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

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.