Background
Epstein-Barr virus (EBV) has a close association with various types of human lymphomas. Animal models are essential to elucidate the pathogenesis of human EBV-associated lymphomas. The aim of the present study is to evaluate the association between human IgG concentration and EBV-associated lymphoma development in huPBL/SCID mice.
Methods
Human peripheral blood lymphocytes (hu-PBL) from EBV-seropositive donors were inoculated intraperitoneally into SCID mouse. Immunohistochemical staining was used to examine differentiated antigens of tumor cells. EBV infection of the induced tumors was detected by in situ hybridization. IgG concentrations in the serums of 12 SCID mice were measured by unidirectional immunodiffusion assay.
Results
21 out of 29 mice developed tumors in their body. Immunohistochemical staining showed that all induced tumors were LCA (leukocyte common antigen) positive, B-cell markers (CD20, CD79a) positive, and T-cell markers (both CD3 and CD45RO) negative. The tumors can be diagnosed as human B-cell lymphomas by these morphological and immunohistochemical features. In situ hybridization exhibited resultant tumor cells had EBV encoded small RNA-1 (EBER-1). Human-derived IgG could be found in the serum from SCID mice on the 15th day following hu-PBL transplantation, and IgG levels increased with the tumor development in 6 hu-PBL/SCID chimeras.
Conclusions
Intraperitoneal transfer of hu-PBLs from EBV+ donors to SCID mice leads to high human IgG levels in mouse serum and B cell lymphomas. Our findings suggest that increasing levels of human-derived IgG in peripheral blood from hu-PBL/SCID mice could be used to monitor EBV-related human B-cell lymphoma development in experimental animals.
Background
Epstein-Barr virus (EBV) is a ubiquitous human herpes virus that persists in most human bodies as a lifelong latent infection in host lymphocytes after a primary viral encounter, and it has been confirmed to be the etiological factor of infectious mononucleosis. More important, EBV, which may be one of human tumor viruses [3], has a close association with human lymphoma and nasopharyngeal carcinoma. Although EBV can transform human lymphocytes and squamous epithelia in vitro, it is impossible to conduct controllable investigation on human body. It is also a difficult problem to induce neoplasm with EBV in animal body. Up to date, no study about infection and oncogenicity of EBV has been done with an ideal animal model.
Animal models of lymphoma are essential to elucidate the pathogenesis of human EBV-associated lymphomas. Severe combined immunodeficient (SCID) mouse (homozygous C.B.-17 scid/scid) expresses a truncated form of the catalytic subunit of the DNA-dependent protein kinase and is unable to properly rearrange the Ig and TCR genes. The ensuing severe combined immunodeficiency endows these mice with the capacity to accept xenografts. Because SCID mice lack functional T or B lymphocytes, they can be engrafted with functioning human hematolymphoid cells to create human/SCID chimeras. In immunosuppressed individuals, such as post-transplant patients, the presence of EBV-infected B cells may lead to lymphoproliferative disease. Injection of human peripheral blood lymphocytes (hu-PBLs) or hematopoietic stem cells from EBV-positive donors into SCID mice induces human lymphoproliferative disease in the humanized SCID recipients. This xenochimeric human-mouse model can be used to elucidate the mechanisms of EBV-specific lymphomagenesis and to assess novel therapeutic approaches. The aim of the present study is to detect molecular biomarkers of the EBV-induced lymphomas in hu-PBL/SCID mice and to measure serum IgG levels in hu-PBL/SCID chimeras.