CYTOKINE CONTROL OF HOST SUSCEPTIBILITY TO PNEUMOCYSTIS

对控制寄主的因素有了进一步的认识 对卡氏肺孢子虫的敏感性可能提供新的治疗方法 针对这种机会主义病原体的方式。我们的 实验室利用卡氏肺孢子虫免疫缺陷小鼠模型 肺炎来研究这种微生物的易感性，模拟 HIV感染者体内存在免疫缺陷。使用这些 卡氏肺孢子虫肺炎免疫缺陷小鼠模型的建立 CD4+和CD8+T细胞在宿主抵抗P. 卡里尼。CD4+和CD8+T细胞都可能控制 通过阐述细胞因子对卡氏肺孢子虫的易感性。近期 信息显示，这两个T细胞亚群都可以表达 Th1或Th2细胞因子谱系。在越来越多的型号中 很明显，磁化率和磁化率之间的平衡 防御不依赖单一的细胞因子和单独的作用。 相反，协调的反应，在强度和时间上精确地调制 序列，控制敏感度。在本报告中提供的初步数据中 应用，我们表征了Th1和Th2细胞因子的产生。 卡氏肺孢子虫感染对免疫活性和免疫缺陷小鼠肺的影响 接种疫苗。我们演示了不同的、依赖于时间的模式 体内细胞因子的产生。此外，我们还成功地使用了 检测特定细胞因子基因缺失的小鼠(“基因敲除”小鼠) 体内对卡氏肺孢子虫的耐受性。根据这些数据，我们假设 需要协调Th1和Th2反应才能成功 对卡氏疟原虫的防御，需要早期Th2样反应和晚期反应 类Th1反应。有四个具体目标：(1) 确定导致成功的细胞因子的细胞来源 体内对卡氏肺孢子虫的防御或敏感性；(2)测定 细胞因子阻断是否会改变抵抗或易感性 (3)分离卡氏肺孢子虫特异性CD4+T细胞。 体外特异的细胞因子谱并确定这些细胞 在体内维持它们的细胞因子谱；以及(4)确定 与确定的谱系的CD4+T细胞的重建改变 对体内感染的易感性。这些强大的动物模型允许 美国将测试细胞因子在控制卡氏肺孢子虫易感性中的作用 使用活体方法模拟人类卡氏肺孢子虫肺炎。 最终，这些研究可以扩展到开发治疗方法。 针对这种重要的机会性病原体的策略。

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.