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Humanized Mouse Models for Transplant Immunology

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Humanized Mouse Models for Transplant Immunology American Journal of Transplantation 2016; 16: 389–397 © Copyright 2015 The American Society of Transplantation Wiley Periodicals Inc. and the American Society of Transplant Surgeons doi: 10.1111/ajt.13520 Humanized Mouse Models for Transplant Immunology L. L. Kenney1, L. D. Shultz2, D. L. Greiner1,* NOD.Cg-PrkdcscidIL2rgtm1Wjl; PBMC, peripheral blood and M. A. Brehm1 mononuclear cell; PD-L1, programmed death ligand 1; Rag2, recombination activating gene 1; Rag2, recom- scid 1 bination activating gene 2; scid, Prkdc , severe Department of Molecular Medicine, Diabetes Center of combined immunodeficiency; SCID/beige, CB17- Excellence, University of Massachusetts Medical School, Lystbg Prkdcscid; TGF-b, transforming growth factor Worcester, MA b; Tregs, regulatory T cells; UCB, umbilical cord blood 2The Jackson Laboratory, Bar Harbor, ME Ã Corresponding author: Dale L. Greiner, Received 20 July 2015, revised 02 September 2015 and [email protected] accepted for publication 04 September 2015 Our understanding of the molecular pathways that Introduction control immune responses, particularly immunomod- ulatory molecules that control the extent and duration MHC-mismatched grafts induce the activation of a cell- of an immune response, have led to new approaches in mediated immune response that leads to graft rejection in the field of transplantation immunology to induce the absence of immunosuppressive therapy. As the allograft survival. These molecular pathways are being technology for transplanting cells and tissues has improved, defined precisely in murine models and translated into the major remaining limiting factor influencing the success of clinical practice; however, many of the newly available an organ transplant is the ability to control this immune drugs are human-specific reagents. Furthermore, many response. Understanding the mechanisms of allograft species-specific differences exist between mouse and rejection is imperative for developing new immune therapies human immune systems. Recent advances in the development of humanized mice, namely, immunode- to improve the long-term success of organ transplants. ficient mice engrafted with functional human immune Mouse models of allogeneic rejection have provided insights systems, have led to the availability of a small animal that have led to the development of several new immuno- model for the study of human immune responses. suppressive and immunomodulatory approaches. Neverthe- Humanized mice represent an important preclinical less, successful immunotherapies in animal models, when model system for evaluation of new drugs and translated into the clinic, have produced limited success to identification of the mechanisms underlying human date, likely in part because of the many species-specific allograft rejection without putting patients at risk. This differences between mouse and human immune review highlights recent advances in the development responses (1). An important additional difference is the of humanized mice and their use as preclinical models presence of memory T cells in humans that are potentially for the study of human allograft responses. alloreactive (2–4) and that are absent in na€ıve mice housed in microisolator cages in specific pathogen-free facilities and Abbreviations: anti-Gr1, anti-granulocyte antibody; anti-GM1, anti–monosialotetrahexosylganglioside 1; explicitly not exposed to viral infections. BAFF, B cell activating factor; beige, Lystbg; BLT, transplantation with fetal liver and thymus and Recent advances in the development of humanized mice injection of autologous liver hematopoietic stem cells; have positioned them as an excellent preclinical model to BRG, C.Cb-Rag2tm1Fva IL2rgtm1Sug; CTLA4, cytotoxic T investigate species-specific molecules, molecular path- lymphocyte associated protein 4; ESC, embryonic stem ways and mechanisms underlying human allograft rejection cell; GVHD, graft-versus-host disease; HSC, hemato- and to investigate and evaluate potential therapies without poietic stem cell; Hu-PBL-SCID, transplantation with putting patients at risk. This review outlines these recent human peripheral blood mononuclear cells; Hu-SRC- advances and the use of humanized mice for the study of SCID, transplantation with human CD34þ hematopoi- transplantation. etic stem cells; IFN-g, interferon-g; IL2rgnull, IL-2 receptor common gamma chain knockout; iPSC, induced pluripotent stem cell; MST, median survival Humanized mouse strain development time; NICC, neonatal porcine islet cell cluster; NOG, The development of immunodeficient mice for engraftment NOD.Cg-PrkdcscidIL2rgtm1Sug; NOD, nonobese diabetic; with functional human immune systems over the past