Evaluation New Targets of CMV Cellular Immunity

描述（由申请人提供）：本申请检查了对人巨细胞病毒（CMV）的免疫应答，重点是造血细胞移植（HCT）后细胞免疫应答（CMI）的选定表位表征。CMV特异性CMI的传统理解是它主要靶向两种CMV蛋白-下基质蛋白CMVpp 65和主要的立即早期蛋白CMV-IE 1。这种CMV特异性CMI对于预防HCT后CMV进展为疾病至关重要。对于CMV血清阳性患者，HCT后CMV感染的发生率为60- 70%。病毒的再活化是指导该HCT患者群体的抗病毒管理的关键事件，并且通过免疫学方法控制再活化成为改善HCT移植的重要目标。尚未回答的问题是，需要什么特异性免疫应答来防止CMV再激活，以及这些免疫应答是否与后来在预防进行性CMV感染和疾病中引起的适应性应答相同？由于病毒体编码的肽抗原的蛋白酶体加工的改变，可能对其他CMV蛋白的免疫应答被改变，以保护病毒再活化的能力。使用转基因HLA-A*0201小鼠模型，可以将免疫应答与免疫逃逸机制分开，以评估哪些其他CMV蛋白可以靶向CMI。 这里测试的主要假设是，对感染早期存在的CMV蛋白的免疫足以保护免受CMV再激活和疾病。考虑到这一点，重要的早期CMV蛋白将被I类免疫处理识别，包括那些参与复制的早期阶段和那些负责免疫逃避。因此，本研究的目的是1）在HCT后的免疫重建期间使用重叠肽库重新评估所有HLA同种异型中对CMV-pp 65和CMV-IE 1的免疫应答的动力学，和2）使用HLA-A*0201小鼠模型，以定义在免疫重建期间早期与所选其它CMV蛋白相关的CD 8表位，并使用CMV野生分离物评价对这些蛋白质的免疫应答。 本项目的重要性在于确定了CMV免疫的新的免疫靶点，为开发新的免疫治疗策略以预防移植后CMV再激活提供了重要信息。

DESCRIPTION (provided by applicant): This application examines the immune response to human cytomegalovirus (CMV) with a focus on selected epitope characterization of the cellular immune response (CMI) after hematopoietic cell transplantation (HCT). The conventional understanding of CMV-specific CMI is that it mainly targets two CMV proteins--the lower matrix protein, CMVpp65, and the major immediate early protein, CMV-IE1. This CMV-specific CMI is essential in prevention of CMV progression to disease after HCT. For CMV seropositive patients, the incidence of CMV infection is 60-70 percent after HCT. Reactivation of virus is the critical event that guides the antiviral management of this population of HCT patients and control of reactivation by immunologic methods becomes an important goal for improvement in HCT transplantation. The question that is unanswered is what specific immune responses are needed to prevent CMV reactivation and are these the same adaptive responses that are being elicited later in protection from progressive CMV infection and disease? Because of virion encoded alterations in proteasome processing of peptide antigens, it is possible that the immune response to other CMV proteins is modified in order to protect the ability of the virus to reactivate. Using a transgenic HLA-A*0201 mouse model, it is possible to dissect the immune response away from the immune escape mechanisms in order to assess which other CMV proteins could be targeted for CMI. The main hypothesis tested here is that immunity to the CMV proteins present early in infection is sufficient to protect from CMV reactivation and disease. With this in mind, important early CMV proteins will be examined for recognition by class I immune processing, including those involved at early stages of replication and those responsible for immune evasion. Therefore, the aims of the study are 1) to reassess the kinetics of the immune response to CMV-pp65 and to CMV-IE1 in all HLA allotypes using pools of overlapping peptides during immune reconstitution after HCT, and 2) using HLA-A*0201 mouse models, to define CD8 epitopes to selected other CMV proteins relevant at early times during immune reconstitution, and to evaluate the immune response to these proteins using CMV wild isolates. The importance of this project is that it will define new immune targets of CMV immunity, and these could provide important information for developing new immunotherapeutie strategies for the prevention of CMV reactivation after transplantation.