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(申请人提供)：噬血细胞淋巴组织细胞增多症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患者经历自发性且经常反复发作的高炎症发作，表现为CD8+T细胞和巨噬细胞的激活和扩张，这些细胞产生大量的促炎细胞因子，包括白细胞介素6(IL)-6、IL-12和干扰素(干扰素)？尽管目前的治疗方法，高达50%的HLH患者死于这些细胞因子的毒性作用，这些细胞因子进一步推动免疫细胞激活，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型细胞因子受体结合后启动的STAT依赖的细胞内信号，这些受体结合了一系列广泛的细胞因子，包括那些在HLH中过度产生的细胞因子。基于促炎症细胞因子在HLH发病机制中的关键作用，我们假设JAKs的药理抑制将减轻炎症和改善疾病。事实上，在对小鼠的初步研究中，我们观察到FDA批准的JAK抑制剂ruxolitinib显著减轻了HLH的表现，包括体重减轻、脾肿大、细胞减少、高细胞分裂素血症和肝脏炎症。在这项探索性赠款研究(PA-13-315)中，我们计划通过确定Ruxolitinib的治疗效果并破译其潜在的作用机制(S)来进一步检验这一假说。使用2个互补的小鼠HLH模型，我们将改进Ruxolitinib给药的剂量和程序，并评估其作为单一药物或与更传统的HLH治疗(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Ruxolitinib如何影响免疫细胞激活和细胞因子产生的模式、JAK和/或STAT磷酸化以及STAT依赖的基因转录。尽管目前的促黄体生成素疗法存在不足，但十多年来在治疗方面没有取得重大进展。通过拟议的研究，我们打算通过靶向JAK依赖的细胞因子网络，一种新的合理的治疗方法来改善HLH患者的预后。为了促进这些研究的成功完成，我们聚集了一支强大的调查团队，其中包括费城儿童医院的Kim Nichols博士、Ed Behrens博士和David Teaceh博士，宾夕法尼亚大学的John Wherry博士和辛辛那提儿童医院医疗中心的Michael Jordan博士。这个团队的成员一起是HLH生物学和细胞因子信号、人类疾病的临床前建模和研究结果的床边翻译方面的专家。因此，如果这项研究继续显示出有益的效果，我们预计它的结果可以很容易地过渡到TE临床，未来以鲁索利替尼为基础的儿童和成人HLH试验的形式。