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

项目总结： 许多炎症性疾病是由过度产生细胞因子(高细胞分裂素血症)引起的， 其中重要的一部分是由不适当或过度的T细胞激活所驱动的。T细胞的两个例子- 介导性高细胞分裂素血症综合征包括家族性噬血细胞淋巴组织细胞增多症(FHL)和骨骼 骨髓移植相关移植物抗宿主病(GVHD)。在FHL中，高细胞分裂素血症 直接导致器官衰竭和死亡，但仍需要一定程度的细胞分裂素血症来控制 引发感染的可能性。对于骨髓移植来说，高细胞分裂素血症的毒性是其主要限制因素。 在癌症治疗中的临床应用。由于T细胞介导的治疗方案有限 高细胞分裂素血症，确定新的治疗策略是必要的。这在T细胞中可能是一个挑战-- 异基因骨髓移植治疗所致的高细胞分裂素血症 T细胞的作用需要分离。 因为阻断TCR信号很可能会同时导致细胞因子产生和 抗肿瘤细胞毒性，靶向只参与T细胞细胞因子释放的非TCR信号通路 可能代表了一种新的策略。此外，对于FHL，目标是一条不完全阻断的通路 细胞因子的产生，而是将其恢复到正常的保护水平是可取的。我们特此建议， IL-33信号是一种常见的机制，可通过一种途径加重T细胞介导的高细胞分裂素综合征 非TCR机制。IL-33是一种“警报蛋白”，是一种在组织损伤时释放的分子，可以调节 免疫反应。我们的数据显示，ST2信号增加了CD8T细胞干扰素的产生，而IL-2 33是FHL和GVHD发病所必需的。因此，我们假设IL-33来源于受损的细胞 是T细胞介导的高细胞分裂素血症的关键，通过增强致病的干扰素T细胞反应，而不是 影响细胞毒性抗肿瘤反应。在这个提案中，我们将定义细胞和分子机制 IL-33在T细胞介导的高细胞分裂症中的作用及揭示其来源和诱导因素 IL-33使用两种不同的临床相关T细胞介导的高细胞分裂素血症模型。我们的研究包括两个方面 IL-33促进动物模型疾病发病机制的研究 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IL-33阻断T细胞介导的高细胞分裂素综合征的最佳策略， 在这些毁灭性的并发症中降低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.