Evaluation New Targets of CMV Cellular Immunity

描述(由申请人提供)：这项申请检验人类巨细胞病毒(CMV)的免疫反应，重点是造血细胞移植(HCT)后细胞免疫反应(CMI)的选定表位特征。对CMV特异性CMI的传统理解是，它主要针对两种CMV蛋白--下基质蛋白CMVpp65和主要的即刻早期蛋白CMV-IE1。这种CMV特异性CMI对于防止巨细胞病毒在HCT后进展为疾病是必不可少的。对于CMV血清阳性的患者，HCT后CMV感染的发生率为60%-70%。病毒的重新激活是指导这一人群HCT患者抗病毒治疗的关键事件，通过免疫学方法控制病毒重新激活成为改进HCT移植的一个重要目标。悬而未决的问题是，需要哪些特定的免疫反应来防止CMV重新激活，这些适应性反应是否与后来在预防进行性CMV感染和疾病时引发的适应性反应相同？由于病毒粒子在多肽抗原的蛋白酶体加工过程中编码的变化，可能会改变对其他CMV蛋白的免疫反应，以保护病毒重新激活的能力。使用转基因的HLA-A*0201小鼠模型，可以从免疫逃逸机制中剖析免疫反应，以评估哪些其他CMV蛋白可以作为CMI的靶标。 这里检验的主要假设是，对感染早期存在的CMV蛋白的免疫力足以防止CMV重新激活和疾病。考虑到这一点，重要的早期CMV蛋白质将被I类免疫处理检查识别，包括那些参与复制早期阶段的蛋白质和那些负责免疫逃避的蛋白质。因此，本研究的目的是：1)在HCT后的免疫重建过程中，利用重叠的多肽池，重新评估所有人类白细胞抗原同种异型对CMV-pp65和CMV-IE1的免疫应答动力学；2)利用人类白细胞抗原-A*0201小鼠模型，确定在免疫重建早期相关的其他CMV蛋白的CD8表位，并利用CMV野生分离株评价对这些蛋白的免疫应答。 本项目的重要意义在于它将定义新的CMV免疫靶点，为开发预防移植后CMV再激活的新的免疫治疗策略提供重要信息。

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.