Home LiteratureArticle Details
PMID: 19659776 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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.

Clinical and experimental immunology ·Vol. 157 ·No. 1 ·2009-07-00 ·Pages 104-18

King MA, Covassin L, Brehm MA, Racki W, Pearson T, Leif J, Laning J, Fodor W, Foreman O, Burzenski L, Chase TH, Gott B, Rossini AA, Bortell R, Shultz LD, Greiner DL

Abstract

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 (IL2rgamma(null)) 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 IL2rgamma(null) mice. These mice develop xenogeneic GVHD consistently (100%) following injection of as few as 5 x 10(6) 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-alpha 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.

MeSH Terms
Animals Etanercept Female Graft vs Host Disease/drug therapy,immunology Humans Immunoglobulin G/therapeutic use Immunosuppressive Agents/therapeutic use Injections, Intravenous Interleukin Receptor Common gamma Subunit/genetics Leukocyte Common Antigens/analysis Leukocytes, Mononuclear/immunology,transplantation Lymphocyte Culture Test, Mixed Major Histocompatibility Complex Male Mice Mice, Inbred NOD Mice, Knockout Mice, SCID Models, Animal Receptors, Tumor Necrosis Factor/therapeutic use Tissue Distribution Transplantation, Heterologous Whole-Body Irradiation
Chemicals
Immunoglobulin G Immunosuppressive Agents Interleukin Receptor Common gamma Subunit Receptors, Tumor Necrosis Factor Leukocyte Common Antigens Etanercept
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
King M A
Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
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
References (56)
56 references, click to expand
  1. Regulation of human cell engraftment and development of EBV-related lymphoproliferative disorders in Hu-PBL-scid mice.
    J Immunol. 2000 Jul 1;165(1):518-27 PMID: 10861091
  2. Graft-versus-host disease in the 21st century: new perspectives on an old problem.
    Semin Hematol. 2006 Jan;43(1):1-2 PMID: 16412783
  3. Emerging trends in transplantation of inherited metabolic diseases.
    Bone Marrow Transplant. 2008 Jan;41(2):99-108 PMID: 18176609
  4. Humanized mice for the study of type 1 diabetes and beta cell function.
    Ann N Y Acad Sci. 2008 Dec;1150:46-53 PMID: 19120266
  5. Pathogenesis of graft-versus-host reactions (GVHR) and GVH-like diseases.
    J Invest Dermatol. 1985 Jul;85(1 Suppl):115s-120s PMID: 3159804
  6. Differential roles of IL-1 and TNF-alpha on graft-versus-host disease and graft versus leukemia.
    J Clin Invest. 1999 Aug;104(4):459-67 PMID: 10449438
  7. Anti-SCID mouse reactivity shapes the human CD4+ T cell repertoire in hu-PBL-SCID chimeras.
    J Exp Med. 1994 Nov 1;180(5):1817-27 PMID: 7964463
  8. Systemic cytokine levels and the effects of etanercept in TNF receptor-associated periodic syndrome (TRAPS) involving a C33Y mutation in TNFRSF1A.
    Rheumatology (Oxford). 2006 Jan;45(1):31-7 PMID: 16287931
  9. Studies on graft versus host (GvH) reactions. I. Impairment of hemopoietic stroma in mice suffering from GvH disease.
    Exp Hematol. 1981 Feb;9(2):101-10 PMID: 7238646
  10. Improved engraftment of human spleen cells in NOD/LtSz-scid/scid mice as compared with C.B-17-scid/scid mice.
    Am J Pathol. 1995 Apr;146(4):888-902 PMID: 7717456
  11. Protective effect of 55- but not 75-kD soluble tumor necrosis factor receptor-immunoglobulin G fusion proteins in an animal model of gram-negative sepsis.
    J Exp Med. 1994 Dec 1;180(6):2173-9 PMID: 7964492
  12. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease.
    Blood. 2008 Feb 15;111(4):2470-5 PMID: 18042798
  13. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report.
    Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56 PMID: 16338616
  14. Humanized mice in translational biomedical research.
    Nat Rev Immunol. 2007 Feb;7(2):118-30 PMID: 17259968
  15. High levels of human peripheral blood mononuclear cell engraftment and enhanced susceptibility to human immunodeficiency virus type 1 infection in NOD/LtSz-scid/scid mice.
