Deconstructing B cell transplantation tolerance

摘要/摘要 移植耐受，一种免疫抑制可以停止，而移植物仍有功能的状态， 是临床移植领域的一个主要目标，因为它承诺减少副作用、成本和非依从性。 与目前需要终身免疫抑制相关的后果。容忍度可以 在罕见的同种异体肾移植受者中自发实现，而在肝移植受者中更常见。 在某些情况下，耐受性是稳定的，而在另一些情况下，同种异体移植最终失败。不断涌现的数据引导我们 假设强大的外周诱导移植耐受依赖于多个冗余细胞- 控制同种异体反应性T和B细胞的内在和外在机制。本提案的重点是定义 控制同种异体反应B细胞的机制。这一重点建立在大量的实验和临床基础上。 有数据表明，供者特异性抗体(DSA)是长期接受移植物的独立障碍，而且临床上 观察到，耐受患者体内抗体的产生最终导致同种异体移植排斥反应。完毕 在过去的几年里，我的实验室一直专注于追踪内源性同种异体反应B细胞的命运 移植排斥和耐受性。在这里，我们建议建立在我们令人兴奋的初步观察的基础上 在小鼠心脏移植耐受模型中制作的供者特异性B细胞并未完全删除，但 获得一种阻止其分化为抗体分泌细胞的细胞自主功能障碍状态 这对T细胞的帮助有抵抗力。然而，这些耐受细胞并不是完全惰性的，值得注意的是，它们是 能够以供者特有的方式抑制幼稚的B细胞。我们建议定义：目标1.活体细胞 对供者反应性B细胞的内在耐受的要求；目标2.维持供者-反应B细胞的机制 特异性B细胞固有耐受性和防止其发展为抗体分泌细胞； 耐受性B细胞介导抑制的机制和后果。我们预计，在完成 这些研究将为导致和维持B细胞耐受的新机制提供洞察力。 区分耐受性B细胞和幼稚或效应/记忆B细胞的生物标志物，以及潜在的治疗 控制移植受者同种异体移植物特异性抗体反应的目标。

Summary/Abstract Transplantation tolerance, a state in which immunosuppression can be stopped while grafts remain functional, is a major goal in clinical transplantation field as it promises to reduce side effects, costs and non-adherence consequences associated with the current need for life-long immunosuppression. Tolerance can be spontaneously achieved in rare recipients of kidney allografts and more frequently in liver transplant recipients. In some cases tolerance is stable, while in others the allografts eventually fail. Emerging data have led us to hypothesize that robust peripherally induced transplantation tolerance depends on multiple redundant cell- intrinsic and -extrinsic mechanisms to control alloreactive T and B cells. This proposal focuses of defining the mechanisms that control alloreactive B cells. This focus is based on considerable experimental and clinical data that donor-specific antibody (DSA) is an independent barrier to long-term graft acceptance, and clinical observation that the development of antibodies in tolerant patients leads ultimately to allograft rejection. Over the past few years, my laboratory has focused on tracing the fate of endogenous alloreactive B cells in transplantation rejection and tolerance. Here, we propose to build on our exciting preliminary observations made in a mouse model of cardiac allograft tolerance that donor-specific B cells are not completely deleted but acquire a cell-autonomous dysfunctional state that prevents their differentiation into antibody-secreting cells and that is resistant to T cell help. However, these tolerant cells are not completely inert and, remarkably, are able to suppress naïve B cells in a donor-specific manner. We propose to define the: Aim 1. in vivo cellular requirements for donor-reactive B cells to become intrinsically tolerant; Aim 2. mechanisms maintaining donor- specific B cell-intrinsic tolerance and preventing their development into antibody-secreting cells; Aim 3. Mechanisms and consequences of tolerant B cell-mediated suppression. We anticipate that the completion of these studies will provide insights into novel mechanisms that result in and maintain B cell tolerance, biomarkers that distinguish tolerant B cells from naïve or effector/memory B cells, and potential therapeutic targets for controlling allograft-specific antibody responses in transplant recipients.