The analysis of the functions of human B and T cells in humanized NOD/shi-scid/gammac(null) (NOG) mice (hu-HSC NOG mice).

'Humanized mice' are anticipated to be a valuable tool for studying the human immune system, but the reconstituted human immune cells have not yet been well characterized. Here, we extensively investigated the differentiation and functions of human B and T cells in a supra-immunodeficient mouse strain, NOD/shi-scid/gammac(null) (NOG) reconstituted with CD34(+) hematopoietic stem cells obtained from umbilical cord blood. In these hu-HSC NOG mice, the development of human B cells was partially blocked, and a significant number of B-cell progenitors accumulated in the spleen. The mature CD19(+)IgM(+)IgD(+) human B cells of the hu-HSC NOG mice could produce IgG in vivo and in vitro by antigenic stimulation. In contrast, although human T cells with an apparently normal phenotype developed, most of them could neither proliferate nor produce IL-2 in response to antigenic stimulation by anti-CD3 and anti-CD28 antibodies in vitro. The positive selection of human T cells in the thymus was sufficiently functional, if not complete, and mainly mediated by mouse class II, suggesting that the human T cells lost their function in the periphery. We found that multiple mechanisms were involved in the T-cell abnormalities. Collectively, our results demonstrate that further improvements are necessary before humanized mice with a functional human immune system are achieved.

[1]  K. Hogquist,et al.  Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla , 2008, The Journal of experimental medicine.

[2]  H. Suemizu,et al.  Establishing EGFP congenic mice in a NOD/Shi-scid IL2Rg(null) (NOG) genetic background using a marker-assisted selection protocol (MASP). , 2008, Experimental animals.

[3]  Mamoru Ito,et al.  A new humanized mouse model of Epstein-Barr virus infection that reproduces persistent infection, lymphoproliferative disorder, and cell-mediated and humoral immune responses. , 2008, The Journal of infectious diseases.

[4]  Dale L. Greiner,et al.  T Cell-Specific siRNA Delivery Suppresses HIV-1 Infection in Humanized Mice , 2008, Cell.

[5]  B. Schraven,et al.  CD28 superagonists: what makes the difference in humans? , 2008, Immunity.

[6]  Inge Jonassen,et al.  Characterization of Early Stages of Human B Cell Development by Gene Expression Profiling1 , 2007, The Journal of Immunology.

[7]  G. Crooks,et al.  Immune-cell lineage commitment: translation from mice to humans. , 2007, Immunity.

[8]  M. Manz Human-hemato-lymphoid-system mice: opportunities and challenges. , 2007, Immunity.

[9]  Dale L. Greiner,et al.  Humanized mice in translational biomedical research , 2007, Nature Reviews Immunology.

[10]  A. Simmons,et al.  Use of a lentivirus/VSV pseudotype virus for highly efficient genetic redirection of human peripheral blood lymphocytes , 2006, Nature Protocols.

[11]  A. Haase,et al.  Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1 , 2006, Nature Medicine.

[12]  Markus G. Manz,et al.  Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2−/−γc−/− mice , 2006, Proceedings of the National Academy of Sciences.

[13]  T. Hanke,et al.  Transient accumulation of human mature thymocytes and regulatory T cells with CD28 superagonist in "human immune system" Rag2(-/-)gammac(-/-) mice. , 2006, Blood.

[14]  H. Spits,et al.  Experimental Models to Study Development and Function of the Human Immune System In Vivo , 2006, The Journal of Immunology.

[15]  A. Palucka,et al.  Humanized mice , 2005, The Journal of experimental medicine.

[16]  R. Budd,et al.  The Death Receptor Fas (CD95/APO-1) Mediates the Deletion of T Lymphocytes Undergoing Homeostatic Proliferation1 , 2005, The Journal of Immunology.

[17]  E. Choi,et al.  Thymocyte-thymocyte interaction for efficient positive selection and maturation of CD4 T cells. , 2005, Immunity.

[18]  W. Leonard,et al.  Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation , 2005, Nature Reviews Immunology.

[19]  K. Akashi,et al.  Development of functional human blood and immune systems in NOD/SCID/IL2 receptor γ chainnull mice , 2005 .

[20]  M. Sata,et al.  Mobilization of Human Lymphoid Progenitors after Treatment with Granulocyte Colony-Stimulating Factor 1 , 2005, The Journal of Immunology.

