The manufacture of the EBV-T/NK LPD model mouse and the study of the clinical condition expression mechanism

EB病毒(Epstein-Barr Virus，EBV)是一种普遍存在的嗜B淋巴细胞疱疹病毒，它通过异位感染T细胞或NK细胞，引起慢性活动性EBV感染(CAEBV)和EBV相关性噬血细胞淋巴组织细胞增多症(EBV-HLH)等严重疾病。我们通过将患者的PBMC移植到NOD/SHI-SCID/IL-2Rcull株免疫缺陷小鼠，建立了CAEBV和EBV-HLH的异种移植模型。在这些模型中，EBV感染的T、NK或B细胞系统地增殖，并复制了这两种疾病的组织学特征。对TCR谱系表达的分析表明，相同的主要EBV感染的T细胞克隆在患者和相应的移植了他们的PBMC的小鼠中增殖。从患者PBMC分离的单个免疫表型亚群以及这些亚群的不同组合的移植表明，CD4_T细胞在EBV感染的T细胞和NK细胞的植入中起着关键作用。根据这一发现，PBMC移植后注射OKT4抗体在体内耗尽了CD4T细胞，阻止了EBV感染的T细胞和NK细胞的植入。这是CAEBV和EBV-HLH动物模型的第一份报告，有望成为开发治疗这些疾病的新治疗策略的有用工具。

Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, ectopically infects T or NK cells to cause severe diseases of unknown pathogenesis, including chronic active EBV infection (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). We developed xenograft models of CAEBV and EBV-HLH by transplanting patients’ PBMC to immunodeficient mice of the NOD/Shi-scid/IL-2Rcnull strain. In these models, EBV-infected T, NK, or B cells proliferated systemically and reproduced histological characteristics of the two diseases. Analysis of the TCR repertoire expression revealed that identical predominant EBV-infected T-cell clones proliferated in patients and corresponding mice transplanted with their PBMC. Transplantation of individual immunophenotypic subsets isolated from patients’ PBMC as well as that of various combinations of these subsets revealed a critical role of CD4_+T cells in the engraftment of EBV-infected T and NK cells. In accordance with this finding, in vivo depletion of CD4_+ T cells by the administration of the OKT4 antibody following transplantation of PBMC prevented the engraftment of EBV-infected T and NK cells. This is the first report of animal models of CAEBV and EBV-HLH that are expected to be useful tools in the development of novel therapeutic strategies for the treatment of the diseases.