NRG-Akita, NOD-Rag1tm1MomIL2gnullIns2Akita; NSG, 25 years has been reviewed extensively (5–7). Simply put, 389 Kenney et al the goal is to generate an immunodeficient mouse that can humanized by the injection of human peripheral blood be engrafted with functional human innate and adaptive mononuclear cells (PBMCs), HSCs or HSCs in combination immune cells or with human hematopoietic stem cells with implantation of autologous fragments of fetal thymus (HSCs). The type of human cells and tissues used partly and liver. The injection of human PBMCs into immunode- determines the quality and robustness of the engrafted ficient mice, also known as the Hu-PBL-SCID model, leads human immune system. The major breakthrough in to the engraftment primarily of T cells (5–8). Hu-PBL-SCID humanized mice in the early 2000s came with the addition mice develop a xenogeneic graft-versus-host-like disease of mutations targeting the IL-2 receptor common gamma (GVHD) within a few weeks, but this model can be used for chain (IL2rgnull) (5–7). The common gamma chain is short-term studies to examine T cell rejection of human essential for high-affinity receptor signaling for IL-2, IL-4, allografts (9). The injection of CD34þ HSCs into newborn or IL-7, IL-9, IL-15 and IL-21. Blocking signaling for this group young mice, also known as the Hu-SRC-SCID model, of cytokines severely inhibits both adaptive and innate allows for the differentiation and development of a more immunity, including NK cell development. Crossing the complete immune system including T cells, B cells and IL2rgnull mutation to mice homozygous for the Prkdcscid innate immune cells. HSCs can be sourced from human (severe combined immunodeficiency [scid]), recombination bone marrow, umbilical cord blood (UCB), fetal liver or activating gene 1 (Rag1null) or recombination activating granulocyte colony-stimulating factor mobilization of HSCs gene 2 (Rag2null) mutation allowed for heightened into the blood. The major limitation of this model is that the human engraftment of both lymphoid and myeloid cells human T cells are selected and educated on mouse MHC and supported the development of a more complete within the host thymus and thus are H2 restricted, leading human immune system following transplantation with to complex interactions of T cells and antigen-presenting HSCs. Three major immunodeficient mouse stocks are cells in the murine host during the development of an widely used currently: NSG (nonobese diabetic strain immune response. To improve this model, human fetal [NOD]; NOD.Cg-PrkdcscidIL2rgtm1Wjl/Sz), NOG (NODShi. thymus can be surgically implanted under the kidney Cg-PrkdcscidIL2rgtm1Sug) and BRG (C.Cg-Rag2tm1Fva capsule of adult conditioned mice, which are then injected IL2rgtm1Sug) mice (5–7) (Table 1). with CD34þ HSCs isolated from the autologous fetal liver (10–12). This enhances the immune system because Engraftment approaches T cells that develop are HLA restricted. This is the most There are three standard approaches to engrafting a human robust human immune system engraftment protocol immune system into immunodeficient mice. Mice can be currently available (5–7). Table 1: Most commonly used immunodeficient strains engrafted with human hematopoietic cells Commonly Common Immunological used strains abbreviations IL2rg mutation Characteristics characteristics Availability NOD.Cg-Prkdcscid NSG Mutation is a NOD strain; Lacks T, B and The Jackson IL2rgtm1Wjl complete null, is not immunodeficient and NK cells, Laboratory, expressed and will relatively radiosensitive additional defects stock 005557 not bind cytokines due to a defect in DNA in innate immune repair cells NOD.cg-Prkdcscid NOG Lacks the NOD strain; Lacks T, B and Taconic IL2rgtm1Sug intracytoplasmic immunodeficient and NK cells, Biosciences,Ã domain and will relatively radiosensitive additional defects stock CIEA bind cytokines but due to a defect in DNA in innate immune NOG mouse will not signal repair cells NOD.Cg-Rag1tm1Mom NRG Mutation is a NOD strain; Lacks T, B and The Jackson IL2rgtm1Wjl complete null, is not immunodeficient and NK cells, Laboratory, expressed and will relatively radioresistant additional defects stock 007799 not bind cytokines in innate immune cells C.Cg-Rag2tm1Fwa BRG Lacks the Mixed background, Lacks T, B and Taconic IL2rgtm1Sug intracytoplasmic predominately BALB/c NK cells, Biosciences,Ã domain and will bind strain; immunodeficient remaining innate stock 11503 cytokines but will not and relatively immune cells are signal radioresistant functional The four strains of immunodeficient mice bearing targeted mutations in the IL-2 receptor common gamma chain that have been most commonly used for humanization. An extensive list of immunodeficient mice that have been engrafted with human immune systems was provided previously (5,8). NOD, nonobese diabetic. Ã Taconic Biosciences,
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