Title

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

UMMS Affiliation

Diabetes Center of Excellence; Department of Pediatrics, Division of Pediatric Pulmonology; Horae Gene Therapy Center

Publication Date

2018-11-01

Document Type

Article

Disciplines

Immunology and Infectious Disease

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 gamma ( IL2rg) (null) (NSG) strains that lack murine MHC class I and II [NSG-beta-2-microglobulin ( B2M) (null) ( IA IE)(null) and NSG -( K(b) D(b)) (null) ( IA(null))]. We observed rapid human IgG clearance in NSG- B2M(null) ( IA IE) (null) mice whereas clearance in NSG -( K(b) D(b)) (null) ( IA(null)) 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 -( K(b) D(b)) (null) ( IA(null)) 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. 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.

Keywords

GVHD, HU-PBL-SCID, humanized, immunodeficient

DOI of Published Version

10.1096/fj.201800636R

Source

FASEB J. 2018 Nov 1:fj201800636R. doi: 10.1096/fj.201800636R. [Epub ahead of print] Link to article on publisher's site

Journal/Book/Conference Title

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Related Resources

Link to Article in PubMed

PubMed ID

30383447

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