Improved Treatment of American Cutaneous Leishmaniasis by Immunomodulation

通过免疫调节改善美国皮肤利什曼病的治疗

基本信息

批准号：
8636396
负责人：
Nancy Gore Saravia
金额：
$ 66.96万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8636396
关键词：
Adjuvant Antigens Benefits and Risks Cell physiology Cells Central America Child Chronic Chronic Disease Clinical Colombia Country Cutaneous Cutaneous Leishmaniasis Dermal Detection Development Disease Drug Delivery Systems Drug Formulations Effectiveness Experimental Models Genetic Healed Health Human Immune Immune response Immunocompetent Immunologics Immunomodulators Immunotherapeutic agent Immunotherapy Individual Infection Inflammatory Response Intervention Leishmania Leishmania viannia Leishmaniasis Life Link Local Therapy Macrophage Activation Measures Mediating Meta-Analysis Miltefosine Modeling Mucocutaneous leishmaniasis Mus Outcome Parasites Parasitic Diseases Pathogenesis Patients Pentamidine Pentoxifylline Pharmaceutical Preparations Phenotype Population Predisposition Reaction Refractory Regulatory T-Lymphocyte Resistance Resolution Role Side South America T cell differentiation T-Lymphocyte Technology Therapeutic Toxic effect Translating Treatment Protocols Viannia base chemotherapy cytokine disorder control experience healing immune function immunoregulation improved innovation mouse model nanoparticle preclinical evaluation response standard of care

项目摘要

DESCRIPTION (provided by applicant): Passive case detection and treatment constitute the principal, often the sole measure of control for cutaneous leishmaniasis (CL) in Central and South America yet first line therapies (pentavalent antimonials, pentamidine and miltefosine) are often ineffective (overall non response is of the order of 24% based on a recent meta analysis [1]) and poorly tolerated. Since pathogenesis of dermal leishmaniasis is mediated by the immune and inflammatory responses, resolution of disease and control of infection are intimately linked to the host response. Consequently, antileishmanial drugs alone are often insufficient to clinically resolve disease even in immunocompetent individuals, and furthermore, do not eliminate infection [2-6]. Although immune mechanisms underlying the outcome of infection differ among Leishmania species [7], non-healing phenotypes of infection by different species can be converted to healing phenotypes and vice versa by intervention of the host immune response [8-12]. In experimental models, a wide range of interventions (including deletion of T cell populations, neutralization or genetic depletion of cytokines that drive T cell differentiation, down regulate macrophage activation, or modulate T regulatory cell function) invert susceptibility and resistance. Importantly, these interventions have broadly targeted immune function rather than responses to specific parasite antigens. The feasibility of translating this experience with murine models to human leishmaniasis is supported by the clinical resolution of cutaneous and mucosal disease unresponsive to chemotherapy alone, by co-adjuvant immunotherapy [13-17]. However, neither the immunological basis of the healing response enabled by these interventions, the mechanisms involved nor the generalizability of any immunotherapeutic intervention (to different species of Leishmania or for the spectrum of clinical outcomes) has been determined. Local as well as systemic and combined therapies have recently been recommended as alternatives for New World cutaneous leishmaniasis by the WHO Expert Committee on Leishmaniasis. Risk/benefit considerations of the toxicity of current systemic treatment regimens, persistence of infection following treatment, and evidence of the effectiveness of various local therapies compelled the amplification of therapeutic options to include local and combined strategies. Such strategies may be optimized through innovative delivery of antileishmanial drugs and immunomodulators via nanoparticle technology. This project seeks to identify the immunologic bases of healing of cutaneous leishmaniasis caused by Leishmania Viannia species, and to discern the mechanisms of immunomodulation that together with chemotherapy, improve clinical outcome, reduce parasite burden and persistence, and preserve the effective life of antileishmanial drugs.

描述（由申请人提供）：被动病例检测和治疗构成了主要的措施，在中美洲和南美洲皮肤利什曼病（CL）的控制唯一措施却是第一线疗法（五价抗微药物，五一个氨基氨基和米尔特福蛋白）通常是无效的（总体上不反应）基于24％的速度，是基于24％的vor vor [1]和1）。由于皮肤利什曼病的发病机理是由免疫和炎症反应介导的，因此疾病的分辨率和感染的控制与宿主反应密切相关。因此，即使在免疫能力的个体中，仅抗精神病药也通常不足以解决临床上的疾病，此外，也不会消除感染[2-6]。尽管利什曼原虫物种的感染结果背后的免疫机制[7]不同，但不同物种感染的非治疗表型可以通过宿主免疫反应的干预转化为愈合表型，反之亦然[8-12]。在实验模型中，多种干预措施（包括删除T细胞群体，中和或遗传耗尽的细胞因子驱动T细胞分化，下调巨噬细胞激活或调节T调节细胞功能）反应敏感性和抵抗力。重要的是，这些干预措施具有广泛针对的免疫功能，而不是对特定寄生虫抗原的反应。通过共辅助免疫疗法将皮肤和粘膜疾病无反应的皮肤和粘膜疾病无反应的临床解决，将这种用鼠模型的经验转化为人类利什曼病的可行性得到了支持[13-17]。但是，尚未确定这些干预措施，涉及的机制以及任何免疫治疗干预措施（对利什曼尼亚不同物种或临床结果范围）的概括性的愈合反应的免疫学基础。 WHO利什曼病专家委员会推荐了当地以及系统性和联合疗法作为新世界皮肤利什曼病的替代方法。风险/收益考虑当前系统治疗方案的毒性，治疗后感染的持久性以及各种局部疗法有效性的证据迫使治疗方案的扩增，以包括局部和合并的策略。可以通过纳米颗粒技术的抗精神病药和免疫调节剂的创新输送来优化此类策略。该项目旨在确定由利什曼原虫（Leishmania Viannia）物种引起的皮肤利什曼病的治疗基础，并辨别免疫调节的机制，这些机制与化学疗法一起，改善临床结果，减少寄生虫负担和持久性，并保留抗精性药物的有效生命。