Development of Novel Major Histocompatibility Complex Class I and Class II-Deficient NOD-SCID IL2R Gamma Chain Knockout Mice for Modeling Human Xenogeneic Graft-Versus-Host Disease

Abstract

Immunodeficient mice have been used as recipients of human peripheral blood mononuclear cells (PBMC) for in vivo analyses of human xeno-graft-versus-host disease (GVHD). This xeno-GVHD model system in many ways mimics the human disease. The model system is established by intravenous or intraperitoneal injection of human PBMC or spleen cells into unconditioned or irradiated immunodeficient recipient mice. Recently, the development of several stocks of immunodeficient Prkdcscid (scid), or recombination activating 1 or 2 gene (Rag1 or Rag2) knockout mice bearing a targeted mutation in the gene encoding the IL2 receptor gamma chain (IL2rγ) have been reported. The addition of the mutated IL2rγ gene onto an immunodeficient mouse stock facilitates heightened engraftment with human PBMC. Stocks of mice with mutations in the IL2rγ gene have been studied in several laboratories on NOD-scid, NOD-Rag1null, BALB/c-Rag1null, BALB/c-Rag2null, and Stock-H2d-Rag2null strain backgrounds. Parameters to induce human xeno-GVHD in H2d-Rag2null IL2rγnull mice have been published, but variability in the frequency of disease and kinetics of GVHD were observed. The availability of the NOD-scid IL2rγnull stock that engrafts more readily with human PBMC than does the Stock-H2d-Rag2null IL2rγnull stock should lead to a more reproducible humanized mouse model of GVHD and for the use in drug evaluation and validation. Furthermore, GVHD in human PBMC-engrafted scid mice has been postulated to result predominately from a human anti-mouse major histocompatibility complex (MHC) class II reactivity. Our recent development of NOD-scid IL2rγnull β2mnull and NOD-scid IL2rγnull Abnull stocks of mice now make it possible to investigate directly the role of host MHC class I and class II in the pathogenesis of GVHD in humanized mice using NOD-scid IL2rγnull stocks that engraft at high levels with human PBMC and are deficient in murine MHC class I, class II, or both classes of MHC molecules.

Human peripheral blood CD4 T cell-engrafted non-obese diabetic-scid IL2rγnull H2-Ab1 tm1GruTg (human leucocyte antigen D-related 4) mice: a mouse model of human allogeneic graft-versus-host disease

“…All previous models of GVHD in immunodeficient mice have been based on human T cells responding to murine antigens in a xenoreaction [48]. Injection of purified human CD4 T cells from HLA-DR4 negative donors into NSG-Ab°D R4 induced a GVHD response that was not observed in NSG-Ab°mice, suggesting that the human cells were responding to the allogeneic HLA-DR4 molecule.…”

Dysregulation of Claudin-5 in HIV-induced Interstitial Pneumonitis and Lung Vascular Injury. Protective Role of Peroxisome Proliferator–activated Receptor-γ

“…Some animals also showed signs of lung pathology with infiltrating mononuclear cells in the alveolar spaces. However, recent studies showed that NOD-SCID mice that receive human PBL can develop xenogenic graft-versus-host disease because of human antimouse major histocompatibility complex class II reactivity (37). Thus, both HIV-1 infection and/or graft-versus-host disease responses inherent to the model could contribute to this pathology and represents a limitation of our animal model.…”

Functional human to mouse adipose tissue xenotransplantation

“…Another possibility is depletion of human PBMC by mouse NK cells: our recipient mice are on C57BL/6 background known to have relatively high NK activity compared with NOD strain (Poulton et al 2001). This may be overcome by breeding an inactivated allele of common cytokine receptor g chain: human PBMC readily expand in NOD.scid mice that carry this defect (V Ablamunits & K C Herold, unpublished observations; King et al 2009, Pino et al 2010. Alternatively, leptin deficiency may be bred onto Rag1-deficient, perforin-deficient NOD mice, which have been reported to lack NK cytotoxicity and allow for a better engraftment of human T cells (Shultz et al 2003).…”