Home LiteratureArticle Details
PMID: 15078896 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Transgenic expression of decoy receptor 3 protects islets from spontaneous and chemical-induced autoimmune destruction in nonobese diabetic mice.

The Journal of experimental medicine ·Vol. 199 ·No. 8 ·2004-04-19 ·Pages 1143-51

Sung HH, Juang JH, Lin YC, Kuo CH, Hung JT, Chen A, Chang DM, Chang SY, Hsieh SL, Sytwu HK

Abstract

Decoy receptor 3 (DCR3) halts both Fas ligand- and LIGHT-induced cell deaths, which are required for pancreatic beta cell damage in autoimmune diabetes. To directly investigate the therapeutic potential of DCR3 in preventing this disease, we generated transgenic nonobese diabetic mice, which overexpressed DCR3 in beta cells. Transgenic DCR3 protected mice from autoimmune and cyclophosphamide-induced diabetes in a dose-dependent manner and significantly reduced the severity of insulitis. Local expression of the transgene did not alter the diabetogenic properties of systemic lymphocytes or the development of T helper 1 or T regulatory cells. The transgenic islets had a higher transplantation success rate and survived for longer than wild-type islets. We have demonstrated for the first time that the immune-evasion function of DCR3 inhibits autoimmunity and that genetic manipulation of grafts may improve the success and survival of islet transplants.

