Aspergillus-specific CD4+ T cells in Invasive Aspergillosis

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。接受强烈化疗方案的白血病患者和骨髓移植患者尤其容易患侵袭性曲霉病(IA)，相关死亡率约为90%。在IA小鼠模型上的研究表明，曲霉菌特异性的干扰素-γ分泌的T细胞通过限制侵袭性真菌疾病发挥保护作用，而产生IL-4和IL-13的T细胞则有有害的影响。尽管从这些研究中可以清楚地看出，CD4T细胞影响烟曲霉菌感染的结局，但决定T细胞激活和募集的许多因素仍然缺乏明确的认识。此外，曲霉菌特异性的CD4T细胞是否能够介导已建立的疾病的解决还有待确定。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性的CD4T细胞，分离了编码T细胞受体(TCR)抗原特异性α链和β链的基因，并产生了TCR转基因小鼠。初步结果表明，这些小鼠表达识别烟曲霉菌丝的功能TCR。曲霉菌特异性CD4T细胞的获得将为候选人提供独特的机会来解决以下目标：1)表征吸入烟曲霉孢子后CD4T细胞的激活和分化；2)确定调节细胞因子IL-10和TGFbeta在这一过程中的作用；3)检测并发的先天炎症反应对T细胞激活的影响；4)确定烟曲霉特异性T细胞是否具有保护作用。此外，这些研究将为CD4T细胞对癌症患者真菌感染的潜在治疗用途奠定基础。里维拉博士将在纪念斯隆·凯特琳癌症中心的埃里克·G·帕默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师职位所需的技能和经验。作为一名波多黎各裔女性，候选人将努力成为年轻拉美裔科学家的杰出榜样。

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.