Control of Diabetes by Manipulation of Bc12 Family Members

描述（由申请人提供）：自体和异体反应性T细胞对宿主抗原的有害和不良免疫反应分别是自身免疫和移植的基础和治疗问题。例如，为了有效治疗1型糖尿病（T1D），我们需要：(i)防止或阻止T细胞介导的对胰岛素产生的胰腺β细胞的破坏，或（ii）保护宿主胰岛细胞群或手术提供的替代胰岛，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，以抑制少数有害的T细胞，这些T细胞负责同基因或异体胰岛细胞的破坏。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令，限制大多数适应性免疫细胞的正常和有益行为，以阻止罕见的流氓T细胞。这种方法有三个主要缺点：(1)缺乏特异性；（ii）增加机会性感染和癌症的风险；（三）引起继发性器官损伤和毒性。因此，很明显，我们需要通过寻找新的和创新的方法来做得更好，以控制不常见但有害的自身免疫T细胞，同时保持对病原体和疫苗有益的记忆T细胞，以及对抗新遇到的病原体所需的na - ve 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想要的T细胞。我们发现，当T细胞在它们的三种主要状态（na - ve， activated和memory）之间转换时，它们表现出不同的动态模式，支持和抗凋亡的Bcl-2家族成员具有基本的生物学后果，例如，设置na - ve T细胞的初始水平，扩大激活的效应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（如Bim、Bax和Bak）和抗凋亡（如Bcl-2、Bcl-xL和Mcl-1） Bcl-2家族成员之间的动态形成了一个控制T细胞个体群体存活的调控回路。由于这些独特的表达模式，激活T细胞和记忆T细胞对凋亡也表现出不同的敏感性，其中活化T细胞最敏感。最近，我们利用Bcl-2家族成员的小分子拮抗剂根据T细胞的激活状态靶向T细胞进行破坏。这些拮抗剂发挥其特异性是基于Bcl-2家族成员的细胞死亡结构域BH3之间的细微结构差异。我们的初步数据表明，体内使用一种BH3抑制剂完全保护小鼠在糖尿病源性CD4+ T细胞过继转移后免受糖尿病的影响，而ABT-737则显著减少抗原特异性CD8+ T细胞记忆细胞。重要的是，激活T细胞对BH3拮抗剂的选择性超敏反应提示了一种创新的方法来解决自身反应性或不需要的T细胞反应问题。我们认为免疫抑制疗法应该彻底改变。与其对所有T细胞进行广泛而生硬的免疫抑制，不如在体内对不需要的自身反应性和同种异体反应性T细胞进行急性激活，然后使用特异性bh3结构域拮抗剂对细胞凋亡进行差异化靶向。最终的结果是，在清除不受欢迎的流氓T细胞的同时，保留有益的免疫。为此，我们提出以下具体目标：目的1：确定特异性新型小分子BH3拮抗剂在CD8+ T细胞中建立功能性T细胞对同基因胰岛的耐受性，同时保持na -和记忆T细胞功能的功效。目的2：确定特异性新型小分子BH3拮抗剂在CD4+ T细胞中建立对同基因胰岛的功能性T细胞耐受性，同时保持na -和记忆T细胞功能的功效。

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.