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，导致胰岛细胞和胰岛素丢失 分泌物。抑制自身免疫和保存？细胞的尝试都取得了不大的临床效果。 在规模和持续时间上。许多试验涉及全身性免疫抑制和/或耗尽各种 免疫细胞类型，或短程疗法，考虑到慢性病的性质，可能无法提供持续的好处 胰岛自身免疫；然而，慢性免疫抑制因安全问题而受到限制。有必要 可提供免疫调节并可长期给予高安全边际的治疗胰岛的疗法 自身免疫力。重要的是开发具有抗原特异性的治疗方法，以增强安全性、有效性和 疾病相关性。细胞因子白介素2(IL-2)对效应性T细胞反应是必不可少的，但对 调节性T(Treg)细胞是自我耐受的关键。小剂量IL-2在几个国家进行的临床试验 免疫介导的疾病报告了与增强的Treg功能相关的显著临床益处， 极佳的安全性能。我们已经证明，人类CD4 Treg细胞对低剂量IL-1具有高度的敏感性。 2与效应T细胞(T细胞)进行比较，并揭示了IL-2通过 小剂量给T1D患者可促进Treg功能和免疫调节，如在 第一个T1D试验并不是为了测试对胰岛素分泌的影响。我们现在提出一项 小剂量IL-2治疗T1D及其作用机制的多中心临床研究 行动。我们将招募12-21岁确诊为T1D(持续4-12个月)的患者；大多数患者满足 C-肽在该人群中确诊并表现出益处后至少2年内符合资格标准 会通过扩大治疗窗口来影响这一领域。参与者将随机服用安慰剂，为期2天 或小剂量IL-2治疗1年或2年。主要的假设是低剂量的IL-2治疗将 安全，将保持胰岛素分泌和增加Treg比例。这项试验将利用T1D的事实 每天需要多次注射胰岛素，因此患者使用关键的T1D自身抗原进行免疫。 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 这一结果将支持利用IL-2联合抗原(S)促进抗原/疾病特异性免疫 自身免疫性疾病的调控。这项研究有三个具体目标：目标1：确定疗效和 小剂量IL-2治疗T1D患者的安全性。初级临床和机械学 目的是观察小剂量IL-2在维持胰岛素分泌和改善Treg比例方面的效果。 细胞，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 小剂量IL-2治疗对免疫稳态、IL-2R信号转导、基因表达的影响 表达，与T细胞代谢有关。目的3.评估小剂量IL-2治疗的能力 自身反应的CD4和CD8T细胞和增加胰岛素特异性树突状细胞。这些数据将与 治疗对血清细胞因子水平及TCR谱的影响。

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.