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自身免疫性疾病的症状而不是原因。的 长期使用免疫抑制剂会导致故意的副作用。一个有吸引力的替代方法是将 在自身免疫性患者中，通过增强调节性T细胞（T细胞）的潜在原因。我们集团成立了 IL-2是调节性T细胞必需的细胞因子。此外，我们在临床前研究中已经确定，低IL-2R 信号传导促进T细胞活化，但不促进T效应/记忆（TEM）细胞。这一发现导致了低剂量 (LD)IL-2可以选择性地扩增T细胞。重要的是，LD IL-2治疗在患者中显示出有希望的结果， 慢性GvHD、HCV血管炎和几种自身免疫性疾病。相应地，一些基本的 关于LD IL-2免疫疗法的问题出现。这些问题包括：LD IL-2对THBE的选择性是什么？ 甲状腺激素优先对低水平IL-2产生反应的机制是什么？是否存在个体差异 对LD IL-2的反应性？LD对Treg和Teff细胞的分子影响是什么 IL-2？长期暴露于LD IL-2是否改变了TcB对IL-2的反应能力？我们的支持数据 当与CD45RO CD4 TEM相比时，定义了人T细胞对IL-2R信号传导的选择性窗口 ++ 细胞然而，Tclase对LD IL-2的排他应答的程度仍然是一个争论点。我们也有 初步数据表明，正常受试者中THBG中IL-2依赖性基因的激活可能不同。后一点是 因为有些人可能更适合这种疗法。我们计划建立在 这些结果，并利用我们对IL-2的专业知识，以更好地了解机制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TEM相比， 细胞中，低水平的IL-2R信号转导选择性地和实质性地激活IL-2依赖性转录因子， TCR中由TCR和共刺激信号独特塑造的程序;这种选择性基因激活 个体之间存在差异，并解释了对LD IL-2治疗的可变反应。以下具体目标 提出了解决这一前提：1）建立IL-2 R的直接和下游后果 LD IL-2对体外人Treg和Teff细胞基因调节的信号传导单独或在TCR和背景下 共刺激信号传导; 2）评估细胞和分子水平，通过所述细胞和分子水平，人的应答 在正常受试者和1型糖尿病患者中，IL-2的水平与LD不同; 3）为了评估IL-2的水平， 在接受LD IL-2治疗的患者中Treg和TEM细胞中IL-2的结果。这些实验将 评估由于IL-2剂量和自身免疫性疾病类型的变化而导致的IL-2R信号传导的结果。

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.