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

• 批准号: 8438476
• 负责人: Nancy Gore Saravia
• 金额: $ 62.7万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438476
• 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

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中美洲和南美洲皮肤利什曼病 (CL) 的主要控制措施，通常是唯一的控制措施，但一线疗法（五价锑剂、喷他脒和米替福辛）通常无效（根据最近的荟萃分析，总体无反应率为 24% [1]）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，单独的抗利什曼病药物也常常不足以在临床上解决疾病，而且不能消除感染[2-6]。 尽管利什曼原虫物种之间感染结果的免疫机制有所不同[7]，但通过宿主免疫反应的干预，不同物种感染的非治愈表型可以转化为治愈表型，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、中和或基因敲除驱动 T 细胞分化的细胞因子、下调巨噬细胞活化或调节 T 调节细胞功能）可逆转敏感性和耐药性。重要的是，这些干预措施广泛针对免疫功能，而不是针对特定寄生虫抗原的反应。通过联合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支持了将小鼠模型的这一经验转化为人类利什曼病的可行性[13-17]。然而，这些干预措施所带来的治愈反应的免疫学基础、所涉及的机制以及任何免疫治疗干预措施（针对不同利什曼原虫种类或临床结果范围）的普遍性都尚未确定。 世界卫生组织利什曼病专家委员会最近推荐局部、全身和联合疗法作为新世界皮肤利什曼病的替代疗法。当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疗法有效性的证据的风险/效益考虑迫使治疗方案的扩大，包括局部和联合策略。这些策略可以通过纳米颗粒技术创新地递送抗利什曼病药物和免疫调节剂来优化。 该项目旨在确定由维尼亚利什曼原虫引起的皮肤利什曼病治愈的免疫学基础，并了解免疫调节机制，与化疗结合使用，改善临床结果，减少寄生虫负担和持久性，并保持抗利什曼病药物的有效寿命。