Aspergillus-specific CD4+ T cells in Invasive Aspergillosis

侵袭性曲霉病中曲霉特异性 CD4 T 细胞

• 批准号: 7142098
• 负责人: Amariliz Rivera
• 金额: $ 10.82万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142098
• 关键词: Aspergillus; aspergillosis

DESCRIPTION (provided by applicant): Aspergillus fumigatus is a clinically important fungal pathogen that causes invasive disease in immunocompromised hosts. Leukemia patients receiving intense chemotherapy regimens and bone marrow transplanted patients are particularly at risk for Invasive Aspergillosis (IA) with an associated mortality rate of approximately 90%. Studies in mouse models of IA have suggested that Aspergillus-specific IFN-gamma secreting T lymphocytes play a protective role by limiting invasive fungal disease while IL-4 and IL-13 producing T cells have a deleterious impact. Although it is clear from these studies that CD4 T cells influence the outcome of A. fumigatus infection, many of the factors that determine T cell activation and recruitment remain poorly defined. Moreover, it remains to be determined whether Aspergillus-specific CD4 T cells can mediate the resolution of established disease. In order to begin to address these questions, the candidate, Dr. Amariliz Rivera, cloned CD4 T cells specific for A. fumigatus, isolated the genes encoding the antigen specific alpha and beta chains of the T cell receptor (TCR) and generated TCR transgenic mice. Preliminary results demonstrate that these mice express a functional TCR that recognizes A. fumigatus hyphae. The availability of monoclonal Aspergillus-specific CD4 T cells will give the candidate the unique opportunity to address the following aims: 1) to characterize the activation and differentiation of CD4 T cell responses to inhaled A. fumigatus spores, 2) to establish the role of the regulatory cytokines IL-10 and TGFbeta in this process, 3) to examine the influence of concurrent innate inflammatory responses on T cell activation and 4) to establish whether A. fumigatus-specific T cells can confer protection from IA. Furthermore, these studies will establish the foundation for the potential therapeutic use of CD4 T cells against fungal infections in the cancer patient. Dr. Rivera will perform these studies under the guidance of Dr. Eric G. Pamer at Memorial Sloan Kettering Cancer Center. Through this K01 award the candidate will gain the skills and experience necessary to successfully compete for an independent faculty position. As a woman of Puerto Rican descent the candidate will strive to be an outstanding role model for younger Hispanic scientists.

描述（由申请人提供）：烟曲霉是一种临床上重要的真菌病原体，可在免疫功能低下的宿主中引起侵袭性疾病。接受强化化疗方案的白血病患者和骨髓移植患者尤其面临侵袭性曲霉病 (IA) 的风险，相关死亡率约为 90%。对 IA 小鼠模型的研究表明，曲霉菌特异性 IFN-γ 分泌 T 淋巴细胞通过限制侵袭性真菌病发挥保护作用，而产生 IL-4 和 IL-13 的 T 细胞则具有有害影响。尽管从这些研究中可以清楚地看出 CD4 T 细胞影响烟曲霉感染的结果，但决定 T 细胞激活和募集的许多因素仍不清楚。此外，曲霉菌特异性 CD4 T 细胞是否可以介导已确定疾病的消退仍有待确定。为了开始解决这些问题，候选人 Amariliz Rivera 博士克隆了烟曲霉特异的 CD4 T 细胞，分离了编码 T 细胞受体 (TCR) 抗原特异性 α 和 β 链的基因，并生成了 TCR 转基因小鼠。初步结果表明，这些小鼠表达了识别烟曲霉菌丝的功能性 TCR。单克隆曲霉特异性 CD4 T 细胞的出现将为候选者提供实现以下目标的独特机会：1) 表征 CD4 T 细胞对吸入烟曲霉孢子反应的激活和分化，2) 确定调节细胞因子 IL-10 和 TGFbeta 在此过程中的作用，3) 检查同时发生的先天炎症反应对 T 细胞的影响 激活；4) 确定烟曲霉特异性 T 细胞是否可以提供针对 IA 的保护。此外，这些研究将为 CD4 T 细胞对抗癌症患者真菌感染的潜在治疗用途奠定基础。 Rivera 博士将在纪念斯隆凯特琳癌症中心的 Eric G. Pamer 博士的指导下进行这些研究。通过这个 K01 奖项，候选人将获得成功竞争独立教职职位所需的技能和经验。作为波多黎各裔女性，候选人将努力成为年轻的西班牙裔科学家的杰出榜样。