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）：本研究的目的是提高内脏利什曼病（VL）患者的治疗效果。在VL中，寄生虫在组织巨噬细胞内靶向、失活和复制。除非巨噬细胞激活宿主免疫机制或给予化疗，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发挥作用，以放大和加速对药物的初始反应，并产生持久的治疗后效应，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主要手段，（B）可用的化学疗法不是最佳的，（c）对激活或灭活抗性的机制的实验理解是可靠的，并且可以建立在其基础上，（d）候选宿主机制可以在体内模型中鉴定，和（e）这些机制的实验性调整在已建立的内脏感染中是可行的和治疗性的。 尽管如此，差距存在于我们的特定宿主机制的发病机制的理解，以目标在VL和如何最好地制定和应用免疫化疗。我们提出的杜氏利什曼原虫（Ld）感染模型的工作将填补这些空白，为未来的干预与化疗奠定基础。为了实现特定目标，研究计划测试了体内反应、对已建立感染的影响以及相关组织病灶中的假设，其中寄生的巨噬细胞、流入的单核细胞和T细胞以及上调和下调免疫炎症机制均与药物交叉。 目的1：确定宿主Th 1机制如何将化疗转化为杀利什曼原虫。目的1测试在组装的组织肉芽肿内控制对药物的反应的机制：潜在治疗性趋化因子引起的单核细胞募集、GM-CSF诱导的血液单核细胞流入和肉芽肿重塑，以及在被包围的寄生的巨噬细胞中改变药物药理学的作用。目标二：表征近端和远端靶点，然后在反调节、失活机制中使其失效，该机制驱动发病机制并限制化疗。目的2检测该机制的远端效应产物（IL-6、TGF-2、IL-27），其存在于基于IL-10的失活细胞因子网络中，然后通过TLR（TLR 2）和MAPK（ERK 1/2）信号转导其更近端的启动。目的3：分析化疗如何激活宿主免疫机制.目的3探讨了新的匡威思维，即药物治疗本身触发可识别的，相关的和可利用的宿主防御机制，以确保整体疗效。Aim 3的计划在药物治疗时测试对巨噬细胞机制的直接影响，然后关注治疗后阶段，此时出现化疗诱导的IL-12和iNOS/phox非依赖性机制，以协调持续组织感染的静止和长期无复发状态。 公共卫生相关性：这项研究改善了内脏利什曼病患者的治疗，黑热病与NIH的健康使命相关，原因有三：（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）在没有疫苗预防感染的情况下，推进其临床管理的唯一实际途径是新的治疗方法，以及（c）该动物实验研究将显示如何最好地利用宿主免疫机制来有意义地增强抗利什曼病药物治疗的有效性。为了开发和应用联合免疫化疗，我们的研究目标是扩大和加速初始药物诱导的寄生虫杀灭，并加强持久的效果，以防止治疗后残留内脏感染复发。该项目的目标和实验策略也有望改善其他类似感染的治疗，其中宿主防御依赖于最佳激活T细胞依赖性免疫机制。