Immunochemotherapy in Visceral Leishmaniasis

内脏利什曼病的免疫化疗

基本信息

批准号：
8602801
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
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-05 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8602801
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

项目摘要

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.

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。