Targeting the immunoproteasome as a novel therapeutic strategy for hemophagocytic lymphohistiocytosis

靶向免疫蛋白酶体作为噬血细胞性淋巴组织细胞增多症的新型治疗策略

基本信息

批准号：
10741624
负责人：
KIM Erika NICHOLS
金额：
$ 27.3万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-05 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10741624
关键词：
Address Allogenic Anemia Animals Antigen Presentation Antigen-Presenting Cells Antigens Automobile Driving B-Lymphocytes Blood Body Weight decreased CD8-Positive T-Lymphocytes CD8B1 gene Cells Clinical Clinical Trials Coculture Techniques Defect Development Dexamethasone Disease Epitopes Etoposide Exposure to Feedback Ferritin Flare Flow Cytometry Future Glucocorticoids Harvest Height Hematopoietic Hematopoietic Stem Cell Transplantation Hemophagocytic Lymphohistiocytoses Hereditary Disease Histology Homeostasis Human ITGAX gene Immune Immune System Diseases Immune response Immune system Immunity Immunologic Deficiency Syndromes In Vitro Individual Infection Infiltration Inflammation Inflammatory Interferon Type II Investigation Jordan Label Laboratories Learning Lymphocytic choriomeningitis virus Macrophage Major Histocompatibility Complex Measures Modeling Mus Natural Killer Cells OVA-8 Organ Outcome Pathogenesis Patients Peptides Pharmaceutical Preparations Play Process Production Proliferating Proteins Public Health Regimen Research Project Grants Role Schedule Serum Signs and Symptoms Sorting Splenocyte Splenomegaly Surface Antigens T-Cell Activation T-Cell Proliferation T-Lymphocyte TNF gene Testing Therapeutic Therapeutic Effect Thrombocytopenia Tissues Toxic effect VDAC1 gene Viral Viral Load result Viral Proteins Virus Virus Diseases Visceromegaly chemotherapeutic agent clinically significant congenital immunodeficiency cytokine cytotoxic effective therapy familial hemophagocytic lymphohistiocytosis immune activation immunopathology improved in vitro Assay in vitro Model in vivo inhibitor insight interest mouse model novel novel therapeutic intervention perforin peripheral blood pharmacologic protein complex response targeted agent therapeutic target

项目摘要

PROJECT SUMMARY Primary hemophagocytic lymphohistiocytosis (pHLH) comprises an expanding array of inherited disorders of the immune system characterized by severe hyperinflammation. Despite use of the glucocorticoid dexamethasone, chemotherapeutic agent etoposide, specific cytokine-targeting agents, and allogeneic hematopoietic stem cell transplantation, up to 40% of pHLH patients die due to uncontrolled disease or the complications of its treatment. Accordingly, there is a pressing need to develop new and more effective therapies. To date, much of what we have learned about the pathogenesis of pHLH has come from the study of humans and mice lacking expression of perforin, a pore forming protein essential for the cytotoxic function of CD8 T cells and natural killer (NK) cells. Following infection with Lymphocytic Choriomeningitis virus (LCMV), perforin-deficient mice develop a fatal HLH-like illness characterized by organomegaly, anemia, thrombocytopenia, hypercytokinemia, hyperferritinemia, and fulminant tissue inflammation. Due to their cytolytic defects, perforin- deficient CD8 T and NK cells cannot eliminate LCMV-infected antigen presenting cells (APCs). It has been proposed that the persistence of these activated APCs results in a feed-forward loop to further drive T cell proliferation and proinflammatory cytokine production, ultimately culminating in the signs and symptoms of HLH. Within APCs, the immunoproteasome processes endogenous and exogenous proteins, including viral proteins, into peptides that are loaded onto Major Histocompatibility Complex class I (MHCI) molecules for presentation to other cells of the immune system. Given the persistence of activated APCs in pHLH and the central role for antigen presentation in driving immune cell activation, we hypothesize that inhibiting the immunoproteasome will serve as a rational and potentially beneficial therapeutic maneuver. Indeed, using an in vitro model of LCMV infection, we observe that the immunoproteasome inhibitors ONX-914 and KZR-616 significantly reduce LCMV-specific CD8 T cell proliferation and interferon-gamma (IFNg) production. Similarly, treatment of LCMV-infected perforin-deficient mice with KZR-616 significantly diminishes the manifestations of HLH, including splenomegaly, CD8 T cell expansion, tissue immunopathology, and serum IFNg levels. In this R21 Exploratory Research Grant, which is being submitted in response to Notice of Special Interest: Investigations on Inborn Errors of Immunity/Primary Immunodeﬁciencies (NOT-AI-21-032), we will further explore the therapeutic effects and mechanisms of action of immunoproteasome inhibition using the perforin- deficient mouse model. In Aim 1, we will examine the extent to which immunoproteasome inhibition ameliorates clinical disease, testing specific drug schedules and combinations. Aim 2 will explore the mechanistic basis using complementary in vivo and in vitro assays. If successful, these studies will elucidate whether immunoproteasome inhibition lessens inflammation in pHLH and set the stage for future clinical trials aimed at improving the overall outcome for individuals with these often-fatal immune system disorders.

