IL12 AS AN IMMUNOPOTENTIATOR IN LEISHMANIASIS

IL12 作为利什曼病的免疫增强剂

• 批准号: 6373386
• 负责人: PHILLIP SCOTT
• 金额: $ 37.98万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6373386
• 关键词: Leishmania major; T lymphocyte; bioassay; cell differentiation; cellular immunity; disease /disorder model; enzyme linked immunosorbent assay; genetically modified animals; helper T lymphocyte; immunization; immunomodulators; immunotherapy; interferon gamma; interleukin 12; laboratory mouse; leishmaniasis; microorganism disease chemotherapy; microorganism genetics; natural killer cells; polymerase chain reaction; protozoal vaccine; receptor expression

Leishmaniasis is a widespread and debilitating protozoal disease of man and animals. An improved understanding of the immunologic aspects of this infection should provide the basis for new therapies. We propose to study how IL-12 can be used to promote the development of a protective immune response, specifically focusing on the development of a therapeutic vaccine for chronic cutaneous leishmaniasis. Experimental infections in mice mimic to a large extent the spectrum of clinical presentations associated with human disease, and have been used extensively to study immunologic responses in leishmaniasis. From such studies we have learned a great deal about the factors involved in the differentiation and regulation of T cell subsets. Our hypothesis is that during chronic leishmanial infections mice are non-responsive to IL-12, leading to the inability to promote the development of a Th1-type immune response. We will define the factors that regulate IL-12 responsiveness, by identifying the cells that need to respond to IL-12 in order to shift a T cell population from a Th2 to a Th1 phenotype, defining the requirements for CD28-B7 interactions for effective IL-12 function, and determining what regulates the IL-12 receptor during Leishmania infection. Our approach will be to manipulate in vitro and in vivo levels of cytokines and costimulatory interactions to promote a shift in the Th2 population from L. major infected BALB/c mice towards a protective Th1 phenotype. We will use an in vitro system to define the cells and cytokines involved in switching, and we will then validate our in vitro findings with in vivo studies. Because antigen-reactive cells are difficult to track, due to their low frequency in a normal (or even infected) animal and the lack of reagents that specifically identify them, for some studies we will use cells from an OVA T cell receptor (TCR) transgenic mouse (DO11.10) in combination with an OVA expressing L. major parasite. The expression of OVA by L. major establishes this antigen as a model parasite antigen, that will be exposed to the same environment that shapes the T cell response to other antigens produced by L. major. An additional advantage to using DO11.10 TCR transgenic mice is that regulation of the IL-12 receptor by these T cells has been well studied. We will apply the information gained from these in vitro studies to design the best approach for promoting a Th1 response in infected L. major infected mice using a therapeutic vaccine.

利什曼病是一种广泛传播的使人衰弱的原虫病 和动物 提高对免疫学方面的理解， 这种感染应该为新的治疗方法提供基础。 我们提出 研究IL-12如何用于促进 保护性免疫反应，特别是侧重于发展 一种慢性皮肤利什曼病的治疗性疫苗。 实验 小鼠中的感染在很大程度上模拟了 与人类疾病相关的表现，并已被用于 广泛研究利什曼病的免疫反应。 从该等 研究我们已经了解了很多有关的因素， T细胞亚群的分化和调节。 我们的假设是 在慢性利什曼原虫感染期间，小鼠对 IL-12，导致不能促进Th 1型 免疫反应 我们将定义调节IL-12的因子 通过识别需要对IL-12做出反应的细胞， 为了将T细胞群从Th 2表型转变为Th 1表型， 定义有效IL-12的CD 28-B7相互作用的要求 功能，并确定是什么调节IL-12受体， 利什曼原虫感染。 我们的方法是在体外操纵， 细胞因子和共刺激相互作用的体内水平， Th 2群体从L.主要感染BALB/c小鼠， 保护性Th 1表型。我们将使用体外系统来定义 细胞和细胞因子参与转换，然后我们将验证我们的 体外研究结果与体内研究结果。 因为抗原反应细胞 很难跟踪，因为它们在正常（甚至 感染）动物和缺乏试剂，具体确定 在一些研究中，我们将使用来自OVA T细胞受体的细胞， (TCR)转基因小鼠（DO11.10）与表达OVA的小鼠组合， L.主要寄生虫 用L.少校确立了这一点 抗原作为模型寄生虫抗原，将暴露于相同的抗原 环境，塑造T细胞对其他抗原产生的反应 由L.少校 使用DO11.10 TCR转基因的另一个优势 这些T细胞对IL-12受体的调节已经被 好好研究。 我们将应用这些信息在体外 研究设计促进Th 1应答的最佳方法， 感染L.主要感染小鼠使用治疗性疫苗。