NATURAL CELL MEDIATED RESISTANCE IN CRYPTOCOCCOSIS

隐球菌病在危及患者生命的感染中排名第四 获得性免疫缺陷综合征（艾滋病），这种疾病是一种 在细胞受损的个体中常见的严重问题- 介导的免疫反应。 虽然已经确定CD 4 淋巴细胞依赖性免疫应答对于保护至关重要 针对新型隐球菌，天然效应细胞使 有助于有效的第一线主机防御，并通过激活 由免疫T细胞产生的细胞因子，也可以作为效应器 获得性免疫 我们以前已经证明，小鼠NK细胞 细胞在体外直接与C.新形式和损害 有机体 此外，我们和其他人已经表明，NK细胞 参与从感染组织中清除隐球菌。 我们现在 我建议扩展我们对小鼠NK细胞的研究，以确定 这些细胞也抑制C。间接分泌细胞因子 其增强吞噬细胞天然的抗隐球菌活性， 效应细胞 用C. 将对新生儿进行肿瘤坏死因子、γ干扰素检测 和集落刺激因子，和 NK细胞中细胞因子的诱导将通过证明 细胞因子特异性信使RNA的原位杂交。 细胞因子 含有来自C.新生儿刺激的NK细胞， 比较，将评估重组细胞因子的能力， 激活多形核白细胞和巨噬细胞， 有效杀灭隐球菌。 尽管鼠和人NK细胞的功能活性是 类似地，这两个细胞群识别不同肿瘤细胞 目标的 因此，建议进行研究， 来自健康人供体的NK细胞的抗隐球菌活性。 在我们 初步研究，人外周血NK细胞，以及T 细胞，附着并破坏隐球菌细胞。 我们建议定义 人的超微结构和表型特征 外周血淋巴细胞与C.新型隐球菌和 比较和对比两个不同的人类效应器群体， 隐球菌细胞的要求 交互. 此外，我们将确定淋巴因子激活的NK细胞是否 细胞显示出比新鲜细胞更强的直接抗隐球菌活性 分离的NK细胞，如果人类NK细胞具有 通过细胞因子的产生间接参与， 其他天然效应细胞的抗隐球菌活性。 考虑 NK细胞在隐球菌病宿主防御中的潜在作用， 剖析小鼠和人类NK细胞的机制很重要 限制C.新生儿的生长，并描绘免疫调节 NK细胞介导的抗隐球菌感染的细胞因子 阻力

Cryptococcosis ranks fourth in life-threatening infections in patients with acquired immune deficiency syndrome (AIDS, and the disease is a frequent and serious problem in individuals with compromised cell- mediated immune responses. Although it is well established that CD4 lymphocyte-dependent immune responses are essential for protection against Cryptococcus neoformans, natural effecotr cells make significant contributions to effective first-line host defense and, via activation by cytokines produced by immune T cells, may also function as effectors of acquired immunity. We have previously demonstrated that murine NK cells directly interact in vitro with C. neoformans and damage the organism. In addition, we and others have shown that NK cells participate in clearance of ryptococci from infected tissues. We now propose to extend our investigations of murine NK cells to determine if these cells also inhibit C. neoformans indirectly by secreting cytokines which potentiate the anti-cryptococcal activity of phagocytic natural effector cells. Culture supernatants from NK cells incubated with C. neoformans will be assayed for tumor necrosis factor, gamma interferon and colony stimulating factors by functional bioassays and ELISA, and induction of cytokines in NK cells will be confirmed by demonstrating cytokine specific messenger RNA using in situ hybridization. Cytokine containing supernatants from C. neoformans-stimulated NK cells and, for comparison, recombinant cytokines will be assessed for their abilities to activate polymorphonuclear leukocytes and macrophages to more effectively kill cryptoccocci. Although the functional activity of murine and human NK cells are similar, these two populations of cells recognize different tumor cell targets. Studies are proposed, therefore, to examine the anticryptococcal activity of NK cells from healthy human donors. In our preliminary studies, human peripheral blood NK cells, as well as T cells, attached to and damaged cryptococcal cells. We propose to define the ultrastructural and phenotypic characteristics of the human peripheral blood lymphocytes which interact with C. neoformans and compare and contrast the two different populations of human effector cells with regard to the requirements for cryptococcal cell interactions. In addition, we will determine if lymphokine-activated NK cells display greater direct anticryptococcal activity than do freshly isolated NK cells and if human NK cells have the capability to participate indirectly via cytokine production to enhance the anticryptococcal activity of other natural effector cells. Considering the potential role of NK cells in host defense in cryptococcosis, it is important to dissect the mechanisms by which mouse and human NK cells restrict C. neoformans growth and to delineate the immunomodulatory cytokines which may be involved in NK cell-mediated anticryptococcal resistance.