Improved Treatment of American Cutaneous Leishmaniasis by Immunomodulation

描述（由申请人提供）：在中美洲和南美洲，被动病例检测和治疗是控制皮肤利什曼病（CL）的主要措施，通常是唯一措施，但一线治疗（五价锑、戊脒和米替福辛）通常无效（根据最近的荟萃分析[1]，总体无反应率约为24%）且耐受性差。由于皮肤利什曼病的发病机制是由免疫和炎症反应介导的，因此疾病的解决和感染的控制与宿主反应密切相关。因此，即使在免疫功能正常的个体中，单独使用抗利什曼原虫药物往往不足以在临床上解决疾病，而且不能消除感染[2-6]。尽管不同利什曼原虫物种之间感染结果的免疫机制不同，但通过干预宿主免疫反应，不同物种感染的非愈合表型可以转化为愈合表型，反之亦然[8-12]。在实验模型中，广泛的干预措施（包括T细胞群的缺失、驱动T细胞分化的细胞因子的中和或遗传耗竭、下调巨噬细胞激活或调节T调节细胞功能）逆转了易感性和耐药性。重要的是，这些干预措施广泛针对免疫功能，而不是对特定寄生虫抗原的反应。将小鼠模型的这一经验转化为人类利什曼病的可行性得到了辅助免疫治疗对单独化疗无反应的皮肤和粘膜疾病的临床解决的支持[13-17]。然而，这些干预措施所产生的愈合反应的免疫学基础、所涉及的机制以及任何免疫治疗干预（针对不同种类的利什曼原虫或临床结果的范围）的普遍性都尚未确定。世卫组织利什曼病专家委员会最近建议将局部以及全身和联合疗法作为新世界皮肤利什曼病的替代疗法。考虑到目前全身治疗方案的毒性、治疗后感染的持续性以及各种局部治疗有效性的证据，必须扩大治疗方案，包括局部和联合策略。这种策略可以通过纳米颗粒技术提供抗利什曼药物和免疫调节剂来优化。本项目旨在确定由利什曼原虫引起的皮肤利什曼病愈合的免疫学基础，并了解免疫调节机制与化疗结合，改善临床结果，减少寄生虫负担和持久性，并保持抗利什曼药物的有效寿命。

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.