Immunochemotherapy in Visceral Leishmaniasis

内脏利什曼病的免疫化疗

• 批准号: 8210939
• 负责人: HENRY W. MURRAY
• 金额: $ 48.29万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-05 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8210939
• 关键词: 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one; Aftercare; Animals; Antimony; Cells; Clinical Management; Cytokine Network Pathway; Disabled Persons; Distal; Effectiveness; Ensure; Equilibrium; Future; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Granuloma; Granuloma by Site; Granulomatous; Health; Host Defense; Host Defense Mechanism; Immune; Immune response; Infection; Infection Control; Infection prevention; Inflammation; Inflammatory; Interleukin-10; Interleukin-12; Interleukin-6; Intervention; Learning; Leishmania donovani; Link; MAPK3 gene; Macrophage Activation; Methods; Mission; Mitogen-Activated Protein Kinases; Modeling; Mononuclear; Network-based; Outcome; Parasites; Parasitic Diseases; Pathogenesis; Pathway interactions; Patients; Phagocytes; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Prevention; Relapse; Research; Residual state; Resistance; Rest; Route; Signal Transduction; Signal Transduction Pathway; Site; Solid; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Time; Tissues; Toll-Like Receptor 2; Treatment Effectiveness; Treatment Efficacy; Treatment outcome; Vaccines; Visceral; Visceral Leishmaniasis; Work; cancer immunotherapy; chemokine; chemotherapy; cytokine; improved; in vivo; in vivo Model; killings; macrophage; monocyte; neglect; novel; prevent; public health relevance; research study; response; success; treatment duration; treatment effect

DESCRIPTION (provided by applicant): The goal of this research is to improve the efficacy of treatment in patients with visceral leishmaniasis (VL). In VL, parasites target, deactivate and replicate within tissue macrophages. Replication does not cease nor are parasites killed unless macrophage-activating host immune mechanisms supervene or chemotherapy is given. A logical route to optimizing treatment, then, is combining activated host mechanisms with chemotherapy. This project's objective is to understand how host mechanisms act with chemotherapy to amplify and accelerate the initial response to drug and produce long-lasting post-treatment effects to prevent relapse. VL is an ideal candidate for immunochemotherapy and its testing, since in this infection: (a) there is no vaccine, making drug therapy the mainstay of clinical management, (b) available chemotherapy is not optimal, (c) experimental understanding of mechanisms which activate or deactivate resistance is solid and ready to be built upon, (d) candidate host mechanisms can be identified in an in vivo model, and (e) experimental adjustment of these mechanisms is both feasible and therapeutic in established visceral infection. Nonetheless, gaps exist in our pathogenetic understanding of specific host mechanisms to target in VL and in how to best formulate and apply immunochemotherapy. Our proposed work in a model of Leishmania donovani (Ld) infection will fill in these gaps, laying the groundwork for future interventions to employ with chemotherapy. To accomplish the Specific Aims, the Research Plan tests responses in vivo, effects in established infection and hypotheses in the relevant tissue focus where parasitized macrophages, influxing monocytes and T cells, and up- and downregulating immunoinflammatory mechanisms all intersect with drug. Aim 1: Determine how host Th1 mechanisms transform chemotherapy to leishmanicidal. Aim 1 tests mechanisms which govern responses to drug within the assembled tissue granuloma: mononuclear cell recruitment by potentially therapeutic chemokines, GM-CSF-induced blood monocyte influx and granuloma remodeling, and effects which alter drug pharmacology in encircled, parasitized macrophages. Aim 2: Characterize and then disable both proximal and distal targets in a counter regulatory, deactivating mechanism which drives pathogenesis and limits chemotherapy. Aim 2 tests the mechanism's distal effector products (IL-6, TGF-2, IL-27) which reside in an IL-10-based network of deactivating cytokines and then its more proximal initiation by TLR (TLR2) and MAPK (ERK1/2) signal transduction. Aim 3: Analyze how chemo- therapy activates host immune mechanisms. Aim 3 examines the novel converse idea that drug therapy itself triggers identifiable, relevant and exploitable host defense mechanisms to ensure overall efficacy. Aim 3's plan tests direct effects on macrophage mechanisms at the time of drug therapy, and then focuses on the post-treatment period, when a chemotherapy-induced, IL-12- and iNOS/phox-independent mechanism emerges to orchestrate quiescence of persistent tissue infection and the long-term, relapse-free state. PUBLIC HEALTH RELEVANCE: This research improving treatment in patients with visceral leishmaniasis (kala-azar) is relevant to NIH's health mission for three reasons: (a) this infection is a most neglected parasitic disease with recognized significance in endemic regions, (b) without vaccine to prevent infection, the only practical avenue to advancing its clinical management is new treatment approaches, and (c) this experimental research in animals will show how to best harness host immune mechanisms to meaningfully enhance effectiveness of antileishmanial drug therapy. To develop and apply combination immunochemotherapy, our research objectives are to amplify and accelerate initial drug-induced parasite killing and strengthen long-lasting effects to prevent post-treatment relapse of residual visceral infection. This project's objectives and experimental strategies also hold the promise of improving treatment in other similar infections in which host defense depends on optimally activating T cell- dependent immune mechanisms.

