Evaluation New Targets of CMV Cellular Immunity

描述（由申请人提供）：本申请考察了对人巨细胞病毒（CMV）的免疫反应，重点是造血细胞移植（HCT）后细胞免疫反应（CMI）的选择表位特征。对CMV特异性CMI的传统理解是，它主要针对两种CMV蛋白——下层基质蛋白CMVpp65和主要的即时早期蛋白CMV- ie1。这种CMV特异性CMI对于预防HCT后CMV进展为疾病至关重要。对于巨细胞病毒血清阳性的患者，HCT后巨细胞病毒感染的发生率为60- 70%。病毒的再激活是指导这一人群HCT患者抗病毒管理的关键事件，通过免疫方法控制病毒的再激活成为改善HCT移植的重要目标。没有答案的问题是需要哪些特定的免疫反应来防止巨细胞病毒再激活，这些适应性反应是否与后来引起的保护免受巨细胞病毒感染和疾病的适应性反应相同？由于在肽抗原的蛋白酶体加工过程中病毒粒子编码的改变，对其他巨细胞病毒蛋白的免疫反应可能被修改，以保护病毒重新激活的能力。利用转基因HLA-A*0201小鼠模型，可以从免疫逃逸机制中剖析免疫应答，从而评估其他CMV蛋白可能是CMI的靶点。

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.