Aspergillus-specific CD4+ T cells in Invasive Aspergillosis

描述（由申请方提供）：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。接受强化疗方案的白血病患者和骨髓移植患者尤其有发生侵袭性巨噬细胞增多症（IA）的风险，相关死亡率约为90%。在IA小鼠模型中的研究表明，曲霉特异性IFN-γ分泌T淋巴细胞通过限制侵袭性真菌疾病而发挥保护作用，而产生IL-4和IL-13的T细胞具有有害影响。虽然从这些研究中可以清楚地看出，CD 4 T细胞影响A.在烟曲霉感染中，许多决定T细胞活化和募集的因素仍然定义不清。此外，它仍然有待确定是否阿吉鲁斯特异性的CD 4 T细胞可以介导的决议建立的疾病。为了开始解决这些问题，候选人Amariliz里维拉博士克隆了A.烟曲霉，分离编码T细胞受体（TCR）的抗原特异性α和β链的基因并产生TCR转基因小鼠。初步结果表明，这些小鼠表达识别A.烟曲霉菌丝单克隆巨噬细胞特异性CD 4 T细胞的可用性将为候选人提供解决以下目标的独特机会：1）表征吸入A的CD 4 T细胞应答的活化和分化。烟曲霉孢子，2）确定调节性细胞因子IL-10和TGF β在该过程中的作用，3）检查同时发生的先天性炎症反应对T细胞活化的影响，和4）确定A.烟曲霉特异性T细胞可以提供针对IA的保护。此外，这些研究将为CD 4 T细胞在癌症患者中对抗真菌感染的潜在治疗用途奠定基础。Dr.里维拉将在Dr. Eric G. Memorial Sloan Kettering癌症中心通过这个K 01奖的候选人将获得必要的技能和经验，成功地竞争一个独立的教师职位。作为一名波多黎各裔妇女，候选人将努力成为年轻西班牙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.