A MOUSE INFECTION MODEL OF LEPROMATOUS LEPROSY

麻风病小鼠感染模型

• 批准号: 3444465
• 负责人: FRANK M. COLLINS
• 金额: $ 13.03万
• 依托单位: TRUDEAU INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-09-30 至 1987-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3444465
• 关键词: Mycobacterium; Mycobacterium leprae; T lymphocyte; antibacterial agents; bacterial antigens; bacterial vaccines; cell cell interaction; disease /disorder model; fluorescence microscopy; gel electrophoresis; histopathology; host organism interaction; immune tolerance /unresponsiveness; immunization; macrophage; microorganism disease chemotherapy; microorganism immunology; model design /development; monoclonal antibody; superoxides; suppressor T lymphocyte; tissue /cell culture; tuberculin test

Mycobacterium leprae is an obligate human intracellular pathogen which has not been cultivated successfully in vitro. Experimental models of this disease do not provide a close parallel, either histopathologically or immunologically. Several atypical Mycobacteria (M. Simiae, M. avium) produce chronic, non-fatal systemic infections in normal immunocompetent mice which offer a number of parallels to lepromatous leprosy, whilst providing the great advantage of ready culturability in vitro. Such mice develop a persistent anergic state to the specific footpad sensitin(s) and fail to express and obvious cell-mediated immunity (CMI). The proposed studies will examine the in vivo interactions between T-cell and macrophage populations within the heavily infected spleen as the infection progresses, using an adoptive cell transfer system which will allow various purified T-cell subpopulations to be tested quantitatively for their expressor/suppressor activities in vivo. These studies should lead to a better understanding of the role played by these cells in the establishment of the persistent M. avium-intracellulare infections in vivo and further establish this infection as a realistic model with which to study the immunology of lepromatous leprosy. The effect of various chemotherapeutic and immunomodulatory agents on this process can then be determined. The second objective will be to study the bactericidial (or bacteriostatic) mechanisms associated with activated macrophages harvested from hypersensitive and anergic donors. In particular, the role played by activated oxygen intermediates and lysosomal enzymes on this process and the expression of resistance to this process by the persister (but not the non-persister) strains of atypical Mycobacteria will be explored. Finally, attempts will be made to isolate and characterize the protein sensitin released by actively multiplying Mycobacteria in vitro (and by inference, by the same organisms growing in vivo) and presumed to be responsible for the induction of both DTH and CMI. Development of the specific monoclonal antibodies will be used to purify the sensitin(s) which will be tested as a potential immunogen and immunotherapeutic agent in vivo by restoring cell-mediated reactivity to the anergic, chronically infected host.

麻风分枝杆菌是一种专性的人类细胞内病原体，它具有 没有在体外成功培养。这方面的实验模型 无论是在组织病理学上还是在组织病理学上，疾病都不能提供密切的相似之处 从免疫学上讲。几种非典型分枝杆菌(西米亚科、禽分枝杆菌) 在免疫能力正常的情况下产生慢性、非致命性系统性感染 与麻风有许多相似之处的小鼠，而 提供了易于体外培养的巨大优势。这样的老鼠 对特定的足垫敏感蛋白产生持续性的无能状态(S)和 未表达明显的细胞免疫(CMI)。建议数 研究将检查T细胞和巨噬细胞之间的体内相互作用 随着感染的进展，严重感染的脾内的种群， 使用采用的细胞转移系统，将允许各种纯化的 T细胞亚群将被定量检测其 体内的表达/抑制活性。这些研究应该导致一个 更好地了解这些细胞在建立中所起的作用 体内持续的禽类支原体-细胞内感染和进一步 建立这种感染的现实模型，用来研究 麻风的免疫学。不同化疗药物的疗效观察 然后就可以确定这一过程中的免疫调节剂。这个 第二个目标是研究杀菌剂(或抑菌剂) 与活化巨噬细胞相关的机制 过敏和无能的捐赠者。尤其是，它所扮演的角色 这一过程中的活性氧中间体和溶酶体酶以及 持久者对这一过程的抵抗表现(但不是 非耐药)菌株的非典型分支杆菌将被探索。最后， 将尝试分离和鉴定该蛋白敏感蛋白 通过在体外主动繁殖分枝杆菌来释放(并通过推断， 由在体内生长的相同微生物)，并被推定为 DTH和CMI的诱导。特异性单抗的研制 将使用抗体来纯化敏感素(S)，这将作为一种 修复后体内潜在的免疫原和免疫治疗剂 细胞对无能的、慢性感染的宿主的反应。