HOST IMMUNOREGULATION OF ANTILEISHMANIAL CHEMOTHERAPY

抗利什曼原虫化疗的宿主免疫调节

• 批准号: 6631645
• 负责人: HENRY W. MURRAY
• 金额: $ 50.16万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-09-30 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6631645
• 关键词: CD28 molecule; CD40 molecule; Leishmania donovani; T lymphocyte; amphotericin B; antimony; antiprotozoal agents; host organism interaction; immunoregulation; interferon gamma; interleukin 10; interleukin 12; intracellular parasitism; laboratory mouse; leishmaniasis; nonhuman therapy evaluation; parasitic disease chemotherapy; pharmacokinetics; prostaglandin endoperoxide synthase; tissue /cell culture

DESCRIPTION (provided by the applicant): Since there is no vaccine to prevent visceral leishmaniasis (VL) (kala-azar), a disseminated intracellular protozoal infection, its practical management revolves around successful drug therapy. Pentavalent antimony (Sb) remains the conventional, albeit suboptimal and now less effective, treatment of choice. To formulate new therapeutic strategies in kala-azar, the two logical complementary approaches are (a) new drug development (amphotericin B (AmB), miltefosine) and (b) identification of immunologic mechanisms which can be regulated and translated into treatment. This application focuses on immuno-regulation of successful host responses to antileishmanial chemotherapy and is directed at the effects of T cells and cytokines. This area of research, immunochemotherapy, is relevant to the field with future as well as already-realized clinical impact. The overall objective is to optimize the host response to treatment by characterizing and then manipulating key immuno-regulatory mechanisms in favor of the host receiving chemotherapy. The unifying hypothesis is that, once targeted, discrete mechanisms can be stimulated or inhibited and then joined with chemotherapy to enhance initial intracellular Leishmania donovani killing in the tissues and also prevent post-treatment relapse. To accomplish the objective and test this translational research strategy, this work wilt be carried out in a clinically relevant sequential fashion and will (a) be directed at in vivo responses, (b) test hypotheses in established infection and (c) incorporate more than one chemotherapeutic agent to probe the host response to current (Sb) as well as more newly used treatments (AmB). Three related Specific Aims support the overall objective and will advance the analysis: Aim 1: Determine how lFN-gamma (Th1 cell-associated response) regulates the response to Sb and converts its action from leishmanistatic to leishmanicidal. Aim 2: Test the hypothesis that synergy with antileishmanial chemotherapy can be induced by specific, linked pharmacologic intervention designed to raise intrinsic host T cell reactivity by: (a) neutralizing the suppressive effect of endogenous interleukin 10, (b) enhancing interleukin 12 action by inhibiting cyclooxygenase-2 (COX2), and (c) triggering antileishmanial T cell costimulatory pathways, CD28:B7 and CD4OL:CD4O. And Aim 3: Characterize immunostimulation in AmB's efficacy, and in recrudescent infection following AmB therapy, pinpoint the likely cytokine-driven T cell mechanism which prevents post-treatment relapse.

描述（由申请人提供）：由于没有疫苗可以预防 内脏利什曼病 (VL)（黑热病），一种播散性细胞内原虫 感染，其实际管理围绕成功的药物治疗。 五价锑 (Sb) 仍然是传统的，尽管不是最理想的，现在 效果较差，首选治疗。制定新的治疗策略 黑热病，两种逻辑上互补的方法是 (a) 新药 开发（两性霉素 B (AmB)、米替福辛）和 (b) 鉴定 可以调节并转化为治疗的免疫机制。 该应用重点关注成功宿主反应的免疫调节 抗利什曼病化疗针对 T 细胞和 细胞因子。这个研究领域，免疫化疗，与该领域相关 具有未来以及已经实现的临床影响。总体目标 是通过表征来优化宿主对治疗的反应，然后 操纵关键的免疫调节机制有利于宿主接受 化疗。统一的假设是，一旦确定目标，离散的 可以刺激或抑制机制，然后与化疗联合使用 增强组织中细胞内杜氏利什曼原虫的初始杀伤能力 还可预防治疗后复发。为了实现目标并测试这一点 转化研究策略，这项工作将在临床上进行 相关的顺序方式并将（a）针对体内反应，（b） 在已确定的感染中检验假设，并且 (c) 合并多个 化疗剂来探测宿主对电流（Sb）的反应以及 更多新使用的治疗方法 (AmB)。 三个相关的具体目标支持总体目标，并将推动 分析：目标 1：确定 IFN-gamma（Th1 细胞相关反应）如何 调节对 Sb 的反应并将其作用从抑制利什曼病转变为 利什曼杀戮。目标 2：检验与抗利什曼尼具有协同作用的假设 化疗可以通过特定的、相关的药物干预来诱导 旨在通过以下方式提高内在宿主 T 细胞反应性：(a) 中和 内源性白细胞介素 10 的抑制作用，(b) 增强白细胞介素 12 的作用 通过抑制环氧合酶-2 (COX2) 发挥作用，以及 (c) 触发 抗利什曼病 T 细胞共刺激途径，CD28:B7 和 CD4OL:CD4O。和目标 图 3：表征 AmB 功效和复发中免疫刺激的特征 AmB 治疗后感染，查明可能的细胞因子驱动的 T 细胞 防止治疗后复发的机制。