Induction of Protection Against Cryptococcus neoformans in Immune Deficient Hosts

描述（由申请人提供）：新型隐球菌感染是艾滋病患者发病和死亡的主要真菌学原因。全球估计数字表明，每年发生100万例隐球菌脑膜炎病例，造成62万多人死亡。临床和实验证据表明，CD4+ th1型细胞的细胞介导免疫（CMI）构成了对新形梭菌感染的保护性宿主防御反应。因此，认为开发一种有效的抗隐球菌疫苗(1)在存在或不存在完整免疫的情况下提供保护，2)在随后的免疫抑制发展中诱导持续保护)是可行的，这似乎是违反直觉的。然而，本文提出的研究表明，用IFN-?免疫B细胞缺陷小鼠产生新型C.的菌株，记为H99？随后，T细胞的耗尽能够对野生型（WT）新生C.的致命肺部攻击产生保护性免疫反应。这些发现表明，在缺乏经典适应性免疫的情况下，先天免疫细胞群可以被诱导产生保护性的抗隐球菌免疫反应。这些结果挑战了我们传统的适应性免疫和先天免疫模型，因为先天细胞不被认为在缺乏抗原特异性T细胞和/或B细胞的情况下经历快速扩增来介导增强的效应细胞功能和保护。在没有T和/或B CMI的情况下，确定先天细胞群和保护性抗隐球菌免疫反应发生的机制将标志着适应性免疫与先天免疫的经典二分法的范式改变。因此，我们假设“先天免疫可以在缺乏T细胞和B细胞介导的适应性免疫反应的情况下提供对新型C.感染的保护”。我们计划通过追求以下特定目标来验证我们的假设：(1)确定在缺乏经典适应性免疫的情况下对新生隐球菌具有保护作用的先天细胞群；(2)确定从免疫、T细胞和B细胞缺陷小鼠中分离的先天细胞抗隐球菌活性的介质。

DESCRIPTION (provided by applicant): Cryptococcus neoformans infections are a leading mycological cause of morbidity and mortality among AIDS patients. Global estimates suggest that one million cases of cryptococcal meningitis occur each year resulting in over 620,000 deaths. Clinical and experimental evidence show that cell-mediated immunity (CMI) by CD4+ Th1-type cells constitutes the protective host defense response against C. neoformans infections. Consequently, it may seem counterintuitive to suggest that development of an effective anti-cryptococcal vaccine that 1) confers protection in the presence or absence of intact immunity and 2) induces protection that endures during the subsequent development of immune suppression is feasible. However, studies presented herein show that B cell deficient mice immunized with an IFN-?-producing C. neoformans strain, denoted H99?, and subsequently depleted of T cells were capable of mounting protective immune responses against an otherwise lethal pulmonary challenge with wild-type (WT) C. neoformans. These findings suggest that an innate population of immune cells can be induced to mount protective anti-cryptococcal immune responses in the absence of classical adaptive immunity. These results challenge our traditional model of adaptive and innate immunity in that innate cells are not considered to undergo rapid expansion to mediate enhanced effector cell function and protection in the absence of antigen-specific T and/or B cells. Identifying the innate cell population/s and mechanism by which protective anti-cryptococcal immune responses occurs in the absence of T and/or B CMI will mark a paradigm change from the classical dichotomy of adaptive versus innate immunity. We therefore hypothesize that "innate immunity can be primed to provide protection against C. neoformans infection that endures during the absence of T and B cell-mediated adaptive immune responses". We plan to test our hypothesis by pursuing the following Specific Aims: (1) to identify the innate cell population(s) that confers protection against C. neoformans in the absence of classical adaptive immunity, and (2) to determine the mediators of anti-cryptococcal activity of innate cells isolated from immunized, T and B cell deficient mice. PUBLIC HEALTH RELEVANCE: Cryptococcus neoformans is an opportunistic fungal pathogen that causes life-threatening infections in immune compromised individuals. The studies proposed in this application are designed to determine a mechanism for inducing protective immunity against C. neoformans in immune suppressed patients. My expectation is that these studies will lead to the development of therapies and/or vaccines to treat or prevent fungal infections.