Control of Diabetes by Manipulation of Bc12 Family Members

描述（由申请人提供）：自身和同种异体反应性T细胞对宿主抗原的有害和不期望的免疫应答分别是自身免疫和移植中的基本和治疗问题。例如，为了有效治愈1型糖尿病（T1 D），我们需要：（i）防止或停止T细胞介导的对产生胰岛素的胰腺β细胞的破坏，或（ii）保护宿主胰岛细胞团或经血管供应的替代胰岛免受抗原特异性T细胞的破坏。迄今为止，这些目标仍未实现。虽然新的非甾体T细胞免疫抑制药物已经取得了进展，但潜在的策略仍然是全面抑制所有T细胞介导的免疫，以抑制负责同基因或同种异体胰岛细胞破坏的少数有害效应T细胞。这种广泛的抑制方法虽然暂时有效，但相当于宣布免疫戒严，减少大多数适应性免疫细胞的正常和有益作用，以阻止罕见的流氓T细胞。这种方法有三个主要缺点：（i）缺乏特异性;（ii）增加机会性感染和癌症的风险;（iii）引起继发性器官损伤和毒性。因此，很明显，我们需要找到新的和创新的方法来控制不常见的，但有害的自身免疫T细胞，同时保持有益的记忆T细胞对病原体和疫苗以及对抗新遇到的病原体所需的幼稚T细胞。我们相信我们有一种新的方法来特异性靶向体内不需要的T细胞。我们发现，随着T细胞在三种主要状态-幼稚，激活和记忆-之间过渡，它们表现出促凋亡和抗凋亡Bcl-2家族成员的独特和动态模式，这些模式具有基本的生物学后果，例如，设置幼稚T细胞的初始水平，扩增激活的效应T细胞，恢复激活后的稳态，并增强记忆T细胞的长期存活。因此，促凋亡（例如，Bim、Bax和巴克）和抗凋亡（例如，Bcl-2 Bcl-xL和Mcl-1）Bcl-2家族成员形成控制单个T细胞群体存活的调节回路。由于这些独特的表达模式，幼稚、活化和记忆T细胞也表现出对凋亡的不同敏感性，其中活化T细胞最敏感。最近，我们已经使用Bcl-2家族成员的小分子拮抗剂来靶向T细胞，以基于其活化状态进行破坏。这些拮抗剂基于Bcl-2家族成员的细胞死亡、BH 3结构域之间的细微结构差异发挥其特异性。我们的初步数据表明，在体内治疗一个BH 3抑制剂完全保护小鼠从糖尿病过继转移致糖尿病的CD 4 + T细胞，而ABT-737显着减少抗原特异性CD 8 + T细胞记忆细胞。重要的是，活化T细胞对BH 3拮抗作用的选择性超敏反应表明了攻击自身反应性或不需要的T细胞应答问题的创新手段。我们认为免疫抑制疗法应该彻底改变。不是使用所有T细胞的广泛和钝的免疫抑制，而是不需要的自身和同种异体反应性T细胞应该在体内被急性激活，然后使用特异性BH 3结构域拮抗剂差异靶向凋亡。净效应将是保留有益的免疫力，同时清除不受欢迎的流氓T细胞。为此，我们提出了以下具体目标：目标1：确定特定的新型小分子BH 3拮抗剂在建立功能性T细胞对同源胰岛的耐受性同时保留CD 8 + T细胞中的幼稚和记忆T细胞功能方面的功效。目标二：确定特异性新型小分子BH 3拮抗剂在建立功能性T细胞对同源胰岛的耐受性同时保留CD 4 + T细胞中的幼稚和记忆T细胞功能方面的功效。

DESCRIPTION (provided by applicant): The deleterious and undesirable immune response by auto- and allo-reactive T cells to host antigens is the fundamental and therapeutic problem in autoimmunity and transplantation, respectively. For example, to impart an effective cure for type 1 diabetes (T1D), we would need to: (i) prevent or halt the T cell-mediated destruction of insulin-producing, pancreatic beta cells, or (ii) preserve the host islet cell mass or surgically-supplied replacement islets, from destruction by antigen- specific T cells. To date, these goals remain unfulfilled. While progress has been made with new non-steroidal T cell immunosuppressive drugs, the underlying strategy remains global suppression of all T cell-mediated immunity to inhibit the few detrimental effector T cells responsible for syngeneic or allogeneic islet cell destruction. This broad inhibitory approach, while temporally effective, is the equivalent of declaring immunologic martial law, curtailing the normal and beneficial actions of most adaptive immune cells in order to stop the rare rogue T cell. This approach has three major drawbacks: (i) it lacks specificity; (ii) it increases the risks of opportunistic infections and cancers; and (iii) it causes secondary organ damage and toxicity. Thus, it is clear that we need to do better by finding novel and innovative means of controlling infrequent, yet injurious, autoimmune T cells while maintaining beneficial memory T cells to pathogens and vaccines and na¿ve T cells needed to combat newly encountered pathogens. We believe we have a novel approach to the specific targeting of unwanted T cells in vivo. We find that as T cells transition between their three major states - na¿ve, activated and memory - they exhibit distinct and dynamic patterns of pro- and anti-apoptotic Bcl-2 family members that have fundamental biologic consequences, for example, setting the initial levels of na¿ve T cells, expanding activated effector T cells, restoring post-activation homeostasis, and potentiating long-term survival of memory T cells. Thus, the dynamism between pro-apoptotic (e.g., Bim, Bax, and Bak) and the anti-apoptotic (e.g., Bcl-2 Bcl-xL, and Mcl-1) Bcl-2 family members forms a regulatory circuit that controls the survival of individual populations of T cells. Owing to these unique expression patterns, na¿ve, activated, and memory T cells also exhibit differential sensitivity to apoptosis, with activated T cells being most sensitive. Recently, we have used small-molecule antagonists of Bcl-2 family members to target T cells for destruction based on their activation state. These antagonists exert their specificity based on the subtle structural differences among the cell-death, BH3, domains of Bcl-2 family members. Our preliminary data demonstrate that in vivo treatment with one BH3 inhibitor completely protects mice from diabetes following adoptive transfer of diabetogenic CD4+ T cells, while ABT-737 dramatically reduces antigen-specific CD8+ T cell memory cells. Importantly, the selective hypersensitivity of activate T cells to BH3 antagonism suggests an innovative means of attacking the problem of autoreactive or unwanted T cell responses. We believe immunosuppression therapy should be turned on its head. Rather than using broad and blunt immunosuppression of all T cells, unwanted auto- and allo-reactive T cells should be acutely activated, in vivo, and then differentially targeted for apoptosis using specific BH3-domain antagonists. The net effect would be to spare beneficial immunity, while purging undesirable rogue T cells. To this end, we propose the following specific aims: Aim 1: To determine the efficacy of specific novel small-molecule BH3 antagonists in establishing functional T cell tolerance to syngeneic islets while preserving na¿ve and memory T cell function in CD8+ T cells. Aim 2: To determine the efficacy of specific novel small-molecule BH3 antagonists in establishing functional T cell tolerance to syngeneic islets while preserving na¿ve and memory T cell function in CD4+ T cells.