[21]  M. Kotb,et al.  Human Lymphoid and Myeloid Cell Development in NOD/LtSz-scid IL2Rγnull Mice Engrafted with Mobilized Human Hemopoietic Stem Cells 12 , 2004, The Journal of Immunology.

[22]  P. Lipsky,et al.  Regulation of B Cell Differentiation and Plasma Cell Generation by IL-21, a Novel Inducer of Blimp-1 and Bcl-61 , 2004, The Journal of Immunology.

[23]  Markus G. Manz,et al.  Development of a Human Adaptive Immune System in Cord Blood Cell-Transplanted Mice , 2004, Science.

[24]  Lawrence S. Chan,et al.  Human Immune System , 2003 .

[25]  Mamoru Ito,et al.  Functional CD5+ B cells develop predominantly in the spleen of NOD/SCID/gammac(null) (NOG) mice transplanted either with human umbilical cord blood, bone marrow, or mobilized peripheral blood CD34+ cells. , 2003, Experimental hematology.

[26]  Mamoru Ito,et al.  Complete reconstitution of human lymphocytes from cord blood CD34+ cells using the NOD/SCID/gammacnull mice model. , 2003, Blood.

[27]  Mamoru Ito,et al.  NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. , 2002, Blood.

[28]  T. Nomura,et al.  The in vivo development of human T cells from CD34(+) cells in the murine thymic environment. , 2002, International immunology.

[29]  Y. Ueyama,et al.  Functional Human T Lymphocyte Development from Cord Blood CD34+ Cells in Nonobese Diabetic/Shi-scid, IL-2 Receptor γ Null Mice1 , 2002, The Journal of Immunology.

[30]  J. Gebe,et al.  T Cell Selection and Differential Activation on Structurally Related HLA-DR4 Ligands1 , 2001, The Journal of Immunology.

[31]  T. Kitamura,et al.  Plat-E: an efficient and stable system for transient packaging of retroviruses , 2000, Gene Therapy.

[32]  Y. Matsuo,et al.  Flow cytometric diagnosis of the cell lineage and developmental stage of acute lymphoblastic leukemia by novel monoclonal antibodies specific to human pre-B-cell receptor. , 1998, Blood.

[33]  David A. Williams,et al.  Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: Implications for gene therapy , 1996, Nature Medicine.

[34]  M. Katsuki,et al.  Modulation of hematopoiesis in mice with a truncated mutant of the interleukin-2 receptor gamma chain. , 1996, Blood.

[35]  W. Leonard,et al.  Role of the Common Cytokine Receptor γ Chain in Cytokine Signaling and Lymphoid Development , 1995, Immunological reviews.

[36]  W. Leonard,et al.  Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. , 1995, Immunity.

[37]  A. Fischer,et al.  Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[38]  T. Lebien,et al.  The growth response to IL-7 during normal human B cell ontogeny is restricted to B-lineage cells expressing CD34. , 1995, Journal of immunology.

[39]  D. Greiner,et al.  Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. , 1995, Journal of immunology.

[40]  M. Roncarolo,et al.  Anti-SCID mouse reactivity shapes the human CD4+ T cell repertoire in hu-PBL-SCID chimeras , 1994, The Journal of experimental medicine.

[41]  J. Dick,et al.  Engraftment of human lymphoid cells into newborn SCID mice leads to graft-versus-host disease. , 1993, International immunology.

[42]  F. Finkelman,et al.  Inhibition of murine B and T lymphopoiesis in vivo by an anti- interleukin 7 monoclonal antibody , 1993, The Journal of experimental medicine.

[43]  D. V. van Bekkum,et al.  Acute human vs. mouse graft vs. host disease in normal and immunodeficient mice , 1992, European Journal of Immunology.

[44]  D. Gray,et al.  Mice lacking MHC class II molecules , 1991, Cell.

[45]  I. Weissman,et al.  The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. , 1988, Science.

[46]  C. F. Shaffer,et al.  MAINTENANCE OF SKIN XENOGRAFTS OF WIDELY DIVERGENT PHYLOGENETIC ORIGIN ON CONGENITALLY ATHYMIC (NUDE) MICE , 1973, The Journal of experimental medicine.

[47]  H. Nakauchi,et al.  Simplified retroviral vector gcsap with murine stem cell virus long terminal repeat allows high and continued expression of enhanced green fluorescent protein by human hematopoietic progenitors engrafted in nonobese diabetic/severe combined immunodeficient mice. , 2001, Human gene therapy.

[48]  Identification and characterization of circulating human transitional B cells , 2022 .