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）是一种广泛存在的B淋巴细胞疱疹病毒，可异位感染T细胞或NK细胞，引起慢性活动性EB病毒感染（chronic active EBV infection，CAEBV）和EB病毒相关噬血细胞性淋巴组织细胞增生症（Hemophagocytic lymphohistiocytosis，EBV-HLH）。我们通过将患者的PBMC移植到NOD/Shi-scid/IL-2 Rcnull品系的免疫缺陷小鼠中，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细胞全身性增殖，并再现了这两种疾病的组织学特征。TCR库表达的分析显示，相同的主要EBV感染的T细胞克隆增殖的患者和相应的小鼠与他们的PBMC移植。从患者PBMC分离的单个免疫表型亚群以及这些亚群的各种组合的移植揭示了CD 4 +T细胞在EBV感染的T细胞和NK细胞的植入中的关键作用。根据这一发现，通过在PBMC移植后施用OKT 4抗体来体内消耗CD 4 + T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动物模型的首次报道，这些动物模型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.