描述（由申请人提供）：本研究的目标是提高内脏利什曼病（VL）患者的治疗效果。在 VL 中，寄生虫瞄准组织巨噬细胞、使其失活并在组织巨噬细胞内复制。除非巨噬细胞激活宿主免疫机制随之出现或给予化疗，否则复制不会停止，寄生虫也不会被杀死。因此，优化治疗的合理途径是将激活的宿主机制与化疗相结合。该项目的目标是了解宿主机制如何与化疗一起作用，以放大和加速对药物的初始反应，并产生持久的治疗后效果以防止复发。 VL 是免疫化疗及其测试的理想候选者，因为在这种感染中：(a) 没有疫苗，使得药物治疗成为临床管理的支柱，(b) 可用的化疗不是最佳的，(c) 对机制的实验了解激活或失活抵抗力是可靠的，可以建立起来，（d）可以在体内模型中识别候选宿主机制，（e）这些机制的实验调整在已建立的内脏感染中既可行又具有治疗作用。 尽管如此，我们对 VL 靶向的特定宿主机制以及如何最好地制定和应用免疫化疗的发病机制理解仍存在差距。我们提出的杜氏利什曼原虫 (Ld) 感染模型研究将填补这些空白，为未来与化疗结合使用的干预措施奠定基础。为了实现具体目标，该研究计划测试体内反应、已确定感染的影响以及相关组织焦点的假设，其中寄生的巨噬细胞、涌入的单核细胞和T细胞以及上调和下调免疫炎症机制都与药物相交叉。 目标 1：确定宿主 Th1 机制如何将化疗转变为杀利什曼病。目标 1 测试在组装的组织肉芽肿内控制药物反应的机制：潜在治疗趋化因子的单核细胞募集、GM-CSF 诱导的血液单核细胞流入和肉芽肿重塑，以及改变包围的寄生巨噬细胞中药物药理学的作用。目标 2：表征并禁用反调节、失活机制中的近端和远端靶点，从而驱动发病机制并限制化疗。目标 2 测试该机制的远端效应产物（IL-6、TGF-2、IL-27），这些产物驻留在基于 IL-10 的失活细胞因子网络中，然后由 TLR (TLR2) 和 MAPK (ERK1/ 2）信号转导。目标 3：分析化疗如何激活宿主免疫机制。目标 3 检验了新的逆向想法，即药物治疗本身会触发可识别、相关和可利用的宿主防御机制，以确保整体疗效。 Aim 3 的计划测试药物治疗时对巨噬细胞机制的直接影响，然后重点关注治疗后阶段，此时化疗诱导的、IL-12 和 iNOS/phox 独立机制出现，协调持久性组织的静止状态感染和长期、无复发状态。 公共健康相关性：这项改善内脏利什曼病（黑热病）患者治疗的研究与 NIH 的健康使命相关，原因有以下三个：(a) 这种感染是一种最被忽视的寄生虫病，在流行地区具有公认的重要性，(b)疫苗来预防感染，推进其临床管理的唯一实际途径是新的治疗方法，并且（c）这项动物实验研究将展示如何最好地利用宿主免疫机制来有意义地提高有效性抗利什曼病药物治疗。为了开发和应用联合免疫化疗，我们的研究目标是放大和加速药物诱导的初始寄生虫杀灭，并加强持久效果，以防止残留内脏感染的治疗后复发。该项目的目标和实验策略还有望改善其他类似感染的治疗，在这些感染中，宿主防御依赖于最佳激活 T 细胞依赖性免疫机制。