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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.

项目总结