项目概要原发性噬血细胞性淋巴组织细胞增多症 (pHLH) 包括一系列不断扩大的遗传性疾病尽管使用了糖皮质激素地塞米松，但免疫系统仍存在严重的过度炎症。化疗药物依托泊苷、特异性细胞因子靶向药物、同种异体造血干细胞移植后，高达 40% 的 pHLH 患者因疾病不受控制或其并发症而死亡因此，迄今为止，迫切需要开发新的且更有效的疗法。我们对 pHLH 发病机制的了解大部分来自对人类和小鼠的研究缺乏穿孔素的表达，穿孔素是一种对 CD8 T 细胞的细胞毒功能至关重要的孔形成蛋白，自然杀伤（NK）细胞感染淋巴细胞性脉络膜脑膜炎病毒（LCMV）后，穿孔素缺乏。小鼠出现致命的 HLH 样疾病，其特征是器官肿大、贫血、血小板减少症、高细胞因子血症、高铁蛋白血症和暴发性组织炎症由于其细胞溶解缺陷，穿孔素- 缺陷的 CD8 T 和 NK 细胞无法消除 LCMV 感染的抗原呈递细胞 (APC)。提出这些激活的 APC 的持续存在会导致前馈循环进一步驱动 T 细胞增殖和促炎细胞因子的产生，最终导致 HLH 的体征和症状。在 APC 内，免疫蛋白酶体处理内源性和外源性蛋白质，包括病毒蛋白、装入肽中，加载到主要组织相容性复合物 I 类 (MHCI) 分子上进行呈现鉴于活化的 APC 在 pHLH 中的持续存在及其核心作用。对于驱动免疫细胞激活的抗原呈递，我们勇敢地抑制事实上，免疫蛋白酶体将作为一种合理且潜在有益的治疗手段。在 LCMV 感染的体外模型中，我们观察到免疫蛋白酶体抑制剂 ONX-914 和 KZR-616 显着减少 LCMV 特异性 CD8 T 细胞增殖和干扰素 γ (IFNg) 产生。用 KZR-616 治疗 LCMV 感染的穿孔素缺陷小鼠可显着减轻 HLH，包括脾肿大、CD8 T 细胞扩增、组织免疫病理学和血清 IFNg 水平。 R21 探索性研究补助金，是为了响应特别兴趣通知而提交的：关于先天性免疫缺陷/原发性免疫缺陷的调查（NOT-AI-21-032），我们将进一步探讨使用穿孔素抑制免疫蛋白酶体的治疗效果和作用机制在目标 1 中，我们将检查免疫蛋白酶体抑制的改善程度。目标 2 将探索临床疾病的具体药物方案和组合的机制基础。如果成功，这些研究将阐明是否使用互补的体内和体外测定。免疫蛋白酶体抑制可减轻 pHLH 的炎症，并为未来的临床试验奠定基础旨在改善患有这些往往致命的免疫系统疾病的个体的总体结果。