    J Infect Dis. 1995 Oct;172(4):974-82 PMID: 7561218
  16. Pathophysiology of acute graft-versus-host disease: recent advances.
    Transl Res. 2007 Oct;150(4):197-214 PMID: 17900507
  17. Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines.
    Blood. 1997 Oct 15;90(8):3204-13 PMID: 9376604
  18. Effect of total body irradiation, busulfan-cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft-versus-host disease in H-2-incompatible transplanted SCID mice.
    Blood. 1994 Apr 15;83(8):2360-7 PMID: 8161803
  19. Umbilical cord blood regulatory T-cell expansion and functional effects of tumor necrosis factor receptor family members OX40 and 4-1BB expressed on artificial antigen-presenting cells.
    Blood. 2008 Oct 1;112(7):2847-57 PMID: 18645038
  20. New approaches for preventing and treating chronic graft-versus-host disease.
    Blood. 2005 Jun 1;105(11):4200-6 PMID: 15701727
  21. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells.
    J Immunol. 2005 May 15;174(10):6477-89 PMID: 15879151
  22. A new Hu-PBL model for the study of human islet alloreactivity based on NOD-scid mice bearing a targeted mutation in the IL-2 receptor gamma chain gene.
    Clin Immunol. 2008 Mar;126(3):303-14 PMID: 18096436
  23. Role of tumor necrosis factor alpha in acute graft-versus-host disease and complications following allogeneic bone marrow transplantation.
    Transplant Proc. 1993 Feb;25(1 Pt 2):1234-6 PMID: 8442099
  24. CD28 costimulation is essential for human T regulatory expansion and function.
    J Immunol. 2008 Aug 15;181(4):2855-68 PMID: 18684977
  25. Human BLyS facilitates engraftment of human PBL derived B cells in immunodeficient mice.
    PLoS One. 2008 Sep 11;3(9):e3192 PMID: 18784835
  26. Differential effects of anti-Fas ligand and anti-tumor necrosis factor alpha antibodies on acute graft-versus-host disease pathologies.
    Blood. 1998 Jun 1;91(11):4051-5 PMID: 9596649
  27. Elevation of erythroid colony-stimulating activity in the serum of mice with graft-versus-host disease.
    Exp Hematol. 1984 Nov;12(10):763-7 PMID: 6334610
  28. TNF enhances CD4+ T cell alloproliferation, IFN-gamma responses, and intestinal graft-versus-host disease by IL-12-independent mechanisms.
    J Immunol. 2003 May 15;170(10):5082-8 PMID: 12734353
  29. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists.
    J Immunol. 1993 Aug 1;151(3):1548-61 PMID: 8393046
  30. Quantitative assessment of human T lymphocytes in RAG2(-/-)gammac(-/-) mice: the impact of ex vivo manipulation on in vivo functionality.
    Exp Hematol. 2007 Jan;35(1):117-27 PMID: 17198880
  31. Intravital dye-labeled diabetogenic rat T cells retain dye, home to the pancreas, and induce diabetes.
    Transplant Proc. 1999 May;31(3):1611-4 PMID: 10331021
  32. Immunohistology and immunocytology of human T-cell chimerism and graft-versus-host disease in SCID mice.
    Blood. 1993 Jun 15;81(12):3440-8 PMID: 8099506
  33. Immunobiology of allogeneic hematopoietic stem cell transplantation.
    Annu Rev Immunol. 2007;25:139-70 PMID: 17129175
  34. Evaluation of recombinant human soluble dimeric tumor necrosis factor receptor for prevention of OKT3-associated acute clinical syndrome.
    Transplantation. 1996 Jan 27;61(2):224-8 PMID: 8600628
  35. Alloreactivity as therapeutic principle in the treatment of hematologic malignancies. Studies of clinical and immunologic aspects of allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning.
    Dan Med Bull. 2007 May;54(2):112-39 PMID: 17521527
  36. De novo chronic graft-versus-host disease presenting as hemolytic anemia following partially mismatched related donor bone marrow transplant .
    Bone Marrow Transplant. 1997 Apr;19(8):813-7 PMID: 9134174
  37. Enhanced human CD4+ T cell engraftment in beta2-microglobulin-deficient NOD-scid mice.
    J Immunol. 1997 Apr 15;158(8):3578-86 PMID: 9103418
  38. A new xenograft model for graft-versus-host disease by intravenous transfer of human peripheral blood mononuclear cells in RAG2-/- gammac-/- double-mutant mice.
