T CELLS IN SECONDARY LEISHMANIA INFECTIONS

继发性利什曼原虫感染中的 T 细胞

• 批准号: 2074463
• 负责人: INGRID M MULLER
• 金额: $ 10.37万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2074463
• 关键词: CD4 molecule; CD8 molecule; Leishmania major; T lymphocyte; antigen antibody reaction; antigen presenting cell; cell mediated cytotoxicity; cellular immunity; enzyme linked immunosorbent assay; flow cytometry; host organism interaction; immunologic memory; interferon gamma; laboratory mouse; leishmaniasis; major histocompatibility complex; nitric oxide; nucleic acid probes; relapse /recurrence

Leishmania are intracellular protozoan parasites which cause debilitating disease in many areas of the world. Infection of mice with Leishmania represents a good experimental model for the study of the interactions between the host and intracellular pathogens. In both man and mouse, specific T cell mediated responses are central for the immune defense against infection with Leishmania major. Recovery from natural or experimental infection leads to acquired immunity to reinfection, indicating that the control of leishmaniasis by prophylactic immunization is feasible. The immune response to primary infections with L major is well characterized. However, the mechanisms activated during reinfection have not been well investigated. The generation of long-term immunological memory is essential for the development of vaccines against infectious organisms. The rapid recognition and activation of parasitized macrophages by antigen-specific memory cells is crucially important for the maintenance of immunity to reinfection. The identification of those T cell functions necessary for the immunological control of leishmaniasis will depend upon the characterization of the T cell involved in the recall, or memory, response. The long term objective of the proposed study is to characterize the specific cells triggered in the immune host during the early phase of reinfection and the mechanisms by which they act in order to gain a better understanding for the complex interactions necessary to mount a protective response against reinfection. Therefore, resistant CBA and susceptible BALB/c mice, enabled to overcome their non-healing phenotype by various immuninterventions, will be infected with L major and allowed to recover fully from the primary infection. The immune response of these mice to secondary infectious challenge will then be analyzed. The kinetics of appearance, activation and function of CD4+ and CD8+ will be closely monitored during this process. It will be determined whether different T cell-mediated mechanisms contribute to the initial acquisition of Immunity to L. major and the subsequent resistance to rechallenge. The role of endogenous IFN-gamma during reinfection as well as the cells producing it will be determined by depletion experiments in vivo. Special emphasis will be placed on the contribution of Leishmania- specific CD8+ T cells to the IFN-gamma produced during reinfection. The MHC-restriction, antigen recognition and effector functions of the specific CD8+ T cells will be characterized in greater detail. The proposed contribution of CD8+ T cells to the redirection of the immune response of highly susceptible BALB/c mice, resistant by injection of low doses of promastigotes will be investigated (Bretscher et al., 1992).

利什曼原虫是细胞内的原生动物寄生虫，会导致衰弱 世界许多地区的疾病。小鼠感染利什曼原虫 代表了相互作用研究的良好实验模型 宿主与细胞内病原体之间。无论是在人和老鼠身上， 特异性 T 细胞介导的反应是免疫防御的核心 预防重大利什曼原虫感染。从自然或 实验性感染导致获得对再次感染的免疫力， 表明通过预防性免疫控制利什曼病 是可行的。对大李子原发感染的免疫反应是 特征良好。然而，再感染期间激活的机制 没有得到很好的调查。长期的产生 免疫记忆对于疫苗的开发至关重要 传染性生物体。快速识别并激活寄生体 巨噬细胞的抗原特异性记忆细胞对于 维持对再感染的免疫力。那些人的身份识别 免疫控制利什曼病所需的 T 细胞功能 将取决于参与该过程的 T 细胞的特征 回忆，或记忆，反应。 拟议研究的长期目标是表征 在免疫宿主的早期阶段触发的特定细胞 再感染及其发挥作用的机制 更好地理解安装所需的复杂交互 针对再感染的保护性反应。 因此，抵制CBA和 易感 BALB/c 小鼠，能够克服其不可治愈的表型 通过各种免疫干预，将感染L大调并允许 从原发感染中完全康复。 的免疫反应 然后将分析这些小鼠对二次感染攻击的情况。这 CD4+和CD8+的出现、激活和功能的动力学将是 在此过程中受到严密监控。 将确定是否 不同的 T 细胞介导机制有助于初始 获得对 L. Major 的免疫力以及随后对 L. Major 的抵抗力 重新挑战。内源性 IFN-γ 在再感染过程中的作用 因为产生它的细胞将通过消耗实验来确定 体内。 将特别强调利什曼原虫的贡献- 特异性 CD8+ T 细胞针对再感染过程中产生的 IFN-γ。这 MHC 限制、抗原识别和效应子功能 特定的 CD8+ T 细胞将得到更详细的表征。这 提议 CD8+ T 细胞对免疫重定向的贡献 高度敏感的 BALB/c 小鼠的反应，通过注射低剂量产生耐药性 将研究前鞭毛体的剂量（Bretscher 等，1992）。