Disruption of Treg-dependent Tolerance by B lymphocytes in Islet Transplantation

项目摘要 尽管临床方法针对T细胞、B细胞和免疫效应分子阻止移植 排斥和延缓自身免疫性疾病的进展，这些疗法不能诱导持久免疫。 当治疗停止时，耐受性作为免疫中介的破坏复发。这次失败是由于不平衡造成的。 在调节和效应器免疫方面，目前还没有一种方法能够解决，尤其是 在像胰岛移植治疗T1D这样的方法中遇到困难，在这种方法中，诱导持久的免疫耐受 在胰岛置换的同时也能治愈。T1D患者移植后胰岛丢失和自身免疫攻击 两者都是由抗胰岛抗体的存在所预示，这种抗体在早期胰岛的标志中是如此重要。 他们定义了新的发病阶段1 T1D。传统上，人们认为这些产品的生产 抗体是T-B合作的标志，导致效应细胞激活。该提案将调查一项 另一种假设认为，B淋巴细胞也直接侵蚀免疫调节细胞功能。在缺席时 在B淋巴细胞中，我们发现倾向于T1D的NOD免疫系统变得对诱导 移植耐受性，这在这一背景下是不可能实现的，以及随后的耐受性 在健康的、非自身免疫的受者中，胰岛移植也得到了加强。这次成功的移植 并不是由于在没有B细胞的情况下失去了效应细胞的特异性，而是与 保护胰岛的树突状细胞数量增加，对免疫治疗的反应恢复。因此，我们有 确定B淋巴细胞是成功的免疫重新编程的关键障碍，它们发挥作用 通过破坏Treg的功能。我们假设B细胞和T细胞在发育过程中通过 抗原特异性(信号1)和共刺激(信号2)相互作用形成Tregs和Tregs的平衡 在某种程度上取决于B细胞的耐受性。在这个提案中，我们将从两个方面来研究这一新范式 目标。在目标1中，我们将确定抗原提呈、获取和组织来源在 利用转基因系统控制和追踪B淋巴细胞和Tregs的相互作用。在……里面 目的2，我们将确定B细胞与Treg的有害接触的机制，包括B细胞的作用 发育，B细胞耐受性，包括无能，以及B和T细胞之间的细胞间相互作用， 调节免疫力。总之，这些目标将揭示B细胞如何阻碍耐受诱导以及这是如何实现的 在胰岛移植中，可以修复屏障以允许诱导免疫耐受。

Project Summary Although clinical approaches directed at T cells, B cells, and immune effector molecules prevent transplant rejection and slow the progression of autoimmune disease, these therapies do not induce durable immune tolerance as immune-mediated destruction recurs when therapy is stopped. This failure is due to an imbalance in regulatory and effector immunity that no current approach has been able to address and is particularly difficult in approaches like islet transplantation for T1D where the induction of durable immune tolerance would be curative alongside islet replacement. Islet loss following transplant and autoimmune attack in T1D are both heralded by the presence of anti-islet antibodies, which are so important in signifying incipient islet injury that they define new onset stage 1 T1D. Traditionally, it has been thought that the production of these antibodies is a sign of T-B collaboration that leads to effector cell activation. This proposal will investigate an alternative hypothesis that B lymphocytes also directly erode immune regulatory cell function. In the absence of B lymphocytes, we find that the T1D-prone NOD immune system becomes susceptible to inducible transplantation tolerance, which is not otherwise achievable in this background, and that tolerance following islet transplantation is also enhanced in healthy, non-autoimmune recipients. This successful transplantation was not due to loss of effector cell specificities in the absence of B cells but instead was associated with an increase in islet-protective Tregs and a recovery in their response to immune therapy. Thus, we have determined that B lymphocytes are the critical barrier to successful immune reprogramming and that they act by disrupting Treg function. We hypothesize that B cells interact with T cells during their development through both antigen-specific (signal 1) and co-stimulatory (signal 2) interactions to shape the balance of Tregs and Teffs in a way that depends on B cell tolerance. In this proposal, we will investigate this new paradigm in two aims. In Aim 1, we will determine the role of antigen presentation, acquisition, and tissue origin on the interaction of B lymphocytes and Tregs using transgenic systems to control and trace their relationships. In Aim 2, we will determine the mechanism of deleterious B cell-Treg contact including the roles of B cell development, B cell tolerance including anergy, and the intercellular interactions between B and T cells that modulate immunity. Together, these aims will reveal how B cells impede tolerance induction and how this barrier may be repaired to permit inducible immune tolerance in islet transplantation.