivity to donor MHC antigens. This project will determine the mechanisms of how this form of immune memory disrupts tolerance by addressing the general working model: Non-MHC-directed memory can disrupt tolerance by simultaneous 'linked' recognition of alloantigens and vaccine- or virus-induced antigen specific memory in vivo. Implications of this overall model will be addressed through the following three Specific Aims: Specific Aim 1: Determine the conditions of memory-directed antigen expression required to disrupt tolerance. Specific Aim 2: Determine the impact of memory cells on the activation of naïve, graft reactive T cells. Specific Aim 3: Determine the impact of physiologically relevant host and donor gammaherpesvirus 68 (gHV68) infection on the subsequent capacity to induce transplant tolerance. Taken together, the goal of this project is to dissect how this alternative form of immune memory disrupts tolerance. We propose that understanding how such 'incognito' memory impacts tolerance will identify key target pathways for future intervention and potentially expand how transplant candidates/hosts/recipients are screened for anti-donor immune reactivity prior to transplant.

摘要多年来，动物模型对于解剖同种异体移植物的基本机制非常有用拒绝和宽容。然而，将基础研究转化为临床干预是一项艰巨的任务。挑战.大多数已发表的小动物同种异体移植研究使用相对年轻的健康动物，作为移植捐赠者和接受者。有人可能会说，这些模型往往没有反映几个可能损害耐受过程的临床移植特征。为了应对这一困境，许多最近的研究集中在确定关键的限速，临床相关的障碍，同种异体移植耐受诱导该提案的重点是确定免疫记忆的特定途径如何导致胰岛移植小鼠模型耐受性的破坏。免疫记忆的主流观点作为耐受性的障碍是，先前暴露于环境抗原、病原体和疫苗接种，抗原产生抗原经历的T和B细胞的负荷，这些细胞可以自发地与同种异体MHC分子。然而，我们最近发表的研究表明，疫苗诱导的记忆尽管与供体MHC的交叉反应性很小，但如果供体细胞表达疫苗导向抗原我们将这种反应称为“隐身”免疫记忆，因为它是不容易通过移植前宿主监测抗供体MHC反应性来检测。因此，这种情况模拟了一种常见的移植环境，其中供体移植物含有非MHC抗原，通过先前暴露于病原体、接种疫苗或预先存在的自身免疫我们认为，这种类型的共同宿主免疫力可以忽略，但它可以很容易地不需要与供体MHC抗原交叉反应性而削弱耐受性诱导。这个项目将确定这种形式的免疫记忆如何通过解决免疫耐受性来破坏耐受性的机制。一般工作模型：非MHC指导的记忆可以通过同时“链接”识别来破坏耐受性同种异体抗原和疫苗或病毒诱导的抗原特异性记忆。这一总体影响模型将通过以下三个具体目标来解决：具体目标1：确定条件记忆引导的抗原表达来破坏耐受性。具体目标2：确定记忆细胞对幼稚的移植物反应性T细胞的激活。具体目标3：确定生理相关宿主和供体γ疱疹病毒68（gHV 68）感染对后续能力的影响以诱导移植耐受性。总之，这个项目的目标是剖析这种替代形式免疫记忆会破坏耐受性我们认为，了解这种“隐姓埋名”的记忆如何影响耐受性将确定未来干预的关键目标途径，并可能扩大移植的方式。在移植前筛选候选者/宿主/受体的抗供体免疫反应性。