Human BLyS facilitates engraftment of human PBL derived B cells in immunodeficient mice.
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.
Schmidt
Madelyn R
MR
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America. Madelyn.Schmidt@umassmed.edu
Appel
Michael C
MC
Giassi
Lisa J
LJ
Greiner
Dale L
DL
Shultz
Leonard D
LD
Woodland
Robert T
RT
D000818:Animals; D018941:Antigens, CD19 / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D022242:Pneumococcal Vaccines / Q000627:therapeutic use; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction
D018941:Antigens, CD19; C120197:BLyS receptor; D016328:NF-kappa B; D022242:Pneumococcal Vaccines; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins
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