    Blood. 2003 Oct 1;102(7):2522-31 PMID: 12791667
  39. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain.
    Immunity. 1995 Mar;2(3):223-38 PMID: 7697543
  40. Phase I-II trial of a monoclonal anti-tumor necrosis factor alpha antibody for the treatment of refractory severe acute graft-versus-host disease.
    Blood. 1992 Jun 15;79(12):3362-8 PMID: 1596576
  41. Hematopoietic cell transplantation for thalassemia and sickle cell disease: past, present and future.
    Bone Marrow Transplant. 2008 Jan;41(2):109-17 PMID: 18059330
  42. Non-myeloablative stem cell transplantation for autoimmune diseases.
    Springer Semin Immunopathol. 2004 Nov;26(1-2):57-69 PMID: 15549303
  43. Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation.
    Blood. 1990 Feb 15;75(4):1011-6 PMID: 2405918
  44. Antigen-specific T cell responses in human peripheral blood leucocyte (hu-PBL)-mouse chimera conditioned with radiation and an antibody directed against the mouse IL-2 receptor beta-chain.
    Clin Exp Immunol. 2000 Oct;122(1):117-23 PMID: 11012627
  45. Acute graft-versus-host disease does not require alloantigen expression on host epithelium.
    Nat Med. 2002 Jun;8(6):575-81 PMID: 12042807
  46. Binding and functional comparisons of two types of tumor necrosis factor antagonists.
    J Pharmacol Exp Ther. 2002 May;301(2):418-26 PMID: 11961039
  47. Pathogenesis of acute graft-versus-host disease: cytokines and cellular effectors.
    J Hematother Stem Cell Res. 2000 Jun;9(3):299-306 PMID: 10894351
  48. TNF alpha levels are increased during bone marrow transplantation conditioning in patients who develop acute GVHD.
    Bone Marrow Transplant. 1995 Jan;15(1):99-104 PMID: 7742764
  49. High level functional engraftment of severe combined immunodeficient mice with human peripheral blood lymphocytes following pretreatment with radiation and anti-asialo GM1.
    J Immunol Methods. 1994 Feb 28;169(1):1-15 PMID: 7907638
  50. Apoptosis is the predominant form of epithelial target cell injury in acute experimental graft-versus-host disease.
    J Invest Dermatol. 1996 Sep;107(3):377-83 PMID: 8751974
  51. Pilot study of recombinant human soluble tumor necrosis factor (TNF) receptor (p75) fusion protein (TNFR:Fc; Enbrel) in patients with refractory multiple myeloma: increase in plasma TNF alpha levels during treatment.
    Leuk Res. 2003 May;27(5):375-80 PMID: 12620287
  52. Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease.
    J Exp Med. 1987 Nov 1;166(5):1280-9 PMID: 3316469
  53. Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID beta2mnull mice.
    Exp Hematol. 2007 Dec;35(12):1823-38 PMID: 17764813
  54. Pilot trial on the use of etanercept and methylprednisolone as primary treatment for acute graft-versus-host disease.
    Biol Blood Marrow Transplant. 2005 Sep;11(9):680-7 PMID: 16125638
  55. NOD/LtSz-Rag1nullPfpnull mice: a new model system with increased levels of human peripheral leukocyte and hematopoietic stem-cell engraftment.
    Transplantation. 2003 Oct 15;76(7):1036-42 PMID: 14557749
  56. Tumor necrosis factor- alpha production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease.
    J Clin Invest. 1998 Nov 15;102(10):1882-91 PMID: 9819375
Article Info
Journal
Clinical and experimental immunology
Abbr.
Clin Exp Immunol
ISSN
1365-2249
DOI
10.1111/j.1365-2249.2009.03933.x
Published
2009-07-00
Pages
104-18
Language
English
Region
England
NLM ID
0057202
PMCID
PMC2710598
Subset
IM
Grants
NIAID NIH HHS · AI46629 · United States
NIDDK NIH HHS · DK53006 · United States
NCI NIH HHS · P30 CA034196 · United States
NIDDK NIH HHS · P30 DK032520 · United States
NIDDK NIH HHS · DK32520 · United States
NCI NIH HHS · CA34196 · United States
NIAID NIH HHS · P01 AI046629 · United States
NIDDK NIH HHS · P01 DK053006 · United States
NHLBI NIH HHS · HL077642 · United States
NHLBI NIH HHS · R01 HL077642 · United States
External Links
PubMed source DOI: 10.1111/j.1365-2249.2009.03933.x PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2