A MOUSE INFECTION MODEL OF LEPROMATOUS LEPROSY

麻风分枝杆菌是一种专性人类细胞内病原体， 没有在体外培养成功。 实验模型 疾病没有提供密切的平行，无论是组织病理学或 免疫学上 几种非典型分枝杆菌（M. Simiae，M. avium） 在正常免疫功能正常的人中产生慢性、非致命性全身感染 小鼠提供了许多与瘤型麻风相似的地方， 提供了在体外易于培养的巨大优势。 这样的小鼠 对特定的足垫敏化素产生持续的无反应性状态， 不能表达和明显的细胞介导免疫（CMI）。 拟议 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， 使用过继细胞转移系统， 定量检测T细胞亚群 体内表达/抑制活性。 这些研究将导致 更好地理解这些细胞在建立 持久的M。体内细胞内禽流感感染， 建立这种感染作为一个现实的模型，以研究 瘤型麻风免疫学 各种化疗药物的效果 然后可以确定免疫调节剂对该过程的影响。 的 第二个目标将是研究杀真菌（或抑菌） 与活化的巨噬细胞相关的机制， 过敏和无反应性的供体。 特别是， 活性氧中间体和溶酶体酶在这一过程中， 坚持者对这一过程的抵抗的表达（但不是 非持久性）菌株的非典型分枝杆菌将被探索。 最后， 将尝试分离和表征蛋白质敏化素 通过在体外活跃地增殖分枝杆菌而释放（并且通过推断， 由体内生长的相同生物体引起），并被认为是 DTH和CMI的诱导。 特异性单克隆抗体的研制 抗体将用于纯化敏化素， 潜在的免疫原和免疫抑制剂， 细胞介导的对无反应性、慢性感染宿主的反应性。

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.