Abstract 5665: 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
Authors: Brehm Michael A. , Wiles Michael , Kenney Laurie , Low Ben , Tisch Roland M. , Burzenski Lisa , Keck James G. , Greiner Dale L. , Shultz Leonard D. 
Published: August 2018

The study of human immune system-tumor interactions has been limited historically by a paucity of models that fully reproduce human immune system function. 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 mice) has supported studies of human infectious agents, allograft rejection, and human T cell immune function. The Hu-PBL-SCID model has also 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 graft-versus-host disease (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-B2Mnull with NSG-(IA IEnull) mice, the second by knocking out the MHC class II IAb gene in NSG-(Kb Db)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-(Kb Db)null (IAnull) mice was comparable to that observed in NSG mice. Injection of human PBMC into both strains led to engraftment of human T cells that exhibited an approximate 3:1 CD4:CD8 ratio with long term engraftment and without development of acute GVHD. The engrafted human T cells were functional as documented by their ability to reject human islet allografts. Administration of human recombinant IL2 using AAV-IL2 to NSG-(Kb Db)null (IAnull) mice resulted in increased human CD45 cell engraftment, including heightened levels of human Tregs. However, high IL2 levels led to the development of acute GVHD. Moreover, NSG-(Kb Db)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 can support studies of human immune system-tumor interactions in the absence of acute GVHD and provide a model for evaluation of human antibody therapeutics.

Citation Format: Michael A. Brehm, Michael Wiles, Laurie Kenney, Ben Low, Roland M. Tisch, Lisa Burzenski, James G. Keck, Dale L. Greiner, Leonard D. Shultz. NOD-scid IL2rgnull (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]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5665.