Human peripheral blood leucocyte non‐obese diabetic‐severe combined immunodeficiency interleukin‐2 receptor gamma chain gene mouse model of xenogeneic graft‐versus‐host‐like disease and the role of host major histocompatibility complex

• Published in: Clinical and experimental immunology Vol. 157; no. 1; pp. 104 - 118
• Main Authors: King, M. A., Covassin, L., Brehm, M. A., Racki, W., Pearson, T., Leif, J., Laning, J., Fodor, W., Foreman, O., Burzenski, L., Chase, T. H., Gott, B., Rossini, A. A., Bortell, R., Shultz, L. D., Greiner, D. L.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2009; Blackwell; Blackwell Science Inc
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etanercept; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Fundamental and applied biological sciences. Psychology; Graft vs Host Disease - drug therapy; Graft vs Host Disease - immunology; GVHD; humanized mice; Humans; Hu‐PBL‐scid; IL‐2r gamma chain; Immunoglobulin G - therapeutic use; Immunosuppressive Agents - therapeutic use; Injections, Intravenous; Interleukin Receptor Common gamma Subunit - genetics; Leukocyte Common Antigens - analysis; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - transplantation; Lymphocyte Culture Test, Mixed; Major Histocompatibility Complex; Male; Medical sciences; Metabolic diseases; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Models, Animal; NOD‐scid; Obesity; Receptors, Tumor Necrosis Factor - therapeutic use; Tissue Distribution; Translational Studies; Transplantation, Heterologous; Whole-Body Irradiation; xenogeneic; Endocrinopathy; Animal model; Gamma-Peptide chain; Severe combined immunodeficiency; Leukocyte; Stem cell; Major histocompatibility system; Hematopoietic cell; Homograft; Biochemistry; Xenogeneic system; GVHD; Blood; Gene; IL-2r gamma chain; Graft; Genetics; Hu-PBL-scid; xenogeneic; Nutritional status; Human; Immunopathology; Graft versus host disease; Obesity; Diabetes mellitus; Rodentia; Nutrition disorder; humanized mice; Vertebrata; Mammalia; Mouse; NOD-scid; Interleukin 2 receptor; Combined immune deficiency
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2009.03933.x

Summary Immunodeficient non‐obese diabetic (NOD)‐severe combined immune‐deficient (scid) mice bearing a targeted mutation in the gene encoding the interleukin (IL)‐2 receptor gamma chain gene (IL2rγnull) engraft readily with human peripheral blood mononuclear cells (PBMC). Here, we report a robust model of xenogeneic graft‐versus‐host‐like disease (GVHD) based on intravenous injection of human PBMC into 2 Gy conditioned NOD‐scid IL2rγnull mice. These mice develop xenogeneic GVHD consistently (100%) following injection of as few as 5 × 106 PBMC, regardless of the PBMC donor used. As in human disease, the development of xenogeneic GVHD is highly dependent on expression of host major histocompatibility complex class I and class II molecules and is associated with severely depressed haematopoiesis. Interrupting the tumour necrosis factor‐α signalling cascade with etanercept, a therapeutic drug in clinical trials for the treatment of human GVHD, delays the onset and progression of disease. This model now provides the opportunity to investigate in vivo mechanisms of xenogeneic GVHD as well as to assess the efficacy of therapeutic agents rapidly.