JAK inhibition as a novel treatment for hemophagocytic lymphohistiocytosis

描述（由申请人提供）：噬血细胞性淋巴组织细胞病（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患者经历自发且经常复发的高炎症发作，其特征是CD8+ T细胞和巨噬细胞的激活和扩增，巨噬细胞产生大量的促炎细胞因子，包括白细胞介素(IL)-6、IL-12和干扰素(IFN)- 3。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，这进一步推动免疫细胞活化，促进败血症样综合征的低血压，骨髓抑制和多系统器官功能障碍。Janus激酶（JAKs）转导stat依赖的细胞内信号，这些信号是在I型和II型细胞因子受体结合后启动的，这些受体结合广泛的细胞因子，包括那些在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的药物抑制将减少炎症并改善疾病。事实上，在小鼠的初步研究中，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、细胞运动过多和肝脏炎症。在这项探索性拨款研究（PA-13-315）中，我们计划通过确定ruxolitinib的治疗效果并解读其潜在的作用机制来进一步验证这一假设。使用2个互补的小鼠HLH模型，我们将完善ruxolitinib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ruxolitinib如何影响免疫细胞活化和细胞因子产生，JAK和/或STAT磷酸化和STAT依赖基因转录的模式。尽管目前的HLH疗法存在不足，但十多年来在治疗方面没有取得重大进展。通过提出的研究，我们打算通过靶向jak依赖性细胞因子网络来改善HLH患者的预后，这是一种新的合理的治疗方法。为了促进这些研究的成功完成，我们召集了一个强大的调查小组，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）。这个团队的成员都是HLH生物学和细胞因子信号传导、人类疾病临床前建模和研究成果从实验室到床边的转化方面的专家。因此，如果这项研究继续显示出有益的效果，我们预计其结果可以很容易地以未来以鲁索利替尼为基础的儿童和成人HLH试验的形式转化为临床。

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.