Yaguchi et al. created NOG mice that are MHC class I- and class II-deficient (NOG-dKO) to minimize the effects of graft-versus-host-disease, allowing long-term survival and extended observation of human immune responses following PBMC transplantation. The model could be used to study antigen-specific human B and T cell responses, as well as adoptive cell immunotherapies. However, antigen-presenting cells have short longevity and many immune cell types (including macrophages, Tregs, MDSCs, and NK cells) are not well supported.

Immunodeficient mice engrafted with human peripheral blood cells are promising tools for in vivo analysis of human patient individual immune responses. However, when human peripheral blood mononuclear cells (PBMCs) are transferred into NOG (NOD/Shi-scid, IL-2rgnull) mice, severe graft versus host disease (GVHD) hinders long term detailed analysis. Administration of human PBMCs into newly developed murine MHC class I- and class II-deficient NOG (NOG-dKO; NOG- Iab, B2m-double-knockout) mice showed sufficient engraftment of human immune cells with little sign of GVHD. Immunization with influenza vaccine resulted in an increase in influenza-specific human IgG Ab, indicating induction of antigen-specific B cells in the NOG-dKO mice. Immunization with human dendritic cells pulsed with HLA-A2 restricted cytomegalovirus peptide induced specific cytotoxic T cells, indicating the induction of antigen-specific T cells in the NOG-dKO mice. Adoptive cell therapies (ACTs) using melanoma antigen recognized by T cells (MART-1)-specific TCR-transduced activated T cells showed strong tumor growth inhibition in NOG-dKO mice without any sign of GVHD accompanied by preferential expansion of the transferred MART-1-specific T cells. ACTs using cultured human melanoma infiltrating T cells also showed anti-tumor effects against autologous melanoma cells in NOG-dKO mice, in which changes in human cancer phenotypes by immune intervention, such as increased CD271 expression, could be evaluated. Therefore, NOG-dKO mice are useful tools for more detailed analysis of both the induction and effector phases of T-cell and B-cell responses for a longer period than regular NOG mice.Cellular & Molecular Immunology advance online publication, 20 November 2017; doi:10.1038/cmi.2017.106.

Author Info: (1) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan. (2) Division of Cellular Signaling, Institute for

Author Info: (1) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan. (2) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan. (3) Department of Dermatology, Yamanashi University School of Medicine, Yamanashi 409-3898, Japan. (4) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan. (5) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan. (6) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan. Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo 160-8582, Japan. (7) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan. Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo 160-8582, Japan. (8) Central Institute for Experimental Animals, Kanagawa 210-0821, Japan. (9) Central Institute for Experimental Animals, Kanagawa 210-0821, Japan. (10) Central Institute for Experimental Animals, Kanagawa 210-0821, Japan. (11) Central Institute for Experimental Animals, Kanagawa 210-0821, Japan. (12) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.

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