IL-12 as an immunopotentiator in leishmaniasis

IL-12 作为利什曼病的免疫增强剂

• 批准号: 6547493
• 负责人: PHILLIP SCOTT
• 金额: $ 39.63万
• 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 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6547493
• 关键词: Leishmania major; T lymphocyte; antigen presentation; bioassay; cell differentiation; cellular immunity; dendritic cells; disease /disorder model; enzyme linked immunosorbent assay; genetically modified animals; helper T lymphocyte; immunization; immunologic memory; immunomodulators; immunotherapy; interferon gamma; interleukin 12; laboratory mouse; leishmaniasis; microorganism disease chemotherapy; microorganism genetics; natural killer cells; polymerase chain reaction; protozoal vaccine; receptor expression

DESCRIPTION (provided by the applicant): Experimental Leishmania major infections in mice have been used extensively to understand how cell-mediated immunity (CMI) develops, and to specifically define the factors that dictate whether a Th1 or Th2 response is observed after activation of T cells. Such studies have clearly shown an important role for IL-12 in the development of resistance and a Th1 response. However, despite a great increase in our knowledge of the events that are associated with the development of Th1 responses, little is understood about the rules that govern the maintenance of CMI. Our laboratory has recently shown that IL- 12 is required not only to initiate Thi cell development, but also to maintain this response. This proposal seeks to determine how IL-12 participates in maintaining CMI, and in so doing will more broadly investigate how immunologic memory works in L. major healed mice. Our specific aims address the three critical components for CMI: memory T cell function (Aim 1), the antigen-in this case the role of parasite persistence (Aim 2), and the accessory cells-specifically dendritic cells-that both present antigen and influence the nature of the T cells that develop (Aim 3). The working hypothesis of this proposal is that CMI requires the constant renewal of the Thi population from a non-polarized pool of T cells. To test this hypothesis a series of adoptive transfer experiments are proposed, both with conventional T cells, as well as TCR transgenic T cells recognizing Leishmania and non-Leishmania antigens. The donor cells will be tracked in the recipient mice to assess their fate. An analysis of the role of parasite persistence will use a L. major (dhfr-ts-) thymidine auxotroph that infects mice, but fails to survive. Finally, the role of antigen presentation will be assessed by characterizing the dendritic cell response associated with resistance. Preliminary studies from this laboratory demonstrated that CD4O-CD4OL interactions are not required for immunity, and in this aim, the compensatory role of TRANCE will be tested. Overall, these experiments should provide a clear picture of the dynamic interactions between T cells, dendritic cells and persisting parasites that are required to maintain cell-mediated immunity.

描述（由申请人提供）：小鼠中的实验性利什曼原虫主要感染已被广泛用于了解细胞介导的免疫（CMI）如何发展，并具体定义决定 T 细胞激活后是否观察到 Th1 或 Th2 反应的因素。此类研究清楚地表明 IL-12 在耐药性和 Th1 反应的发展中发挥着重要作用。然而，尽管我们对与 Th1 反应发展相关的事件的了解有了很大的增加，但对于控制 CMI 维持的规则却知之甚少。我们的实验室最近表明，IL-12 不仅是启动 Thi 细胞发育所必需的，而且也是维持这种反应所必需的。该提案旨在确定 IL-12 如何参与维持 CMI，从而更广泛地研究免疫记忆在 L.major 治愈小鼠中的作用。我们的具体目标涉及 CMI 的三个关键组成部分：记忆 T 细胞功能（目标 1）、抗原（在本例中是寄生虫持久性的作用）（目标 2）以及辅助细胞（特别是树突细胞），它们既呈现抗原又影响发育的 T 细胞的性质（目标 3）。该提案的工作假设是 CMI 需要来自非极化 T 细胞池的 Thi 群体不断更新。为了检验这一假设，提出了一系列过继转移实验，其中包括传统 T 细胞以及识别利什曼原虫和非利什曼原虫抗原的 TCR 转基因 T 细胞。将在受体小鼠体内追踪供体细胞以评估它们的命运。对寄生虫持久性作用的分析将使用 L. Major (dhfr-ts-) 胸苷营养缺陷型感染小鼠，但无法存活。最后，将通过表征与耐药性相关的树突细胞反应来评估抗原呈递的作用。该实验室的初步研究表明，CD4O-CD4OL 相互作用并不是免疫所必需的，为此，将测试 TRANCE 的代偿作用。总体而言，这些实验应该清晰地展示 T 细胞、树突状细胞和维持细胞介导免疫所需的持久寄生虫之间的动态相互作用。