Low dose IL-2 and human regulatory T cells

目前针对自身免疫性疾病的治疗针对的是症状，而不是自身免疫的原因。这个 长期使用免疫抑制剂会导致严重的副作用。一个有吸引力的替代方案是治疗 自身免疫患者体内调节性T细胞(Tregs)增强的潜在原因。我们的小组成立了 IL-2是Tregs必不可少的细胞因子。此外，我们在临床前研究中已经确定，低IL-2R 信号转导促进T细胞，但不能促进T效应/记忆(TEM)细胞。这一发现导致了一种观念，即低剂量 (LD)IL-2可选择性扩增Tregs。重要的是，LD IL-2疗法在患者中显示出有希望的结果 患有慢性移植物抗宿主病、丙型肝炎病毒血管炎和几种自身免疫性疾病。相应地，有几个基本原则 关于LD IL-2免疫疗法的问题浮出水面。这些问题包括：LD IL-2对Tregs的选择性是什么？ Treg细胞优先应答低水平IL-2的机制是什么？有个体差异吗？ 对LD IL-2的反应？LD对Treg细胞和Tef细胞的分子效应是什么 白介素2？长期接触白介素2是否会改变树突状细胞对白介素2的反应能力？我们的支持数据有 与CD45RO相比，确定了人Tregs对IL-2R信号的选择性窗口 ++ 细胞。然而，Tregs对LD IL-2的排他性反应程度仍然是一个争议点。我们还有 初步数据表明，在正常受试者中，Treg中依赖IL-2的基因激活可能有所不同。后一点是 值得注意的是，有些人可能更适合这种疗法。我们计划在此基础上 这些结果并利用我们在IL-2方面的专业知识，从机械上更好地了解LD IL-2的潜力- 2作为自身免疫性疾病的治疗平台。这种应用的前提是：与瞬变电磁法相比 细胞，低水平的IL-2R信号选择性地和实质上激活了IL-2依赖的转录 Tregs中的程序，由TCR和共刺激信号独特地塑造；这种选择性的基因激活 对LD IL-2治疗的反应因个体和账户而异。以下是具体目标 建议解决这一前提：1)建立IL-2R的直接和下游后果 LD-IL-2单独或在TCR和TCR联合作用下对人Treg和TJeff细胞基因调控的信号转导 共刺激信号；2)评估细胞和分子水平，通过这些水平人类的反应 在正常受试者和1型糖尿病患者中，Tregs变化为LD IL-2；以及3)评估 接受LD IL-2治疗的患者Treg和TEM细胞中IL-2的结果。这些实验将 评估IL-2剂量变化和自身免疫性疾病类型对IL-2R信号转导的影响。

Current therapies for autoimmune diseases target the symptoms rather than the cause of autoimmunity. The chronic use of immunosuppressants leads to deliberating side effects. An attractive alternative is to treat the underlying cause by boosting regulatory T cells (Tregs) in patients with autoimmunity. Our group established that IL-2 is an essential cytokine for Tregs. Moreover, we have established in pre-clinical studies that low IL-2R signaling promotes Tregs but not T effector/memory (TEM) cells. This finding has led to the notion that low-dose (LD) IL-2 may selectively expand Tregs. Importantly, LD IL-2 therapy has shown promising results in patients with chronic GvHD, HCV vasculitis, and several autoimmune diseases. Correspondingly, several fundamental questions emerge about LD IL-2 immunotherapy. These include: What is the selectivity of LD IL-2 for Tregs? What is the mechanism by which Tregs preferentially respond to low levels of IL-2? Is there individual variation in responsiveness to LD IL-2? What are the molecular consequences in Treg and Teff cells in response to LD IL-2? Does chronic exposure to LD IL-2 alter the capacity of Tregs to respond to IL-2? Our supporting data has defined a window of selectivity of human Tregs for IL-2R signaling when compared to CD45RO CD4 TEM ++ cells. However, the extent that Tregs exclusive respond to LD IL-2 remains a point of contention. We also have preliminary data that IL-2-dependent gene activation in Tregs may vary in normal subjects. This latter point is of interest because some individuals may be more suitable candidates for this therapy. We plan to build on these results and capitalize on our expertise on IL-2 to better understand mechanistically the potential of LD IL- 2 as a treatment platform for autoimmune diseases. The premise of this application is: In comparison to TEM cells, low levels of IL-2R signaling selectively and substantially activates an IL-2-dependent transcriptional program in Tregs that is uniquely shaped by TCR and co-stimulatory signaling; this selective gene activation varies between individuals and accounts for variable responses to LD IL-2 therapy. The following specific aims are proposed to address this premise: 1) To establish the immediate and down-stream consequences of IL-2R signaling by LD IL-2 on gene regulation in human Treg and Teff cells in vitro alone or in the context of TCR and co-stimulatory signaling; 2) to evaluate cellular and molecular levels through which the response by human Tregs varies to LD IL-2 in normal subjects and in patients with Type 1 diabetes; and 3) to evaluate the consequence of IL-2 in Treg and TEM cells in patients undergoing LD IL-2 therapy. These experiments will assess the outcome of IL-2R signaling due to variation of IL-2 dose and the type of autoimmune disease.