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
• 负责人: KIM Erika NICHOLS
• 金额: $ 31.15万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8907502
• 关键词: Acute; Address; Adult; Allogenic; Binding; Biological Response Modifiers; Biology; Blocking Antibodies; Blood; Body Weight decreased; Bone Marrow Suppression; C57BL/6 Mouse; CD8B1 gene; Cells; Child; Chronic; Clinic; Cytokine Network Pathway; Cytokine Receptors; Cytokine Signaling; DNA; Defect; Development; Dexamethasone; Disease; Dose; Etoposide; Exhibits; FDA approved; Ferritin; Functional disorder; Future; Gene Mutation; Generations; Genetic; Genetic Transcription; Grant; Health; Hemophagocytic Lymphohistiocytoses; Hepatic; High Dose Chemotherapy; Human; Hypotension; Immune; Immune Cell Activation; Immune System Diseases; Immune response; Immunity; Immunologic Deficiency Syndromes; Immunologics; Inborn Genetic Diseases; Infection; Inflammation; Inflammatory; Injection of therapeutic agent; Interferons; Interleukin-12; Interleukin-6; Investigation; JAK1 gene; Janus kinase; Jordan; Laboratories; Life; Lymphocyte; Lymphocytic choriomeningitis virus; Macrophage Activation; Mediating; Medical center; Modeling; Mus; Organ; Outcome; Pathogenesis; Patients; Pattern; Pediatric Hospitals; Pennsylvania; Pharmaceutical Preparations; Pharmacodynamics; Philadelphia; Phosphorylation; Pilot Projects; Pre-Clinical Model; Production; Proteins; Public Health; Receptor Signaling; Recurrence; Refractory; Regimen; Role; Schedule; Sepsis; Serum; Signal Transduction; Splenomegaly; Stem cell transplant; Steroids; Syndrome; T-Lymphocyte; TLR9 gene; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Translational Research; Universities; Viral; Virulence; base; bench to bedside; clinically significant; cytokine; cytopenia; cytotoxic; effective therapy; experience; human disease; immunopathology; improved; inhibitor/antagonist; insight; interest; interleukin-10 receptor; intraperitoneal; kinase inhibitor; macrophage; member; non-genetic; novel; perforin

DESCRIPTION (provided by applicant): The hemophagocytic lymphohistiocytoses (HLH) comprise a growing number of inherited and non-inherited disorders of the immune system characterized by the generation of abnormal and severely damaging immune responses. HLH patients experience spontaneous and often recurring episodes of hyper-inflammation marked by the activation and expansion of CD8+ T cells and macrophages that produce copious amounts of pro-inflammatory cytokines, including interleukins (IL)-6, IL-12, and interferon (IFN)-?. Despite current treatments, up to 50% of HLH patients die due to the toxic effects of these cytokines, which further drive immune cell activation and promote a sepsis-like syndrome of hypotension, bone marrow suppression and multisystem organ dysfunction. The Janus kinases (JAKs) transduce STAT-dependent intracellular signals initiated following engagement of the Types I and II cytokine receptors, which bind a broad array of cytokines including those over-produced in HLH. Based on the critical role for pro-inflammatory cytokines in the pathogenesis of HLH, we hypothesize that pharmacologic inhibition of the JAKs will diminish inflammation and ameliorate disease. Indeed, in pilot studies in mice, we observe that the FDA-approved JAK inhibitor ruxolitinib significantly lessens the manifestations of HLH, including weight loss, splenomegaly, cytopenias, hyper-cytokinemias and hepatic inflammation. In this Exploratory Grant Investigation (PA-13-315), we plan to further test this hypothesis by determining the therapeutic effects of ruxolitinib and deciphering its underlying mechanism(s) of action. Using 2 complementary murine HLH models, we will refine the dosing and schedule of ruxolitinib administration and assess its efficacy when used as a single agent or in combination with more conventional HLH therapies (i.e. dexamethasone, etoposide). We will complete immunologic studies to examine how ruxolitinib influences patterns of immune cell activation and cytokine production, JAK and/or STAT phosphorylation and STAT-dependent gene transcription. Despite the inadequacy of current HLH therapies, there have been no significant advances in treatment in more than a decade. Through the proposed studies, we intend to improve the outcome for HLH patients by targeting JAK-dependent cytokine networks, a new and rational approach to treatment. To facilitate the successful completion of these studies, we have gathered a strong investigative team that includes Drs. Kim Nichols, Ed Behrens and David Teachey (The Children's Hospital of Philadelphia), John Wherry (The University of Pennsylvania) and Michael Jordan (Cincinnati Children's Hospital Medical Center). Together, the members of this team are experts in the biology of HLH and cytokine signaling, pre-clinical modeling of human diseases and the bench-to-bedside translation of research findings. Therefore, should this study continue to demonstrate a beneficial effect, we anticipate that its results can be readily transitioned to te clinic in the form of a future ruxolitinib-based trial for children and adults with HLH.

描述（由申请人提供）：噬血细胞性淋巴组织细胞增多症（HLH）包括越来越多的遗传性和非遗传性免疫系统疾病，其特征是产生异常和严重破坏性的免疫反应。 HLH 患者会经历自发且经常反复发作的过度炎症，其特征是 CD8+ T 细胞和巨噬细胞的激活和扩增，产生大量促炎细胞因子，包括白细胞介素 (IL)-6、IL-12 和干扰素 (IFN)-α。尽管目前有治疗方法，但高达 50% 的 HLH 患者死于这些细胞因子的毒性作用，这进一步驱动免疫细胞激活并促进低血压、骨髓抑制和多系统器官功能障碍的脓毒症样综合征。 Janus 激酶 (JAK) 转导在 I 型和 II 型细胞因子受体参与后启动的 STAT 依赖性细胞内信号，这些信号与多种细胞因子结合，包括 HLH 中过量产生的细胞因子。基于促炎细胞因子在 HLH 发病机制中的关键作用，我们假设 JAK 的药理学抑制将减少炎症并改善疾病。事实上，在小鼠试验中，我们观察到 FDA 批准的 JAK 抑制剂鲁索替尼显着减轻了 HLH 的表现，包括体重减轻、脾肿大、血细胞减少、高细胞因子血症和肝脏炎症。在本次探索性拨款调查 (PA-13-315) 中，我们计划通过确定鲁索替尼的治疗效果并破译其潜在的作用机制来进一步检验这一假设。使用 2 个互补的小鼠 HLH 模型，我们将完善鲁索替尼给药的剂量和时间表，并评估其作为单一药物或与更传统的 HLH 疗法（即地塞米松、依托泊苷）联合使用时的疗效。我们将完成免疫学研究，以检查鲁索替尼如何影响免疫细胞激活和细胞因子产生、JAK 和/或 STAT 磷酸化以及 STAT 依赖性基因转录的模式。尽管目前的 HLH 疗法存在不足，但十多年来治疗方法并未取得重大进展。通过拟议的研究，我们打算通过靶向 JAK 依赖性细胞因子网络（一种新的合理治疗方法）来改善 HLH 患者的预后。为了促进这些研究的成功完成，我们聚集了一个强大的调查团队，其中包括博士。 Kim Nichols、Ed Behrens 和 David Teachey（费城儿童医院）、John Wherry（宾夕法尼亚大学）和 Michael Jordan（辛辛那提儿童医院医疗中心）。该团队的成员都是 HLH 生物学和细胞因子信号转导、人类疾病临床前建模以及研究结果从实验室到临床转化的专家。因此，如果这项研究继续证明其有益效果，我们预计其结果可以很容易地以未来针对 HLH 儿童和成人的鲁索替尼试验的形式转移到临床。