IL-12 as an immunopotentiator in leishmaniasis

IL-12 作为利什曼病的免疫增强剂

• 批准号: 7038208
• 负责人: PHILLIP SCOTT
• 金额: $ 38.69万
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038208
• 关键词: Leishmania major; RNase protection assay; T cell receptor; T lymphocyte; antigen antibody reaction; antigen presentation; cell sorting; cellular immunity; dendritic cells; enzyme linked immunosorbent assay; flow cytometry; genetically modified animals; helper T lymphocyte; immunocytochemistry; immunologic memory; immunoregulation; interleukin 12; intracellular parasitism; laboratory mouse; leishmaniasis; leukocyte activation /transformation; natural killer cells; polymerase chain reaction; 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 Thl 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 Thl response. However, despite a great increase in our knowledge of the events that are associated with the development of Thl 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 Thl 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 Thl 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 a leishmanial antigen. The donor cells will be followed in the recipient mice to assess their trafficking patterns, cytokine production and life span. 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 CD40-CD40L interactions are not required for maintenance of 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）：已广泛使用了小鼠的实验利什曼原虫，以了解细胞介导的免疫（CMI）如何发展，并专门定义了在激活T细胞后观察到THL还是TH2反应的因素。此类研究清楚地表明，IL-12在抗药性和THL反应的发展中起着重要作用。但是，尽管我们对与THL响应发展相关的事件的了解大大增加了，但对控制CMI维护的规则几乎没有理解。我们的实验室最近表明，IL-12不仅需要启动THL细胞发育，而且还需要维持这种反应。该提案旨在确定IL-12如何参与CMI，因此，这样做将更广泛地研究免疫记忆如何在主要愈合的小鼠中起作用。我们的具体目的解决了CMI的三个关键组成部分：记忆T细胞功能（AIM 1），抗原在此情况下，寄生虫持久性的作用（AIM 2）以及特定于树突的辅助细胞特定的树突状细胞 - 既存在抗原又会影响T细胞的性质（AIM 3）。该提议的工作假设是CMI需要从非极化T细胞池中持续更新THL群体。为了检验该假设，提出了一系列的收养转移实验，包括常规T细胞以及识别利什曼抗原的TCR转基因T细胞。供体细胞将在接受者小鼠中遵循，以评估其运输模式，细胞因子的产生和寿命。对寄生虫持久性作用的分析将使用感染小鼠但无法生存的主要（DHFR-TS-）胸苷型胸腺胺辅助营养营。最后，将通过表征与抗性相关的树突状细胞反应来评估抗原表现的作用。该实验室的初步研究表明，维持免疫力并不需要CD40-CD40L相互作用，在此目的中，将测试TR的补偿性作用。总体而言，这些实验应清楚地了解T细胞，树突状细胞和维持细胞介导的免疫所需的持续寄生虫之间的动态相互作用。