Engraftment of human peripheral blood lymphocytes in normal strains of mice

Abstract

Transplantation of bone marrow from SCID mice into lethally irradiated normal mice can potentially endow the normal recipients with characteristics typical of the immune-deficient SCID mouse. In the present study, we investigated whether intraperitoneal grafting of human peripheral blood lymphocytes (PBLs), which has been documented in the SCID mouse, can also be achieved in irradiated BALB/c mice radioprotected with SCID bone marrow. Evaluation of different radiation protocols suggested that, considering the quality of engraftment and rate of survival, optimal results were obtained with split dose total body irradiation (TBI; 4 Gy followed 3 days later by 10 Gy). Monitoring of mouse T cells in peripheral blood indicated an inverse correlation between the presence of such cells and the engraftment of human CD45+ cells in the peritoneum. Also, engraftment of human PBLs in nude BALB/c mice, conditioned with the same radiation protocol, was significantly higher than that achieved in their normal counterparts. Further improvement of human PBL engraftment was found when the mice were thymectomized 2 weeks before conditioning with split TBI. After transplantation of 80 x 10(6) human PBLs in such recipients, a marked engraftment of human T cells and B cells in the peritoneum cavity could be detected for at least 2 months, whereas significant amounts of human Ig could be detected for more than 3 months. Migration of human PBLs into internal organs such as spleen, liver, kidney, and lungs (and into thymus in nonthymectomized mice) was found within a few days of grafting and also persisted for 2 to 3 months. The majority of the engrafted lymphocytes were single-positive CD4+ and CD8+ T lymphocytes, about 50% of which were activated, as judged by their expression of HLA- DR. Staining with anti-CD25 antibody was lower compared with that found with anti-HLA-DR. CD20+ B cells were detected in all of the above- mentioned internal organs, but were mainly concentrated in the spleen. CD14+ monocytes could be detected only during the first week posttransplant of PBLs. Total human Ig in peripheral blood reached an average of 2.8 mg/mL 14 days posttransplant, and continued to be significant for several months. In vitro transformation by Epstein-Barr virus of human B cells from different tissues could be established 30 days after transplantation and led to outgrowth of two IgG+ cell lines, two IgM+ cell lines, and one IgA+ cell line producing 0.6 to 4.2 micrograms/mL human Ig in the supernatant.

Histological Assessment of the Sclerotic Graft-versus-Host Response in the Humanized RAG2−/−γc−/− Mouse Model

“…The study of human GVHD development in vivo has used several different experimental models based on immunodeficient mouse strains, including severe combined immunodeficient (SCID) mice, nonobese diabetic severe immunodeficient (NOD-SCID) mice, and the RAG2 2/2 gc 2/2 mice [11][12][13][14][15]. Several xenogeneic mouse models have been reported [15][16][17][18][19][20], but only a few of these are considered specific GVHD models [15,[21][22][23].…”

Nanovaccine for immunotherapy and reduced hepatitis-B virus in humanized model

“…For this purpose, chimera mice had been developed, which stimulate human serum antibody responses by vaccination with the help of recall the antigens [17]. In chimera mice after vaccination, HBsAg was complexed with human anti-HBs, this immunogenic complex (IC) increases HBsAg processing and presenting by enhancing T-cell activity through increased uptake of HBsAg which are present on receptors of antigenpresenting cells (APCs) [18,19]. B cells stimulation occurs in the secondary lymphoid organs, such as the spleen and lymph nodes and its activation is enhanced through the activity of CD21 [20,21].…”

Induction of strong hepatitis B virus (HBV) specific T helper cell and cytotoxic T lymphocyte responses by therapeutic vaccination in the trimera mouse model of chronic HBV infection

“…We have developed an alternative protocol to generate human / mouse chimera employing the transfer of human PBMC into lethally irradiated BALB / c mice radioprotected with SCID mouse bone marrow (BM) 16. Since these chimera contain tissues from three different sources (murine recipient, SCID mouse BM donor, human PBMC donor), the mice were termed trimera 17.…”

“…Since these chimera contain tissues from three different sources (murine recipient, SCID mouse BM donor, human PBMC donor), the mice were termed trimera 17. Due to the existence of preformed murine lymphatic organs, the engraftment of transferred human T and B cells reaches its peak already within the first 3 weeks post‐transplant with formation of lymphoid follicles in peritoneum, lymph nodes and spleen 16, 18. Moreover, high numbers of human lymphocytes can be transplanted into different strains of mice without the complications of GvHD or EBV lymphomas 19.…”