Low-dose IL-2 in Established T1D

1型糖尿病（T1D）是一种慢性自身免疫性疾病，导致胰腺β细胞和胰岛素的损失 分泌物抑制自身免疫和保护胰岛细胞的尝试已经恢复了适度的临床疗效， 在强度和持续时间上。许多试验涉及全身性免疫抑制和/或各种免疫抑制剂的消耗。 免疫细胞类型，或短期治疗，由于慢性性质，可能无法提供持续的益处 胰岛自身免疫;然而，慢性免疫抑制受到安全性问题的限制。有必要 提供免疫调节并可长期给予的治疗方法， 自身免疫重要的是开发具有抗原特异性的疗法，以增强安全性、效力和安全性。 疾病相关性。细胞因子白细胞介素-2（IL-2）对于效应T细胞应答是必需的，但也对于免疫应答是必需的。 调节性T（Treg）细胞是自我耐受的关键。在几个国家进行的低剂量IL-2临床试验 免疫介导疾病报道了与增强的Treg功能相关的显著临床益处， 安全性能极佳。我们已经证明，人CD4 Treg细胞对低剂量IL-10的敏感性增加。 2与效应T细胞（Teff）相比，在体外，并揭示了一些机制，IL-2可以 当以低剂量给予T1D患者时，促进Treg功能和免疫调节，如在 第一个T1D试验，其设计目的不是测试对胰岛素分泌的影响。我们现在提出一个 一项研究低剂量IL-2作为T1D治疗剂及其治疗机制的多中心临床试验 行动上我们将入组12 - 21岁的确诊T1D患者（持续时间4 - 12个月）;大多数患者符合 诊断后至少2年的C肽合格性标准，并在该人群中证明获益 将通过扩大治疗窗口来影响该领域。受试者将被随机分配至安慰剂组， 或低剂量IL-2治疗1年或2年。主要假设是低剂量IL-2治疗将 是安全的，将保持胰岛素分泌和增加Treg比例。这项试验将利用T1D 需要每天多次注射胰岛素，因此患者用关键的T1D自身抗原免疫自己。 我们假设胰岛素治疗通过诱导胰岛素特异性Treg细胞与低剂量IL-2协同作用。这 结果将支持利用IL-2与抗原的组合来促进抗原/疾病特异性免疫 调节自身免疫性疾病。该研究有三个具体目标：目标1：确定疗效和 低剂量IL-2治疗已确诊的T1D患者的安全性。主要临床和机制 目的是低剂量IL-2在维持胰岛素分泌和改善Treg比例方面的功效， 与安慰剂相比。目的2：确定T1D患者的反应机制和生物标志物 通过研究免疫稳态、IL-2R信号传导、基因表达、 表达和T细胞代谢。目标3。评估低剂量IL-2治疗降低 自身反应性CD4和CD8 T细胞，并增加胰岛素特异性T细胞。这些数据将与以下因素的影响有关： 治疗对血清细胞因子水平和TCR库的影响。

Type 1 diabetes (T1D) is a chronic autoimmune disease resulting in loss of pancreatic ß-cells and insulin secretion. Attempts to suppress autoimmunity and preserve ß-cells have returned modest clinical efficacy, both in magnitude and duration. Many trials involved generalized immunosuppression and/or depletion of various immune cell types, or short course therapies, which may not afford sustained benefit given the chronic nature of islet autoimmunity; yet chronic immunosuppression is limited by safety concerns. There is a need for therapies that afford immunomodulation and can be given chronically with high margins of safety to treat islet autoimmunity. It is important to develop therapies with antigen specificity, for enhanced safety, potency and disease relevance. The cytokine Interleukin-2 (IL-2) is essential for effector T cell responses, but also for regulatory T (Treg) cells that are key to self-tolerance. Clinical trials with low-dose IL-2 conducted in several immune-mediated diseases report significant clinical benefit associated with enhanced Treg function, with an excellent safety profile. We have shown that human CD4 Treg cells have heightened sensitivity to low-dose IL- 2 compared to effector T cells (Teff), in vitro, and uncovered some of the mechanisms by which IL-2 could promote Treg function and immune regulation when given at low doses to patients with T1D, as observed in the first T1D trial, which was not designed to did not test effects on insulin secretion. We now propose a multicenter clinical trial to investigate low-dose IL-2 as a therapeutic agent in T1D and its mechanisms of action. We will enroll 12-21 year-old patients with established T1D (4-12 months duration); most patients meet C-peptide eligibility criteria for at least 2 years following diagnosis and demonstrating benefit in this population would impact the field by expanding the therapeutic window. Participants will be randomized to placebo for 2 years, or low-dose IL-2 therapy for either 1 or 2 years. The primary hypothesis is that low-dose IL-2 therapy will be safe, will preserve insulin secretion and increase Treg proportions. This trial will exploit the fact that T1D requires multiple insulin injections daily and thus patients immunize themselves with a key T1D autoantigen. We hypothesize that insulin therapy synergizes with low-dose IL-2 by inducing insulin-specific Treg cells. This result would support exploiting IL-2 in combination with antigen(s) to promote antigen/disease specific immune regulation in autoimmune disease. The study has three specific aims: Aim 1: To determine the efficacy and safety of low-dose IL-2 therapy in patients with established T1D. The primary clinical and mechanistic objectives are the efficacy of low-dose IL-2 in preserving insulin secretion and improving proportions of Treg cells, compared to placebo. Aim 2: To identify mechanisms and biomarkers of response in T1D patients undergoing low-dose IL-2 therapy through the study of immune homeostasis, IL-2R signaling, gene expression, and T cell metabolism. Aim 3. To evaluate the ability of low-dose IL-2 therapy to reduce autoreactive CD4 and CD8 T cells and increase insulin-specific Tregs. These data will be related to effects of the therapy on serum cytokine levels and the TCR repertoires.