NATURAL CELL-MEDIATED RESISTANCE IN CRYPTOCOCCOSIS

隐球菌病中自然细胞介导的耐药性

• 批准号: 3128296
• 负责人: JUNEANN W MURPHY
• 金额: $ 15.47万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-01-01 至 1991-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3128296
• 关键词: Cryptococcus neoformans; cryptococcosis; cyclophosphamide; fungal antigens; fungal genetics; host organism interaction; laboratory mouse; macrophage; microorganism immunology; mutant; neutrophil; tissue /cell culture

Cells and mechanisms involved in natural cell mediated resistance against the yeast-like organism, Cryptococcus neoformans are not well defined. There are three different cell populations in normal unstimulated animals which have the potential to clear cryptococci from tissues. These are polymorphonuclear leukocytes (PMNL), macrophages, and natural killer (NK) cells. Over the past three years, we have studied the effects of natural effector cells on C. neoformans both in vivo and in vitro. From these studies, it is clear that normal mice have cells which have anti-Cryptococcus activity and by numerous criteria, have characteristics matching NK cells. Although NK cells are not capable of sterilizing a culture of 10/3 cryptococci nor totally eliminating C. neoformans from mice infected with 10/4 organisms, they do significantly reduce the numbers of cryptococci in both cases. These findings suggest that NK cells participate along with PMNL and macrophages in initial clearance of cryptococci from host tisuses. NK cells affect C. neoformans by a nonphagocytic mechanism which includes first binding of the NK cells to the organism then later inhibiting the growth of the cryptococci. The lytic effects of cytotoxic T lymphocytes (CTL) and NK cells against appropriate tissue targets appear to be the result of effector cell exocytosis of granules containing cytolytic components. We are proposing that a similar mechanism may be operating in NK cell mediated inhibition of cryptococci growth. However, our earlier studies have shown that the kinetics of NK cell binding to cryptococci and inhibition of cryptococci growth are much slower than with tumor cell targets. This suggests there may be differences in the way the NK cells respond to binding of cryptococci targets versus tumor cell targets and in the active components or the means by which active components of NK cells affect the yeast target. We now propose investigations to gain a basic understanding of interactions of NK cells with cryptococci, a target which is substantially different from previously studied NK targets. To do this we will determine the sequence of steps leading to inhibition of cryptococci growth, study the changes occurring in the effector and target cells after binding using light and electron microscopy techniques, and asses what specific component(s) of the NK cells is responsible for the anti-Cryptococcus activity. These studies should provide new and significant information on the mechanisms of natural cell mediated resistance in cryptococcosis.

参与天然细胞介导的抗肿瘤抗性的细胞和机制 酵母样生物，新型隐球菌还没有很好的定义。 在正常的未受刺激的动物中有三种不同的细胞群 其具有从组织中清除隐球菌的潜力。 这些是 多形核白细胞（PMNL）、巨噬细胞和自然杀伤细胞（NK） 细胞 在过去的三年里，我们研究了自然的影响， C.在体内和体外的新形式。 从这些 研究表明，正常小鼠的细胞具有 抗隐球菌活性，并通过许多标准，具有特征 匹配的NK细胞 虽然NK细胞不能消灭一个 培养10/3隐球菌也不能完全消灭隐球菌。小鼠新变型 感染了10/4的微生物，它们确实显著减少了 隐球菌感染 这些发现表明，NK细胞 参与沿着与PMNL和巨噬细胞在初始清除 从宿主组织中分离出隐球菌。 NK细胞影响C.新形式的一个 非吞噬机制，其包括NK细胞首先结合至 然后抑制隐球菌的生长。 裂解 细胞毒性T淋巴细胞（CTL）和NK细胞对适当的 组织靶似乎是效应细胞胞吐的结果， 含有溶细胞成分的颗粒。 我们建议， NK细胞介导的隐球菌抑制可能是一种机制 增长 然而，我们早期的研究表明，NK的动力学 细胞与隐球菌的结合和隐球菌生长的抑制是非常重要的。 慢于肿瘤细胞靶点。 这表明 NK细胞对隐球菌结合的反应方式的差异 靶点与肿瘤细胞靶点之间的差异以及活性成分或方法中的差异 NK细胞的活性成分通过其影响酵母靶标。 我们现在 建议进行调查，以获得对NK相互作用的基本了解 细胞与隐球菌，一个目标，这是实质上不同的， 以前研究的NK靶点。 为此，我们将确定 步骤导致抑制隐球菌生长，研究变化 在使用光结合后在效应细胞和靶细胞中发生， 电子显微镜技术，并评估什么具体组成部分（S）的 NK细胞负责抗隐球菌活性。 这些研究 应该提供新的和重要的信息，自然的机制， 细胞介导的耐药性