NOD-scid IL2rg null (NSG) mice deficient in murine MHC Class I and Class II expression support engraftment of functional human T cells in the absence of acute xenogeneic GVHD following injection of PBMC

Abstract

Abstract Humanized mice are emerging as an exciting platform to study human immuno-oncology and provide preclinical tools to test cutting edge immunotherapies. An effective and simplistic approach to engraft immunodeficient mice with functional human T cells is the injection of human peripheral blood mononuclear cells (PBMC). This PBMC engraftment model (termed Hu-PBL-SCID) has supported studies of human immune system-tumor interactions following injection of human PBMC into immunodeficient mice implanted with patient-derived (PDX) tumors. However, a major limitation of this model is the development of acute xenogeneic GVHD due to human T cell recognition of murine MHC class I and class II. To address this limitation, we created two strains of NSG mice that lack murine MHC antigens, one by crossing NSG-B2Mnullwith NSG-(IA IEnull) mice, the second by knocking out the MHC class II IAb gene in NSG-(KbDb)null mice using TALEN technology. We observed that human IgG clearance was rapid in NSG-B2Mnull(IA IEnull) mice that lack functional FcRn activity whereas clearance in NSG-(KbDb)null(IAnull) mice was comparable to that observed in NSG mice. Injection of human PBMC into both strains led to long term engraftment of human T cells without development of acute GVHD. The engrafted human T cells were functional as documented by their ability to reject human islet allografts. Moreover, NSG-(KbDb)null(IAnull) mice injected with a PDX tumor and PBMC from an allogeneic donor supported significant tumor growth in the absence of acute GVHD. These data document that NSG mice deficient in murine MHC class I and class II support studies of human immune system-tumor interactions in the absence of acute GVHD and provide a model to evaluate human antibody therapeutics.