Journal Article

Human BLyS Facilitates Engraftment of Human PBL Derived B Cells in Immunodeficient Mice

Appel, Michael C., Schmidt, Madelyn R., Giassi, Lisa J., Woodland, Robert T., Shultz, Leonard D., Greiner, Dale L.

2008

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adoptive transfer / Animals / Antibodies / Antibody response / Antigens / Antigens, CD19 - biosynthesis / Apoptosis / Autoimmune diseases / B cells / B-Lymphocytes - cytology / B-Lymphocytes - metabolism / Biocompatibility / Biomedical materials / BLyS protein / Cancer / Cell Biology/Leukocyte Signaling and Gene Expression / Cell growth / Cell Nucleus - metabolism / Cell Separation / Cell survival / Cooperation / Dendritic cells / Diabetes / Durability / Flow Cytometry / Health aspects / Homeostasis / Humans / Immunodeficiency / Immunoglobulins / Immunological memory / Immunology / Immunology/Immune Response / In vivo methods and tests / Ligands / Lymphocyte receptors / Lymphocytes / Lymphocytes B / Lymphocytes T / Medical schools / Mice / Mice, Inbred NOD / Mice, SCID / Mutation / NF-kappa B - metabolism / NF-κB protein / Pneumococcal Vaccines - therapeutic use / RAG1 protein / Receptors, Tumor Necrosis Factor - metabolism / Receptors, Tumor Necrosis Factor - physiology / Recombinant Proteins - chemistry / Signal Transduction / Stimulators / Surgical implants / Survival / Survival factor / T cells / Thymus / Tumors / Vaccines