Type 1 Diabetes TrialNet Clinical Center: Effects of Alefacept in New Onset T1D

描述（由申请人提供）：T1D发生在遗传易感个体中，是胰腺β细胞进行性、选择性破坏的结果，主要由自身反应性T细胞介导。该疾病过程导致胰岛素分泌丧失和终身胰岛素依赖。目前还没有完全阻断胰岛自身免疫的治疗方法。我们的长期科学目标是了解T1D的自然史及其分子基础，并实施临床试验，评估预防或改善这种疾病的新策略。该提案的目标有两个：1）继续积极参与研究网络。1型糖尿病TrialNet，参与新干预策略的设计和实施; 2）提出一种新的alefacept干预策略，用于近期发作的T1D患者。我们的中心假设是alefacept将在T1D中具有治疗价值，并缓和导致T1D的破坏性自身免疫过程的永久化，保留β细胞及其胰岛素分泌能力。尝试新的试验靶向T1D中的记忆T细胞有坚实的理由：越来越多的证据将记忆T细胞与糖尿病发展联系起来，而alefacept专门针对这些细胞。它被FDA批准用于治疗患有中度至重度慢性斑块状银屑病的成人患者，这也是一种免疫介导的疾病。重要的是，alefacept具有良好的安全性，没有其他免疫抑制剂的典型副作用，这使得它非常适合用于免疫介导疾病的潜在慢性治疗。我们提出了一项I/II期双盲、随机、安慰剂对照试验，以检验阿法塞将保护新近发作的T1D患者的C肽分泌的假设。重要的是，有越来越多的证据表明记忆T细胞在T1D中的作用，并且记忆隔室可能富含胰岛特异性自身反应性T细胞。我们建议在1年内进行两个疗程，并随访一年。主要代谢结果将是刺激胰岛素分泌，如混合餐耐量试验后通过C肽水平评估的。主要的免疫学结果将是在治疗阶段记忆T细胞的频率降低50 - 60%。 公共卫生相关性：1型糖尿病是由胰腺β细胞的自身免疫性破坏引起的，导致胰岛素分泌丧失和终身胰岛素依赖，不幸的是经常影响儿童和青少年。以前的临床试验表明，干扰这种自身免疫破坏性过程是可能的。如果用阿法赛特治疗能安全地阻止或减缓这种破坏性过程，这将是预防与严重病态并发症相关的终身疾病的一个重大进展。

DESCRIPTION (provided by applicant): T1D occurs in genetically predisposed individuals as a consequence of the progressive, selective destruction of pancreatic beta-cells which is primarily mediated by autoreactive T-cells. The disease process results in loss of insulin secretion and life-long insulin-dependence. At present there is no treatment that fully interdicts islet autoimmunity. Our long-range scientific goals are to understand the natural history of T1D and its molecular basis and implement clinical trials evaluating new strategies to prevent or ameliorate this disease. The objectives of this proposal are twofold: 1) to remain an active participant in the research network. Type 1 Diabetes TrialNet, involved in the design and implementation of new intervention strategies; and 2) to propose a novel intervention strategy with alefacept in individuals with recent onset T1D. Our central hypothesis is that alefacept will have therapeutic value in T1D, and temper the perpetuation of the destructive autoimmune process resulting in T1D, preserving beta-cells and their insulin-secreting capacity. There is a solid rationale for attempting new trials to target memory T cells in T1D: growing evidence links memory T cells with diabetes development, and alefacept specifically targets these cells. It is FDA-approved for the treatment of adult patients with moderate to severe chronic plaque psoriasis, which is also an immune-mediated disease. Importantly, alefacept has an excellent safety profile without the typical side effects of other immunosuppressive agents, which makes it ideally suited for potential chronic treatment of immune-mediated diseases. We propose a phase l/ll double-masked, randomized, placebo-controlled trial to test the hypothesis that alefacept will preserve C-peptide secretion in patients with recent onset T1D. Importantly, there is growing evidence for a role of memory T cells in T1D, and the memory compartment is likely to be enriched in islet-specific autoreactive T cells. We propose two treatment courses during a 1-year period and follow-up for an additional year. The primary metabolic outcome will be stimulated insulin secretion as assessed by C-peptide levels after the mixed meal tolerance test. The primary immunological outcome will be a 50-60% reduction in the frequency of memory T cells during the treatment phases. PUBLIC HEALTH RELEVANCE: Type 1 diabetes is caused by autoimmune destruction of pancreatic beta cells, resulting in loss of insulin secretion and life-long insulin dependence, and unfortunately often affects children and adolescents. Previous clinical trials have shown that it is possible to interfere with this autoimmune destructive process. If treatment with alefacept safely stops or slows this destructive process, it would be a major advance toward the prevention of a lifelong disease associated with significant morbid complications.