INTERLEUKIN 12 AS IMMUNOTHERAPY IN LEISHMANIASIS

白细胞介素 12 作为利什曼病的免疫治疗

• 批准号: 2886914
• 负责人: FREDERICK P. HEINZEL
• 金额: $ 20.64万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2886914
• 关键词: CD40 molecule; T lymphocyte; cellular immunity; combination therapy; cytokine receptors; dendritic cells; enzyme linked immunosorbent assay; immunotherapy; interleukin 12; interleukin 4; laboratory mouse; leishmaniasis; leukocyte activation /transformation; macrophage; microorganism culture; microorganism immunology; nonhuman therapy evaluation; polymerase chain reaction; statistics /biometry

Leishmaniasis is a chronic parasitic infection of humans that has emerged as a significant health care problem wold-wide. Using a well- characterized mouse model of healing or progressive cutaneous infection in leishmaniasis to investigations on how IL-12 is regulated by the accessory cell receptor protein, CD40. CD40 is activated by antigen-specific T cells bearing the CD40 ligand and induces IL-12 necessary for Th1 CD4+ cellular responses and cure. Our preliminary data demonstrate CD40-dependent increased synthesis of IL-12 in healing leishmaniasis and show that susceptible BALB/c mice underproduce IL-12 due to CD40 dysfunction and/or decreased accessory cell numbers as disease progresses. We hypothesize that a wide range of CD40 dependent responses jointly promote cure, whereas CD40 dysfunction maintains susceptibility. Our second goal is to use insights gained in these studies to design immunotherapies effective against progressive leishmaniasis, a disease mediated by inappropriate Th2 T cell responses that are IL-12 unresponsive. We hypothesize that the T cell response can be "reset" to an IL-12 responsive state by transient CD4+ cell depletion or that in vivo activation of CD40 by soluble ligand or monoclonal antibody will induce therapeutic microbicidal responses and/or restore IL-12 regulatory effects. Preliminary data support the effectiveness of these proposed immunotherapies. Our specific aims are to: 1. Determine the molecular and cellular basis of IL-12 production during healing or progressive leishmaniasis in resistant C57BL/6 and susceptible BALB\c mice. 2. Determine the full range of protective immune responses dependent on CD40. 3. Identify the lesion(s) responsible for strain dependent differences in IL-12 production during leishmaniasis. These aims are significant in that they address biologic mechanisms responsible for coordinating complex immune responses important in defense against intracellular parasitism and implicated in autoimmunity and transplant rejection. The proposed strategies for reversing pathologic Th- 2 cell responses by "resetting" the T cell response are novel approaches that may be widely applicable to immunotherapy of other Th2-mediated diseases, including severe atopic disorders and helminth-induced pathology.

利什曼病是一种人类慢性寄生虫感染， 成为世界范围内一个重大的卫生保健问题。利用一口井- 特征性小鼠模型的愈合或进行性皮肤感染， 利什曼病的研究IL-12是如何调节的附件 细胞受体蛋白CD 40。CD 40被抗原特异性T细胞激活 携带CD 40配体并诱导Th 1 CD 4+细胞所必需的IL-12 回应与治愈我们的初步数据表明CD 40依赖性 IL-12的合成增加，并显示 易感BALB/c小鼠由于CD 40功能障碍而产生IL-12不足，和/或 随着疾病的进展，辅助细胞数量减少。我们假设 广泛的CD 40依赖性应答共同促进治愈， 而CD 40功能障碍维持易感性。我们的第二个目标是 利用这些研究中获得的见解来设计有效的免疫疗法 针对进行性利什曼病，一种由不适当的Th 2介导的疾病 IL-12无反应的T细胞反应。我们假设T 细胞应答可以通过瞬时的IL-12激活而“重置”到IL-12应答状态 CD 4+细胞耗竭或可溶性配体在体内激活CD 40 或单克隆抗体将诱导治疗性杀微生物反应 和/或恢复IL-12调节作用。初步数据支持 这些免疫疗法的有效性。 我们的具体目标是： 1.确定IL-12产生的分子和细胞基础， 耐药C57 BL/6和易感C57 BL/6的利什曼病的愈合或进行性利什曼病 BALB\c小鼠。 2.确定全方位的保护性免疫反应取决于 CD40。 3.确定导致应变依赖性差异的病变， 利什曼病期间IL-12的产生。 这些目标的重要性在于它们涉及生物学机制 负责协调复杂的免疫反应， 对抗细胞内寄生虫，并与自身免疫有关， 移植排斥反应提出的逆转病理性Th的策略 通过“重置”T细胞反应的2细胞反应是新的方法 这可能广泛适用于其他Th 2介导的免疫治疗， 包括严重特应性疾病和蠕虫引起的 病理