INTERLEUKIN 12 AS IMMUNOTHERAPY IN LEISHMANIASIS

利什曼病是人类的一种慢性寄生性感染，具有 成为世界范围内的一个重大的医疗保健问题。用一口井- 具有愈合或进行性皮肤感染的特征的小鼠模型 利什曼病对IL-12如何受附件调节的研究 细胞受体蛋白CD40。CD40被抗原特异性T细胞激活 携带CD40配体并诱导Th1CD4细胞所需的IL-12 回应和治疗。我们的初步数据显示CD40依赖于 IL-12在治疗利什曼病中的合成增加，表明 易感BALB/c小鼠由于CD40功能障碍和/或产生IL-12不足 随着疾病的发展，副细胞数量减少。我们假设 广泛的CD40依赖反应共同促进治愈， 而CD40功能障碍则维持易感性。我们的第二个目标是 利用在这些研究中获得的见解来设计有效的免疫疗法 抗进行性利什曼病，一种由不适当的Th2介导的疾病 对IL-12无反应的T细胞反应。我们假设T 细胞反应可以通过瞬间“重置”到IL-12的反应状态 CD_4细胞耗竭或可溶性配体体内激活CD_(40) 或单抗会引发治疗性杀微生物剂反应 和/或恢复IL-12的调节作用。初步数据支持 这些拟议的免疫疗法的有效性。 我们的具体目标是： 1.确定IL-12产生的分子和细胞基础 耐药的C57BL/6和易感人群中的治愈或进行性利什曼病 Balb\c小鼠。 2.确定全面的保护性免疫反应依赖于 CD40。 3.确定引起菌株依赖性差异的病变(S) 利什曼病时IL-12的产生。 这些目标具有重要意义，因为它们涉及生物机制。 负责协调在防御中重要的复杂免疫反应 对抗细胞内寄生，并与自身免疫和 移植排斥反应。建议的逆转病理性Th-1的策略 2“重置”T细胞反应是一种新的方法 这可能广泛适用于其他Th2介导的免疫治疗 疾病，包括严重的特应性疾病和蠕虫引起的疾病 病理学。

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.