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.

A novel small animal model for HIV‐1 infection

“…In contrast to the previous hu-PBL-SCID models (15,23,24), human PBMC in the Trimera mice do not become anergic and are capable of mounting primary and secondary cellular and humoral specific immune responses (21,25,26). In distinction to hu-PBL-SCID mice, the tempo of engraftment and the appearance of human T and B cells subpopulations are greatly enhanced in different internal organs as early as 24 h after transplantation (20,21,27). The Trimera mice have been successfully used for studying human infections, such as hepatitis C (HCV) (28), hepatitis B (HBV) (29), and influenza (30), and for evaluation of influenza and hepatitis B vaccines (30,31).…”

“…Trimera mice were prepared as described previously (20,21), according to the Weizmann Institute Animal Committee guidelines. Briefly, Balb/c mice (8-10 wk old) were exposed to split lethal dose of total body irradiation of 4 Gy followed 3 days later by 9.5 Gy (21).…”

“…In this model, most of the hematopoietic system is ablated by split-dose total body irradiation. The mice are then radioprotected by murine SCID bone marrow and converted to Trimera mice by intraperitoneal injection of human PBMC (20)(21)(22). In contrast to the previous hu-PBL-SCID models (15,23,24), human PBMC in the Trimera mice do not become anergic and are capable of mounting primary and secondary cellular and humoral specific immune responses (21,25,26).…”

“…The mice are then radioprotected by murine SCID bone marrow and converted to Trimera mice by intraperitoneal injection of human PBMC (20)(21)(22). In contrast to the previous hu-PBL-SCID models (15,23,24), human PBMC in the Trimera mice do not become anergic and are capable of mounting primary and secondary cellular and humoral specific immune responses (21,25,26). In distinction to hu-PBL-SCID mice, the tempo of engraftment and the appearance of human T and B cells subpopulations are greatly enhanced in different internal organs as early as 24 h after transplantation (20,21,27).…”

Amelioration of lupus manifestations by a peptide based on the complementarity determining region 1 of an autoantibody in severe combined immunodeficient (SCID) mice engrafted with peripheral blood lymphocytes of systemic lupus erythematosus (SLE) patients

“…One model has been of human PBL engrafted severe combined immunodeficient (SCID) mice, whereas the second model of human/mouse chimera was based on the previously reported studies of Lubin et al . [19]. Some of the SLE serological (human anti-DNA antibodies) and clinical manifestations (proteinuria, immune complex deposits in kidneys) of SLE were observed in the successfully engrafted mice of both models [18].…”