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Lack of acute xenogeneic graft- versus-host disease, but retention of T-cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression.
FASEB J. 2019 03; 33(3):3137-3151.FJ

Abstract

Immunodeficient mice engrafted with human peripheral blood mononuclear cells (PBMCs) support preclinical studies of human pathogens, allograft rejection, and human T-cell function. However, a major limitation of PBMC engraftment is development of acute xenogeneic graft- versus-host disease (GVHD) due to human T-cell recognition of murine major histocompatibility complex (MHC). To address this, we created 2 NOD- scid IL-2 receptor subunit γ (IL2rg) null (NSG) strains that lack murine MHC class I and II [NSG-β-2-microglobulin (B2M) null (IA IE)null and NSG -(Kb Db) null (IAnull)]. We observed rapid human IgG clearance in NSG- B2Mnull (IA IE) null mice whereas clearance in NSG -(Kb Db) null (IAnull) mice and NSG mice was comparable. Injection of human PBMCs into both strains enabled long-term engraftment of human CD4+ and CD8+ T cells without acute GVHD. Engrafted human T-cell function was documented by rejection of human islet allografts. Administration of human IL-2 to NSG -(Kb Db) null (IAnull) mice via adeno-associated virus vector increased human CD45+ cell engraftment, including an increase in human regulatory T cells. However, high IL-2 levels also induced the development of GVHD. These data document that NSG mice deficient in murine MHC support studies of human immunity in the absence of acute GVHD and enable evaluation of human antibody therapeutics targeting human T cells.-Brehm, M. A., Kenney, L. L., Wiles, M. V., Low, B. E., Tisch, R. M., Burzenski, L., Mueller, C., Greiner, D. L., Shultz, L. D. Lack of acute xenogeneic graft- versus-host disease, but retention of T-cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression.

Authors+Show Affiliations

Diabetes Center of Excellence University of Massachusetts Medical School, Worcester, Massachusetts, USA.Diabetes Center of Excellence University of Massachusetts Medical School, Worcester, Massachusetts, USA.The Jackson Laboratory, Bar Harbor, Maine, USA.The Jackson Laboratory, Bar Harbor, Maine, USA.Department of Immunology and Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; and.The Jackson Laboratory, Bar Harbor, Maine, USA.Department of Pediatrics and Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.Diabetes Center of Excellence University of Massachusetts Medical School, Worcester, Massachusetts, USA.The Jackson Laboratory, Bar Harbor, Maine, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30383447

Citation

Brehm, Michael A., et al. "Lack of Acute Xenogeneic Graft- Versus-host Disease, but Retention of T-cell Function Following Engraftment of Human Peripheral Blood Mononuclear Cells in NSG Mice Deficient in MHC Class I and II Expression." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 33, no. 3, 2019, pp. 3137-3151.
Brehm MA, Kenney LL, Wiles MV, et al. Lack of acute xenogeneic graft- versus-host disease, but retention of T-cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression. FASEB J. 2019;33(3):3137-3151.
Brehm, M. A., Kenney, L. L., Wiles, M. V., Low, B. E., Tisch, R. M., Burzenski, L., Mueller, C., Greiner, D. L., & Shultz, L. D. (2019). Lack of acute xenogeneic graft- versus-host disease, but retention of T-cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 33(3), 3137-3151. https://doi.org/10.1096/fj.201800636R
Brehm MA, et al. Lack of Acute Xenogeneic Graft- Versus-host Disease, but Retention of T-cell Function Following Engraftment of Human Peripheral Blood Mononuclear Cells in NSG Mice Deficient in MHC Class I and II Expression. FASEB J. 2019;33(3):3137-3151. PubMed PMID: 30383447.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lack of acute xenogeneic graft- versus-host disease, but retention of T-cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression. AU - Brehm,Michael A, AU - Kenney,Laurie L, AU - Wiles,Michael V, AU - Low,Benjamin E, AU - Tisch,Roland M, AU - Burzenski,Lisa, AU - Mueller,Christian, AU - Greiner,Dale L, AU - Shultz,Leonard D, Y1 - 2018/11/01/ PY - 2020/03/01/pmc-release PY - 2018/11/2/pubmed PY - 2019/11/19/medline PY - 2018/11/2/entrez KW - GVHD KW - HU-PBL-SCID KW - humanized KW - immunodeficient SP - 3137 EP - 3151 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J. VL - 33 IS - 3 N2 - Immunodeficient mice engrafted with human peripheral blood mononuclear cells (PBMCs) support preclinical studies of human pathogens, allograft rejection, and human T-cell function. However, a major limitation of PBMC engraftment is development of acute xenogeneic graft- versus-host disease (GVHD) due to human T-cell recognition of murine major histocompatibility complex (MHC). To address this, we created 2 NOD- scid IL-2 receptor subunit γ (IL2rg) null (NSG) strains that lack murine MHC class I and II [NSG-β-2-microglobulin (B2M) null (IA IE)null and NSG -(Kb Db) null (IAnull)]. We observed rapid human IgG clearance in NSG- B2Mnull (IA IE) null mice whereas clearance in NSG -(Kb Db) null (IAnull) mice and NSG mice was comparable. Injection of human PBMCs into both strains enabled long-term engraftment of human CD4+ and CD8+ T cells without acute GVHD. Engrafted human T-cell function was documented by rejection of human islet allografts. Administration of human IL-2 to NSG -(Kb Db) null (IAnull) mice via adeno-associated virus vector increased human CD45+ cell engraftment, including an increase in human regulatory T cells. However, high IL-2 levels also induced the development of GVHD. These data document that NSG mice deficient in murine MHC support studies of human immunity in the absence of acute GVHD and enable evaluation of human antibody therapeutics targeting human T cells.-Brehm, M. A., Kenney, L. L., Wiles, M. V., Low, B. E., Tisch, R. M., Burzenski, L., Mueller, C., Greiner, D. L., Shultz, L. D. Lack of acute xenogeneic graft- versus-host disease, but retention of T-cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/30383447/Lack_of_acute_xenogeneic_graft__versus_host_disease_but_retention_of_T_cell_function_following_engraftment_of_human_peripheral_blood_mononuclear_cells_in_NSG_mice_deficient_in_MHC_class_I_and_II_expression_ L2 - http://www.fasebj.org/doi/full/10.1096/fj.201800636R?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -