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

IL-33 阻断作为 T 细胞介导的高细胞因子血症综合征的新疗法

• 批准号: 9291411
• 负责人: EDWARD M BEHRENS
• 金额: $ 59.85万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-08 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291411
• 关键词: Affect; Allogeneic Bone Marrow Transplantation; Animal Model; Antibodies; Antigen-Presenting Cells; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Compartmentation; Cell physiology; Cells; Cessation of life; Clinical; Cytoplasmic Granules; Cytotoxic T-Lymphocytes; Data; Disease; Exocytosis; Graft-Versus-Tumor Induction; Hematopoietic; Human; Immune response; Inbred BALB C Mice; Infection; Inflammation; Inflammatory; Interferon Type II; Interferons; Investigation; Lead; Lymphocyte; Lymphoma; Malignant Neoplasms; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Organ failure; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Predictive Value; Production; Receptor Signaling; Role; Serum; Signal Transduction; Signaling Molecule; Source; Syndrome; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TNF gene; Testing; Therapeutic; Tissues; Toxic effect; base; cell injury; cell type; clinically relevant; cytokine; cytotoxic; cytotoxicity; familial hemophagocytic lymphohistiocytosis; graft vs host disease; improved; irradiation; killings; mortality; mouse model; novel strategies; novel therapeutic intervention; novel therapeutics; perforin; receptor; response; treatment strategy; tumor

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.

项目概要： 许多炎症性疾病是由细胞因子过度产生（高细胞因子血症）引起的， 其中一个重要的子集是由不适当或过度的 T 细胞激活驱动的。 T 细胞的两个例子 介导的高细胞因子血症综合征包括家族性噬血细胞性淋巴组织细胞增多症 (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 的触发感染。对于 BMT 而言，高细胞因子血症的毒性是其应用的主要限制。 临床用于治疗癌症。由于 T 细胞介导的治疗方法有限 高细胞因子血症，有必要确定新的治疗策略。这对于 T 细胞来说可能具有挑战性 介导的同种异体 BMT 疗法诱导的高细胞因子血症，其中抗肿瘤和产生细胞因子的药物 T 细胞的作用需要分开。 由于 TCR 信号传导阻断可能会导致细胞因子产生和 抗肿瘤细胞毒性，针对仅参与 T 细胞细胞因子释放的非 TCR 信号通路 可能代表一种新颖的策略。此外，对于 FHL 来说，针对的是一条不会完全阻断的途径 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。我们在此建议 IL-33 信号传导是一种常见机制，可通过以下途径加剧 T 细胞介导的高细胞因子血症综合征： 非TCR机制。 IL-33 是一种“警报素”，是一种在组织损伤时释放的分子，可以调节 免疫反应。我们的数据表明 ST2 信号传导可增加 CD8+ T 细胞的 IFNγ 产生，并且 IL- 33 是 FHL 和 GVHD 发病机制所必需的。因此，我们假设 IL-33 源自受损细胞 通过增强致病性 IFN-T 细胞反应，对 T 细胞介导的高细胞因子血症至关重要，而无需 影响细胞毒性抗肿瘤反应。在本提案中，我们将定义细胞和分子机制 IL-33 有助于 T 细胞介导的高细胞因子血症并揭示其来源和诱导因素 IL-33 使用 2 个独立的 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 在动物模型中研究 IL-33 促进疾病发病机制的机制 将这些发现与患有这些疾病的人类患者相关联。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， 降低这些破坏性并发症的死亡率和发病率的潜力。