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.

抽象的多年以来，动物模型对于剖析合金的基本机制非常有用拒绝和宽容。但是，将基础研究转化为临床干预一直是艰巨的挑战。大多数已发表的小动物同种异体移植研究都使用相对年轻的健康动物，作为移植捐赠者和接受者。有人可以说这些模型通常不会反映几个临床移植的特征，可能会损害公差过程。为了应对这一困境，许多最近的研究重点是识别同种异体移植的关键限制，临床上相关的障碍耐受性诱导。该建议重点是确定特定的免疫记忆途径如何导致小鼠移植的小鼠模型中的公差破坏。免疫记忆的普遍视图作为公差的障碍是事先接触环境抗原，病原体和疫苗接种抗原产生了抗原经验的T和B细胞的燃烧，可以赞助转化为同种异体MHC分子。但是，我们最近发表的研究表明疫苗诱导的记忆几乎没有对供体MHC的交叉反应性，如果供体细胞表达疫苗定向的抗原。我们将这种反应性称为“隐身”免疫记忆仅仅是因为它是移植前宿主监测抗Donor MHC反应性无法轻易检测到。因此，这种情况模型一种常见的移植设置，其中供体移植物具有非MHC抗原，可以是通过事先暴露于病原体，疫苗接种或预先存在的宿主免疫识别自身免疫性。我们肯定的是，这种类型的常见宿主免疫可以被忽略，但可以很容易地降低耐受性诱导，无需对供体MHC抗原的交叉反应性。这个项目将确定这种免疫记忆形式如何通过解决该的机制来破坏公差一般工作模型：非MHC指导的内存可以通过简单的“链接”识别来破坏公差体内抗原和疫苗或病毒诱导的抗原特异性记忆。整体的含义模型将通过以下三个特定目的来解决：具体目标1：确定条件破坏公差所需的记忆指导的抗原表达。特定目标2：确定记忆细胞对幼稚的移植反应性T细胞的激活。特定目标3：确定生理上相关的宿主和供体伽马梅病毒68（GHV68）感染以随后的能力诱导移植耐受性。综上所述，该项目的目标是剖析这种替代形式免疫记忆会破坏容忍度。我们建议理解这种“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，并有可能扩大移植的方式在移植之前，对候选者/宿主/接受者进行抗抑制免疫反应性。