HLA Alleles and the Progression of Human Cryptococcosis

项目摘要 隐球菌继续在免疫功能低下的个体中引起重大疾病， 艾滋病毒/艾滋病患者。了解人类免疫系统与此之间的相互作用 如果我们希望改善临床结果，致病真菌是至关重要的。总体科学目标 这项研究是为了了解人类的免疫系统是如何导向一种保护性或 隐球菌感染的有害反应，而本提案的具体目标是 确定影响隐球菌脑膜炎患者辅助性T细胞反应的因素。 值得注意的是，特别感兴趣的是HLA/MHC系统如何影响CD 4 + T细胞在其免疫应答中的表达。 对隐球菌的反应要做到这一点，第一个目标是确定最普遍的HLA 隐球菌病患者的等位基因。假设某些HLA等位基因是 与发展进行性疾病相关，而其他与衰减或 防止疾病。建立HLA-疾病关联不仅具有重要的临床意义 和治疗意义，但为进一步的免疫学研究创造了知识基础。目的 两个将使用免疫表型模式来确定隐球菌中的辅助性T细胞反应， 特异性免疫反应。CD 4 + T细胞四聚体在来自HIV感染者的细胞上的应用 为研究传染病特异性T细胞反应提供了一个概念验证模型， 性新此外，对同一队列进行活化诱导标记物（AIM）测定将 提供了一个比较方法，在测试的假设，即Th 1辅助性T细胞反应是更多的 Th 2应答对隐球菌病的保护作用更强。这项研究产生的数据将推动 疫苗开发、个性化医疗和卫生系统领域的创新 实施.通过建立我们研究人群HLA流行率的必要数据， 成功实施我们提出的免疫学方法来确定疾病特异性T细胞 响应，我们将为未来的临床和基础科学研究奠定基础，以了解如何 人类免疫系统对隐球菌感染作出反应，并操纵该反应， 减少疾病。

Project Summary Cryptococcus continues to cause significant disease in immunocompromised individuals, particularly those with HIV/AIDS. Understanding the interplay between the human immune system and this pathogenic fungus is critical if we hope to improve clinical outcomes. The overall scientific objective of the research is to understand how the immune system in humans is directed towards a protective or deleterious response in Cryptococcus infection, while the specific objective of this proposal is to determine factors that impact the helper T cell response in humans during cryptococcal meningitis. Notably, there is particular interest in how the HLA/MHC system influences CD4+ T cells in their response to Cryptococcus. To accomplish this, the first aim is to identify the most prevalent HLA alleles in persons with cryptococcal disease. The hypothesis is that certain HLA alleles are associated with developing progressive disease, while others are associated with attenuating or protecting against disease. Establishing HLA-disease associations not only carries important clinical and therapeutic implications, but creates the knowledge base for further immunological studies. Aim two will use immunophenotyping modalities to determine helper T cell responses in the cryptococcal- specific immune response. The use of CD4+ T cell tetramers on cells from HIV-infected humans provides a proof-of-concept model for the study of infectious disease-specific T cell responses going forward. Additionally, performing activation induced marker (AIM) assays on the same cohort will provide a comparator method in the testing of the hypothesis that Th1 helper T responses are more protective in cryptococcosis than Th2 responses. The data generated by this study will drive innovation in the areas of vaccine development, personalized medicine, and health systems implementation. By establishing the necessary data on HLA prevalence of our study population and successfully implementing our proposed immunology methods to determine disease-specific T cell responses, we will lay the foundation for future clinical and basic science studies to understand how the human immune system responds to infection with Cryptococcus and manipulate that response to reduce disease.