MeSH Terms
Animals Base Sequence DNA Primers/genetics Diabetes Mellitus, Type 1/immunology,pathology,prevention & control Female Gene Expression Graft Survival Islets of Langerhans/immunology,pathology Islets of Langerhans Transplantation Male Membrane Glycoproteins/genetics,physiology Mice Mice, Inbred NOD Mice, SCID Mice, Transgenic Receptors, Cell Surface/genetics,physiology Receptors, Tumor Necrosis Factor Receptors, Tumor Necrosis Factor, Member 6b Th1 Cells/immunology Th2 Cells/immunology
Chemicals
DNA Primers Membrane Glycoproteins Receptors, Cell Surface Receptors, Tumor Necrosis Factor Receptors, Tumor Necrosis Factor, Member 6b
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Sung Hsiang-Hsuan
Graduate Institute of Life Sciences, National Defense Medical Center, MinChuan East Road, Neihu, Taipei, Taiwan.
Juang Jyuhn-Huarng
Lin Yu-Chun
Kuo Chien-Hung
Hung Jung-Tung
Chen An
Chang Der-Ming
Chang Sun-Yran
Hsieh Shie-Liang
Sytwu Huey-Kang
References (36)
36 references, click to expand
  1. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes.
    Nature. 1993 Nov 4;366(6450):69-72 PMID: 7694152
  2. A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis.
    J Biol Chem. 1999 May 14;274(20):13733-6 PMID: 10318773
  3. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases.
    Immunol Today. 1995 Jan;16(1):34-8 PMID: 7880387
  4. Genetic control of autoimmune diabetes in the NOD mouse.
    Annu Rev Immunol. 1995;13:179-200 PMID: 7612220
  5. Insulin-dependent diabetes mellitus.
    Cell. 1996 May 3;85(3):291-7 PMID: 8616883
  6. The roles of Fas/APO-1 (CD95) and TNF in antigen-induced programmed cell death in T cell receptor transgenic mice.
    Immunity. 1996 Jul;5(1):17-30 PMID: 8758891
  7. The role of Fas in autoimmune diabetes.
    Cell. 1997 Apr 4;89(1):17-24 PMID: 9094710
  8. Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster.
    Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1230-5 PMID: 10655513
  9. Significant role for Fas in the pathogenesis of autoimmune diabetes.
    J Immunol. 2000 Mar 1;164(5):2523-32 PMID: 10679090
  10. Transgenic mice expressing surface markers for IFN-gamma and IL-4 producing cells.
    Mol Immunol. 2000 Apr;37(6):281-93 PMID: 11000402
  11. Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand-induced apoptosis and chemotaxis.
    Cancer Res. 2001 Mar 15;61(6):2759-65 PMID: 11289159
  12. Modulation of T-cell responses to alloantigens by TR6/DcR3.
    J Clin Invest. 2001 Jun;107(11):1459-68 PMID: 11390428
  13. Reversal of spontaneous autoimmune insulitis in nonobese diabetic mice by soluble lymphotoxin receptor.
    J Exp Med. 2001 Jun 4;193(11):1327-32 PMID: 11390440
  14. A critical role for lymphotoxin-beta receptor in the development of diabetes in nonobese diabetic mice.
    J Exp Med. 2001 Jun 4;193(11):1333-40 PMID: 11390441
  15. Multiple immuno-regulatory defects in type-1 diabetes.
    J Clin Invest. 2002 Jan;109(1):131-40 PMID: 11781358
  16. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator.
    Immunity. 2002 Mar;16(3):479-92 PMID: 11911831
  17. Modulation of dendritic cell differentiation and maturation by decoy receptor 3.
    J Immunol. 2002 May 15;168(10):4846-53 PMID: 11994433
  18. Overexpression of extracellular-SOD in islets of nonobese diabetic mice and development of diabetes.
    Free Radic Biol Med. 2002 Jul 1;33(1):71-5 PMID: 12086684
  19. Effects of multiple site implantation on islet transplantation.
    Transplant Proc. 2002 Nov;34(7):2698-9 PMID: 12431579
  20. Contribution of Fas to diabetes development.
    Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):628-32 PMID: 12525697
  21. Decoy receptor 3 (DcR3) is proteolytically processed to a metabolic fragment having differential activities against Fas ligand and LIGHT.
    Biochem Pharmacol. 2003 Feb 15;65(4):657-67 PMID: 12566095
  22. Pharmacokinetics, metabolic stability, and subcutaneous bioavailability of a genetically engineered analog of DcR3, FLINT [DcR3(R218Q)], in cynomolgus monkeys and mice.
    Drug Metab Dispos. 2003 Apr;31(4):502-7 PMID: 12642478
  23. Surface and intracellular Fas expression associated with cytokine-induced apoptosis in rodent islet and insulinoma cells.
    J Mol Endocrinol. 2003 Apr;30(2):163-71 PMID: 12683940
  24. DcR3/TR6 effectively prevents islet primary nonfunction after transplantation.
    Diabetes. 2003 Sep;52(9):2279-86 PMID: 12941767
  25. Death decoy receptor TR6/DcR3 inhibits T cell chemotaxis in vitro and in vivo.
    J Immunol. 2003 Oct 1;171(7):3407-14 PMID: 14500635
  26. Immunomodulatory effect of decoy receptor 3 on the differentiation and function of bone marrow-derived dendritic cells in nonobese diabetic mice: from regulatory mechanism to clinical implication.
    J Leukoc Biol. 2004 Feb;75(2):293-306 PMID: 14634066
  27. Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma.
    Cell. 1988 Mar 11;52(5):773-82 PMID: 2449974
  28. Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice.
    J Exp Med. 1997 Aug 18;186(4):613-8 PMID: 9254659
  29. Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice.
    J Exp Med. 1997 Oct 6;186(7):989-97 PMID: 9314549
  30. Spontaneous autoimmune diabetes in monoclonal T cell nonobese diabetic mice.
    J Exp Med. 1997 Nov 17;186(10):1663-76 PMID: 9362527
  31. TGF-beta1 alters APC preference, polarizing islet antigen responses toward a Th2 phenotype.
    Immunity. 1998 May;8(5):601-13 PMID: 9620681
  32. Abrogation of autoimmune diabetes in nonobese diabetic mice and protection against effector lymphocytes by transgenic paracrine TGF-beta1.
    J Clin Invest. 1998 Aug 1;102(3):499-506 PMID: 9691086
  33. Pancreatic beta cell-specific expression of thioredoxin, an antioxidative and antiapoptotic protein, prevents autoimmune and streptozotocin-induced diabetes.
    J Exp Med. 1998 Oct 19;188(8):1445-51 PMID: 9782121
  34. Mechanisms of beta cell death in diabetes: a minor role for CD95.
    Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13818-22 PMID: 9811884
  35. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer.
    Nature. 1998 Dec 17;396(6712):699-703 PMID: 9872321
  36. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice.
    Nature. 1993 Nov 4;366(6450):72-5 PMID: 8232539
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20031939
Published
2004-04-19
Epub
2004-00-12
Pages
1143-51
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2211895
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20031939 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