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.

抽象的多年来，动物模型对于剖析同种异体移植的基本机制非常有用然而，将基础研究转化为临床干预是一项艰巨的任务。大多数已发表的小动物同种异体移植研究都利用相对年轻的健康动物，可以说，无论是作为移植捐献者还是接受者，这些模型通常都不能反映多种情况。临床移植的特点可能会损害耐受过程。针对这种困境，许多人提出了解决方案。最近的研究重点是确定同种异体移植的关键限速、临床相关障碍该提案的重点是确定免疫记忆的特定途径如何产生。胰岛移植小鼠模型中耐受性的破坏免疫记忆的流行观点。耐受性的障碍是先前接触环境抗原、病原体和接种疫苗抗原会产生大量经历过抗原的 T 细胞和 B 细胞，这些细胞可以自发地交叉反应然而，我们最近发表的研究表明疫苗诱导记忆。与供体 MHC 几乎没有交叉反应性，但如果供体细胞表达我们将这种类型的反应称为“隐身”免疫记忆，因为它是移植前宿主监测抗供体 MHC 反应性不易检测到，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，可以通过先前接触病原体、接种疫苗或预先存在的病原体而产生的宿主免疫力所识别我们认为这种常见的宿主免疫可以被忽视，但它很容易被忽视。损害耐受诱导，无需与供体 MHC 抗原发生交叉反应。将通过解决以下问题来确定这种形式的免疫记忆如何破坏耐受性的机制一般工作模型：非 MHC 定向记忆可以通过同时“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体内抗原特异性记忆的影响。模型将通过以下三个具体目标来解决：具体目标 1：确定条件破坏耐受性所需的记忆导向抗原表达的具体目标 2：确定破坏耐受性的影响。记忆细胞对初始移植物反应性 T 细胞的激活具体目标 3：确定记忆细胞的影响。生理相关宿主和供体伽马疱疹病毒 68 (gHV68) 感染对后续能力的影响总而言之，该项目的目标是剖析这种替代形式是如何产生的。我们建议了解这种“隐身”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对候选者/宿主/接受者进行抗供体免疫反应性筛查。