Regulation of RBC Alloimmunization by Different Types of Recipient Inflammation

描述(申请人提供)：该职业发展奖的候选人是一位在输血医学方面受过专门临床培训的儿科血液学家。她的职业目标是成为一名独立的内科科学家研究员，能够弥合从基础长凳研究到转化医学的差距。这项建议的目的是促进对红细胞(RBC)异体免疫的基础科学理解，同时为候选人提供成为独立研究人员所需的基础科学研究培训。在一些长期输血的患者中，尤其是那些患有血红蛋白疾病的患者，红细胞同种异体免疫是一个临床上重要的问题。一旦患者对多种RBC抗原产生同种异体免疫，为将来的输血找到相容的血液可能会很困难(有时是不可能的)。对输注的红细胞的免疫反应有很大的差异，影响红细胞同种异体免疫率的因素还很少被了解。这位候选人报告了这一新发现，即受体炎症会影响红细胞异基因免疫率。病毒样刺激(多聚肌苷多胞苷，Poly(I：C))可增加同种免疫，而细菌样刺激(脂多糖，LPS)可降低同种免疫。这项拟议的研究利用尖端免疫学工具(包括明确定义的模型RBC抗原、TCR和BCR转基因和基因敲除小鼠)来进行细胞和分子阐明不同类型的炎症如何调节RBC同种免疫。这位候选人利用了埃默里大学多个系的资源，包括儿科血液科/肿瘤科/骨髓移植科、输血和细胞疗法中心以及免疫学和病理学项目。她组建了一个由多个专业组成的指导委员会，并制定了全面的职业发展计划。这种有指导的研究培训的高潮将是广泛的红细胞免疫学基础科学培训，并为作为一名内科科学家的独立职业生涯奠定基础。相关性(见说明)：通过拟议的研究获得的公共卫生知识将为合理开发有针对性的治疗干预措施以降低红细胞同种异体免疫率提供机械性的理解。因此，这项研究可能会影响对红细胞免疫的5%的输血接受者(美国每年有1400万单位的红细胞被输注)。

DESCRIPTION (provided by applicant): The candidate for this career development award is a Pediatric Hematologist with specialized clinical training in Transfusion Medicine. Her career goal is to become an independent physician scientist researcher, capable of bridging the gap from basic bench research to translational medicine. The goal of this proposal is to advance the basic science understanding of red blood cell (RBC) alloimmunization, while providing the candidate with the basic science researchtraining required to become an independent investigator. RBC alloimmunization is a clinically ignificant problem in some chronically transfused patients, especially those with hemoglobinopathies. Once a patient becomes alloimmunized to multiple RBC antigens, locating compatible blood for future transfusions can be difficult (and sometimes not possible). There is wide variability in immune responses to transfused RBCs, and factors that influence rates of RBC alloimmunization are poorly understood. The candidate has reported the novel finding that recipient inflammation affects rates of RBC alloimmunization. While a viral-like stimulus (polyinosinic polycytidylic acid, poly (I:C)) increases alloimmunization, a bacterial-like stimulus (lipopolysaccharide, LPS) decreases alloimmunization. The proposed research utilizes cutting-edge immunological tools (including well defined model RBC antigens, TCR and BCR transgenic and knockout mice) to perform cellular and molecular elucidations of how different types of inflammation regulate RBC alloimmunization. The candidate has taken advantage of resources in multiple departments at Emory University, including the Division of Pediatric Hematology/Oncology/BMT, Center for Transfusion and Cellular Therapies, and Immunology and Pathogenesis Program. She has assembled a multi-specialty mentoring committee and a comprehensive career development plan. The culmination of this mentored research training will be extensive basic science training in RBC immunology and the basis for an independent career as a physician scientist. RELEVANCE (See instructions): The public health knowledge gained by the proposed research will provide a mechanistic understanding for the rational development of targeted therapeutic interventions to decrease rates of RBC alloimmunization. This research will thus potentially impact the 5% of transfusion recipients that become alloimmunized to RBCs (with 14 million units of RBCs being transfused annually in the US).