Regulation of RBC Alloimmunization by Different Types of Recipient Inflammation

描述（由申请人提供）：该职业发展奖的候选人是一名儿科血液学家，在输血医学方面接受过专门的临床培训。她的职业目标是成为一名独立的医生科学家研究员，能够弥合从基础实验室研究到转化医学的差距。该提案的目标是促进对红细胞（RBC）同种免疫的基础科学理解，同时为候选人提供成为独立研究者所需的基础科学研究培训。 红细胞同种异体免疫在一些慢性输血患者，特别是血红蛋白病患者中是一个临床上重要的问题。一旦患者对多种RBC抗原产生同种免疫，为将来的输血寻找相容的血液可能很困难（有时甚至不可能）。对输注红细胞的免疫应答存在很大的差异，影响红细胞同种免疫率的因素知之甚少。候选人报告了新的发现，即受体炎症影响RBC同种异体免疫的速率。而病毒样刺激（聚肌胞苷酸，聚（I：C））增加同种异体免疫，细菌样刺激（脂多糖，LPS）减少同种异体免疫。拟议的研究利用尖端的免疫学工具（包括定义明确的模型RBC抗原，TCR和BCR转基因和敲除小鼠）对不同类型的炎症如何调节RBC同种免疫进行细胞和分子阐明。 候选人利用了埃默里大学多个部门的资源，包括儿科血液学/肿瘤学/BMT部门，输血和细胞治疗中心以及免疫学和发病机制计划。她组建了一个多专业的指导委员会和一个全面的职业发展计划。这种指导研究培训的高潮将是RBC免疫学的广泛基础科学培训，以及作为医生科学家独立职业的基础。相关性（参见说明）：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RBC同种异体免疫率提供机制性理解。因此，这项研究可能会影响5%的输血接受者，他们对RBC产生同种免疫（美国每年输注1400万单位的RBC）。

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).