IL-33 Blockade as a Novel Therapeutic for T-cell Mediated Hypercytokinemia Syndromes

项目概要： 许多炎性疾病是由细胞因子过度产生（高细胞因子血症）引起的， 这些疾病中的重要子集由不适当或过度的T细胞活化驱动。两个T细胞的例子 介导的高细胞因子血症综合征包括家族性噬血细胞性巨噬组织细胞增多症（FHL）和骨 骨髓移植（BMT）相关的移植物抗宿主病（GVHD）。在FHL中，高细胞因子血症是 直接导致器官衰竭和死亡，但仍需要一定程度的细胞因子血症来控制 引发感染的原因对于BMT，高细胞因子血症的毒性是其治疗的主要限制。 用于治疗癌症的临床用途。由于治疗T细胞介导的 高细胞因子血症，确定新的治疗策略是必要的。这在T细胞中可能是具有挑战性的- 介导的高细胞因子血症诱导的同种异体BMT治疗，其中抗肿瘤和产精氨酸 T细胞的作用需要分开。 由于TCR信号传导阻断可能导致细胞因子产生的同时消除， 抗肿瘤细胞毒性，靶向仅参与T细胞细胞因子释放的非TCR信号通路 可能是一种新的策略。此外，对于FHL，靶向不能完全阻断 细胞因子的产生，而是将其恢复到正常的保护水平是期望的。我们在此提议， IL-33信号传导是通过调节T细胞介导的高细胞因子血症综合征的常见机制。 非TCR机制。IL-33是一种“警报素”，一种在组织损伤时释放的分子，可以调节 免疫反应。我们的数据表明，ST 2信号增加了CD 8 + T细胞的IFN γ产生，IL-10也增加了CD 8 + T细胞的IFN γ产生。 33是FHL和GVHD发病机制所必需的。因此，我们假设IL-33来源于受损细胞， 对T细胞介导的高细胞因子血症至关重要，通过增强致病性IFN γ T细胞应答， 影响细胞毒性抗肿瘤反应。在这个建议中，我们将定义细胞和分子机制 IL-33在T细胞介导的高细胞因子血症中的作用，并揭示了IL-33的来源和诱导因素， IL-33，使用2个单独的T细胞介导的高细胞因子血症临床相关模型。我们的研究包括 研究IL-33在动物模型中促进疾病发病的机制 将这些发现与患有这些疾病的人类患者联系起来。有了这些信息，我们将 准备开发T细胞介导的高细胞因子血症综合征中IL-33阻断的最佳策略， 降低这些毁灭性并发症的死亡率和发病率的潜力。

Project Summary: A number of inflammatory diseases result from excessive cytokine production (hypercytokinemia), with an important subset of these driven by inappropriate or excessive T-cell activation. Two examples of T-cell- mediated hypercytokinemia syndromes include Familial Hemophagocytic Lymphohistiocytosis (FHL) and bone marrow transplantation (BMT)-associated graft-versus-host disease (GVHD). In FHL, hypercytokinemia is directly responsible for organ failure and death, and yet some degree of cytokinemia is still needed for control of the triggering infections. For BMT, the toxicity of hypercytokinemia represents a major limitation for its clinical use in treating cancer. As limited options are available for treatment of T-cell-mediated hypercytokinemia, identification of new therapeutic strategies is necessary. This could be challenging in T-cell- mediated hypercytokinemia induced by allogeneic BMT therapy, where the anti-tumor and cytokine-producing effects of T cells need to be separated. Since TCR signaling blockade would likely lead to simultaneous abrogation of cytokine production and anti-tumor cytotoxicity, targeting a non-TCR signaling pathway that is involved only in T cell cytokine release may represent a novel strategy. Furthermore for FHL, targeting a pathway that does not completely block cytokine production, but rather restores it to normal protective levels is desirable. We hereby propose that the IL-33 signaling is a common mechanism that exacerbates T-cell-mediated hypercytokinemia syndromes via a non-TCR mechanism. IL-33 is an “alarmin”, a molecule released upon tissue damage that can modulate immune responses. Our data show that ST2 signaling increases IFN production by CD8+ T cells and that IL- 33 is required for FHL and GVHD pathogenesis. Thus, we hypothesize that IL-33 derived from damaged cells is critical for T-cell-mediated hypercytokinemia by enhancing the pathogenic IFN T-cell response without affecting cytotoxic anti-tumor responses. In this proposal, we will define the cellular and molecular mechanisms by which IL-33 contributes to T-cell-mediated hypercytokinemia and uncover the source and inducing factors of IL-33 using 2 separate clinically relevant models of T-cell-mediated hypercytokinemia. Our studies include both the investigation of the mechanisms by which IL-33 promotes disease pathogenesis in animal models as well as correlating these findings to human patients with these diseases. Armed with this information, we will be poised to develop the best strategy for IL-33 blockade in T cell-mediated hypercytokinemia syndromes, with the potential to reduce mortality and morbidity in these devastating complications.