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Mouse Models for Drug Discovery

Volume 602 of the series Methods in Molecular Biology pp 105-117

Date:

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

  • Steve PinoAffiliated withDepartment of Medicine, The University of Massachusetts Medical School
  • , Michael A. BrehmAffiliated withDepartment of Medicine, The University of Massachusetts Medical School
  • , Laurence Covassin-BarberisAffiliated withDepartment of Medicine, The University of Massachusetts Medical School
  • , Marie KingAffiliated withDepartment of Medicine, The University of Massachusetts Medical School
  • , Bruce GottAffiliated withThe Jackson Laboratory
  • , Thomas H. ChaseAffiliated withThe Jackson Laboratory
  • , Jennifer WagnerAffiliated withThe Jackson Laboratory
  • , Lisa BurzenskiAffiliated withThe Jackson Laboratory
  • , Oded ForemanAffiliated withThe Jackson Laboratory
    • , Dale L. GreinerAffiliated withDepartment of Medicine, The University of Massachusetts Medical School
    • , Leonard D. ShultzAffiliated withThe Jackson Laboratory

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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 Prkdc scid (scid) and 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-Rag1 null , BALB/c-Rag1 null , BALB/c-Rag2 null , and Stock-H2d-Rag2 null strain backgrounds. Parameters to induce human xeno-GVHD in H2d-Rag2 null IL2rγ null mice have been published, but variability in the frequency of disease and kinetics of GVHD were observed. The availability of the NOD-scid IL2rγ null stock that engrafts more readily with human PBMC than does the Stock-H2d-Rag2 null IL2rγ null 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 IL2rγ null β2m null and NOD-scid IL2rγ null Ab null 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 IL2rγ null 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.

Key words

scid Rag humanized mice GVHD immunodeficient mice MHC class I MHC class II