Tolerance Blockade by Immune Memory

摘要 多年来，动物模型在剖析同种异体移植的基本机制方面发挥了重要作用。 拒绝和宽容。然而，将基础研究转化为临床干预一直是一项艰巨的任务 挑战。大多数已发表的小动物同种异体移植研究使用的是相对年轻的健康动物， 无论是作为移植捐赠者还是接受者。人们可以争辩说，这些模型往往没有反映出几个 临床移植可能损害耐受过程的特征。为了应对这一困境，许多人 最近的研究集中在识别同种异体移植的关键限速、临床相关障碍。 耐受性诱导。这项建议的重点是确定一条特定的免疫记忆路径如何导致 胰岛移植小鼠模型中耐受性的破坏。免疫记忆的主流观点 作为耐受性的障碍是事先接触环境抗原、病原体和接种疫苗 抗原产生大量经历过抗原的T和B细胞，它们可以自发地与 同种异体MHC分子。然而，我们最近发表的研究表明，疫苗诱导记忆 如果供体细胞表达MHC，则MHC几乎不会与供体发生交叉反应，但会破坏耐受性 疫苗导向的抗原。我们把这种类型的反应称为‘隐姓埋名’免疫记忆，因为它是 移植前宿主监测抗供体MHC反应性不容易检测到。因此，这个场景 模拟常见的移植环境，其中供者移植物含有非MHC抗原，可以 通过先前接触病原体、接种疫苗或预先存在而产生的宿主免疫识别 自身免疫力。我们假设这种常见的宿主免疫可以被忽略，但它很容易 损伤耐受诱导，不需要与供体MHC抗原发生交叉反应。这个项目 将确定这种形式的免疫记忆如何通过解决 一般工作模式：非MHC定向记忆可以通过同时的“关联”识别来破坏耐受性 体内同种异体抗原和疫苗或病毒诱导的抗原特异性记忆。这一总体上的影响 模式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的抗原表达。具体目标2：确定 记忆细胞对幼稚的激活，移植物反应性T细胞。具体目标3：确定 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 以诱导移植耐受。综上所述，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。我们建议理解这种隐姓埋名的记忆是如何影响的 耐受性将确定未来干预的关键靶向途径，并可能扩大移植的方式 在移植前对候选人/宿主/受者进行抗供者免疫反应筛查。

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.