Control of Diabetes by Manipulation of Bc12 Family Members

描述(申请人提供)：自身和异体反应性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本和治疗问题。例如，要有效治愈1型糖尿病(T1D)，我们需要：(I)防止或停止T细胞介导的对产生胰岛素的胰岛β细胞的破坏，或(Ii)保护宿主胰岛细胞团或手术提供的替代胰岛，使其免受抗原特异性T细胞的破坏。到目前为止，这些目标仍然没有实现。虽然在新的非类固醇T细胞免疫抑制药物方面取得了进展，但潜在的策略仍然是全局抑制所有T细胞介导的免疫，以抑制少数负责同种或同种异体胰岛细胞破坏的有害效应T细胞。这种广泛的抑制方法虽然在短期内有效，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活动，以阻止罕见的无赖T细胞。这种方法有三个主要缺点：(I)缺乏特异性；(Ii)它增加了机会性感染和癌症的风险；(Iii)它导致继发性器官损伤和毒性。因此，很明显，我们需要做得更好，找到新的和创新的方法来控制罕见的、但具有伤害性的自身免疫T细胞，同时保持有益的对病原体和疫苗的记忆T细胞以及对抗新遇到的病原体所需的NA？我们相信我们有了一种新的方法来在体内特异性地靶向不想要的T细胞。我们发现，当T细胞在其三个主要状态-NAVE、ACTIVATED和Memory之间转换时，它们表现出不同的、动态的促凋亡和抗凋亡的Bcl2家族成员的模式，这些模式具有基本的生物学后果，例如，设定NAVE T细胞的初始水平，扩大激活的效应性T细胞，恢复激活后的动态平衡，以及增强记忆性T细胞的长期存活。因此，促凋亡(如Bim、Bax和Bak)和抗凋亡(如Bcl2、Bclxl和Mcl-1)Bcl2家族成员之间的动态形成了一个调控电路，控制着单个T细胞群体的生存。由于这些独特的表达模式，NA细胞、激活T细胞和记忆T细胞对凋亡也表现出不同的敏感性，其中激活的T细胞最敏感。最近，我们利用Bcl2家族成员的小分子拮抗剂，根据T细胞的激活状态来靶向破坏T细胞。这些拮抗剂基于细胞死亡、BH3、Bc l-2家族成员结构域之间的细微结构差异而发挥其特异性。我们的初步数据显示，体内用一种BH3抑制剂治疗完全保护过继转移糖尿病原性CD4+T细胞后的小鼠，而ABT-737显著减少抗原特异性CD8+T细胞记忆细胞。重要的是，激活的T细胞对BH3拮抗剂的选择性超敏表明了一种解决自身反应或不想要的T细胞反应问题的创新方法。我们认为免疫抑制疗法应该彻底改变。与其广泛而迟钝地对所有T细胞进行免疫抑制，不需要的自体和异体反应性T细胞应该在体内被敏锐地激活，然后使用特定的BH3结构域拮抗剂进行差异性的靶向凋亡。净效果将是节省有益的免疫力，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：目的1：确定新型小分子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，同时保留NA和记忆性T细胞功能的效果。目的：研究新型小分子BH3受体拮抗剂在建立功能性T细胞对同基因胰岛的耐受性的同时，在维持CD4+T细胞的NA和记忆性T细胞功能方面的作用。

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.