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:
- 金额:$ 27.3万
- 依托单位:
- 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:
- 关键词:AddressAllogenicAnemiaAnimalsAntigen PresentationAntigen-Presenting CellsAntigensAutomobile DrivingB-LymphocytesBloodBody Weight decreasedCD8-Positive T-LymphocytesCD8B1 geneCellsClinicalClinical TrialsCoculture TechniquesDefectDevelopmentDexamethasoneDiseaseEpitopesEtoposideExposure toFeedbackFerritinFlareFlow CytometryFutureGlucocorticoidsHarvestHeightHematopoieticHematopoietic Stem Cell TransplantationHemophagocytic LymphohistiocytosesHereditary DiseaseHistologyHomeostasisHumanITGAX geneImmuneImmune System DiseasesImmune responseImmune systemImmunityImmunologic Deficiency SyndromesIn VitroIndividualInfectionInfiltrationInflammationInflammatoryInterferon Type IIInvestigationJordanLabelLaboratoriesLearningLymphocytic choriomeningitis virusMacrophageMajor Histocompatibility ComplexMeasuresModelingMusNatural Killer CellsOVA-8OrganOutcomePathogenesisPatientsPeptidesPharmaceutical PreparationsPlayProcessProductionProliferatingProteinsPublic HealthRegimenResearch Project GrantsRoleScheduleSerumSigns and SymptomsSortingSplenocyteSplenomegalySurface AntigensT-Cell ActivationT-Cell ProliferationT-LymphocyteTNF geneTestingTherapeuticTherapeutic EffectThrombocytopeniaTissuesToxic effectVDAC1 geneViralViral Load resultViral ProteinsVirusVirus DiseasesVisceromegalychemotherapeutic agentclinically significantcongenital immunodeficiencycytokinecytotoxiceffective therapyfamilial hemophagocytic lymphohistiocytosisimmune activationimmunopathologyimprovedin vitro Assayin vitro Modelin vivoinhibitorinsightinterestmouse modelnovelnovel therapeutic interventionperforinperipheral bloodpharmacologicprotein complexresponsetargeted agenttherapeutic 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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KIM Erika NICHOLS其他文献
KIM Erika NICHOLS的其他文献
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{{ truncateString('KIM Erika NICHOLS', 18)}}的其他基金
Pathogenesis of ETV6-Related Acute Lymphoblastic Leukemia
ETV6相关急性淋巴细胞白血病的发病机制
- 批准号:
10837399 - 财政年份:2020
- 资助金额:
$ 27.3万 - 项目类别:
Pathogenesis of ETV6-Related Acute Lymphoblastic Leukemia
ETV6相关急性淋巴细胞白血病的发病机制
- 批准号:
10247963 - 财政年份:2020
- 资助金额:
$ 27.3万 - 项目类别:
JAK inhibition as a novel treatment for hemophagocytic lymphohistiocytosis
JAK 抑制作为噬血细胞性淋巴组织细胞增多症的新型治疗方法
- 批准号:
8907502 - 财政年份:2014
- 资助金额:
$ 27.3万 - 项目类别:
Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
SAP、SLAM 和 Fyn 在 NKT 细胞个体发育和激活中的作用
- 批准号:
8110525 - 财政年份:2007
- 资助金额:
$ 27.3万 - 项目类别:
Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
SAP、SLAM 和 Fyn 在 NKT 细胞个体发育和激活中的作用
- 批准号:
7662291 - 财政年份:2007
- 资助金额:
$ 27.3万 - 项目类别:
Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
SAP、SLAM 和 Fyn 在 NKT 细胞个体发育和激活中的作用
- 批准号:
7302925 - 财政年份:2007
- 资助金额:
$ 27.3万 - 项目类别:
Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
SAP、SLAM 和 Fyn 在 NKT 细胞个体发育和激活中的作用
- 批准号:
7886595 - 财政年份:2007
- 资助金额:
$ 27.3万 - 项目类别:
Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
SAP、SLAM 和 Fyn 在 NKT 细胞个体发育和激活中的作用
- 批准号:
7473119 - 财政年份:2007
- 资助金额:
$ 27.3万 - 项目类别:
ROLE OF SH2D1A/SAP IN NKT CELL DEVELOPMENT AND FUNCTION
SH2D1A/SAP 在 NKT 细胞发育和功能中的作用
- 批准号:
6987827 - 财政年份:2004
- 资助金额:
$ 27.3万 - 项目类别:
ROLE OF SH2D1A/SAP IN NKT CELL DEVELOPMENT AND FUNCTION
SH2D1A/SAP 在 NKT 细胞发育和功能中的作用
- 批准号:
6852322 - 财政年份:2004
- 资助金额:
$ 27.3万 - 项目类别:
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