CYTOKINE CONTROL OF HOST SUSCEPTIBILITY TO PNEUMOCYSTIS

提高对控制主机的因素的认识 对卡氏肺孢子虫易感性可提供新的治疗方法 针对这种机会性病原体的治疗方法。 我们 实验室利用卡氏肺孢子虫的免疫缺陷小鼠模型 研究对这种微生物的易感性， HIV感染者的免疫缺陷。 使用这些 免疫缺陷小鼠卡氏肺孢子虫肺炎模型，我们证实 CD 4+和CD 8 + T细胞在宿主防御疟原虫中的作用。 卡里尼 CD 4+和CD 8 + T细胞都可能控制 通过细胞因子的加工对卡氏肺孢子虫的易感性。 最近 信息显示，这两种T细胞亚群都可以表达 Th 1或Th 2细胞因子库。 在越来越多的模型中， 系统，很明显，敏感性和 防御不依赖于具有孤立作用的单一细胞因子。 相反，协调的反应，在强度和 顺序，控制敏感性。 在本报告提供的初步数据中， 应用中，我们表征了Th 1和Th 2细胞因子的产生， 卡氏肺吸虫感染后免疫活性和免疫缺陷小鼠的肺 接种。 我们展示了不同的，时间依赖的模式， 体内细胞因子产生。 此外，我们还成功地利用 删除特定细胞因子基因的小鼠（“敲除”小鼠） 卡氏肺孢子虫的易感性。 基于这些数据，我们假设 Th 1和Th 2反应的协调是成功的关键。 针对卡氏肺孢子虫的防御，需要早期Th 2样应答和晚期Th 2样应答。 Th 1类反应。 具体目标有四个：（1） 确定细胞因子的细胞来源， 体内对卡氏肺孢子虫的防御或易感性;（2）确定 细胞因子阻断是否可以改变对 P.（3）分离卡氏肺孢子虫特异性CD 4 + T细胞， 体外特异性细胞因子谱，并确定这些细胞是否 维持其体内细胞因子谱;和（4）确定是否 与具有确定库的CD 4 + T细胞的重建改变了 对体内感染的易感性。 这些强大的动物模型 本研究旨在检测细胞因子在控制卡里尼疟原虫易感性中的作用 使用模拟人类卡氏肺孢子虫肺炎的体内方法。 最终，这些研究可以扩展到开发治疗 针对这种重要的机会致病菌的策略。

An improved understanding of the factors contorlling host susceptibility to Pneumocystis carinii could provide novel therapeutic modalities directed against this opportunistic pathogen. Our laboratory utilizes immunodeficient mouse models of P. Carinii pneumonia to study susceptibility to this organism, modeling the immune deficits present in HIV-infected individuals. Using these immunodeficient mouse models of P. Carinii pneumonia, we confirmed the roles of both CD4+ and CD8+ T cells in host defense against P. Carinii. Both CD4+ and CD8+ T cells are likely to control susceptibility to P. Carinii by elaboration of cytokines. Recent information shows that both of these T cell subsets can express either Th1 or Th2 cytokine repertoires. In an increasing number of model systems, it is apparent that the balance between susceptibility and defense does not depend on single cytokines with isolated actions. Rather, coordinated responses, precisely modulated in intensity and in sequence, control susceptibility. In preliminary data presented in this application, we characterize Th1 and Th2 cytokine production in the lungs of immunocompetent and immunodeficient mice after P. Carinii inoculation. We demonstrate differential, time-dependent patterns of cytokine production in vivo. Furthermore, we have successfully used mice deleted of specific cytokine genes ("knockout" mice) to examine suceptibility to P. Carinii in vivo. Based o these data, we hypothesize that coordinated Th1 and Th2 responses are required for successful defense against p. Carinii, requiring early Th2-like responses and late Th1-like responses. There are four specific objectives: (1) to determine the cellular sources of cytokines responsible for successful defense against or susceptibility to P. Carinii in vivo; (2) to determine whether cytokine blockade can alter defense against or susceptibility to P. Carinii in vivo; (3) to isolate P. Carinii-specific CD4+ T cells with specific cytokine profiles in vitro and to determine whether these cells maintain their cytokine profiles in vivo; and (4) to determine whether reconstitution with CD4+ T cells of defined repertoire alters susceptibility to infection in vivo. These powerful animal models allow us to test the roles of cytokines in control of susceptibility to P. Carini using in vivo approaches that model human P. Carinii pneumonia. Ultimately, these studies can be extended to develop therapeutic strategies directed against this important opportunistic pathogen.