Graduate School of Biomedical Sciences; Department of Molecular Genetics and Microbiology; Department of Medicine, Division of Diabetes
Medical Subject Headings
Animals; Antigens, CD19; B-Lymphocytes; Cell Nucleus; Cell Separation; Flow Cytometry; Humans; Mice; Mice, Inbred NOD; Mice, SCID; NF-kappa B; Pneumococcal Vaccines; Receptors, Tumor Necrosis Factor; Recombinant Proteins; Signal Transduction
Life Sciences | Medicine and Health Sciences
The production of fully immunologically competent humanized mice engrafted with peripheral lymphocyte populations provides a model for in vivo testing of new vaccines, the durability of immunological memory and cancer therapies. This approach is limited, however, by the failure to efficiently engraft human B lymphocytes in immunodeficient mice. We hypothesized that this deficiency was due to the failure of the murine microenvironment to support human B cell survival. We report that while the human B lymphocyte survival factor, B lymphocyte stimulator (BLyS/BAFF) enhances the survival of human B cells ex vivo, murine BLyS has no such protective effect. Although human B cells bound both human and murine BLyS, nuclear accumulation of NF-kappaB p52, an indication of the induction of a protective anti-apoptotic response, following stimulation with human BLyS was more robust than that induced with murine BLyS suggesting a fundamental disparity in BLyS receptor signaling. Efficient engraftment of both human B and T lymphocytes in NOD rag1(-/-) Prf1(-/-) immunodeficient mice treated with recombinant human BLyS is observed after adoptive transfer of human PBL relative to PBS treated controls. Human BLyS treated recipients had on average 40-fold higher levels of serum Ig than controls and mounted a de novo antibody response to the thymus-independent antigens in pneumovax vaccine. The data indicate that production of fully immunologically competent humanized mice from PBL can be markedly facilitated by providing human BLyS.
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Citation: PLoS ONE. 2008 Sep 11;3(9):e3192. Link to article on publisher's site
Schmidt, Madelyn R.; Appel, Michael C.; Giassi, Lisa J.; Greiner, Dale L.; Shultz, Leonard D.; and Woodland, Robert T., "Human BLyS facilitates engraftment of human PBL derived B cells in immunodeficient mice" (2008). GSBS Student Publications. 1557.