Home LiteratureArticle Details
PMID: 9819366 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Local expression of immunoregulatory IL-12p40 gene prolonged syngeneic islet graft survival in diabetic NOD mice.

The Journal of clinical investigation ·Vol. 102 ·No. 10 ·1998-11-15 ·Pages 1807-14

Yasuda H, Nagata M, Arisawa K, Yoshida R, Fujihira K, Okamoto N, Moriyama H, Miki M, Saito I, Hamada H, Yokono K, Kasuga M

Abstract

Local production of immunosuppressive cytokines will be one of the most suitable therapeutic strategies against organ-specific autoimmune diabetes. To establish such a new therapy, we constructed recombinant adenoviral vectors with inserted mIL-12p40 (Ad.IL-12p40) and mIL-10 (Ad.IL-10). Sufficient amounts of IL-12p40 and IL-10 were secreted by relevant adenovirus-transfected nonobese diabetic (NOD) islets. Shortly after transfection, 400 NOD islets transfected with Ad.IL-12p40 or Ad.IL-10 were transplanted under the renal capsule of a newly diabetic NOD mouse. NOD mice with IL-12p40-producing islet grafts kept normoglycemia in all of 14 grafted mice for over 4 wk after transplantation. In contrast, NOD mice with IL-10-producing islet grafts became diabetic in all of six grafted mice within 2 wk af-ter transplantation. Reverse transcription-PCR analysis revealed that local production of IL-12p40 led to the decrease of interferon-gamma and the augmentation of transforming growth factor-beta at the graft site. These results suggest that IL-12 plays an important role in the destruction of islet cells at the inflamed site of autoimmunity. Such a local blockade of IL-12 would be a useful gene therapy for human autoimmune diabetes.

MeSH Terms
Adenoviridae Animals Diabetes Mellitus, Type 1/prevention & control Female Flow Cytometry Genetic Vectors Graft Survival/immunology Insulin/metabolism Interleukin-10/metabolism Interleukin-12/genetics,metabolism Islets of Langerhans/metabolism Islets of Langerhans Transplantation/immunology Kidney/surgery Leukocytes, Mononuclear/cytology Male Mice Mice, Inbred NOD
Chemicals
Insulin Interleukin-10 Interleukin-12
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Yasuda H
Second Department of Internal Medicine, Kobe University School of Medicine, Kobe 650-0017, Japan.
Nagata M
Arisawa K
Yoshida R
Fujihira K
Okamoto N
Moriyama H
Miki M
Saito I
Hamada H
Yokono K
Kasuga M
References (48)
48 references, click to expand
  1. Breeding of a non-obese, diabetic strain of mice.
    Jikken Dobutsu. 1980 Jan;29(1):1-13 PMID: 6995140
  2. Interleukin-4 or interleukin-10 expressed from adenovirus-transduced syngeneic islet grafts fails to prevent beta cell destruction in diabetic NOD mice.
    Transplantation. 1997 Oct 15;64(7):1040-9 PMID: 9381527
  3. Type I diabetes mellitus. A chronic autoimmune disease.
    N Engl J Med. 1986 May 22;314(21):1360-8 PMID: 3517648
  4. The renal subcapsular site offers better growth conditions for transplanted mouse pancreatic islet cells than the liver or spleen.
    Diabetologia. 1986 Sep;29(9):670-2 PMID: 3098614
  5. Recurrence of disease in pancreas transplants.
    Diabetes. 1989 Jan;38 Suppl 1:85-7 PMID: 2642862
  6. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties.
    Annu Rev Immunol. 1989;7:145-73 PMID: 2523712
  7. Destruction of pancreatic islet cells by cytotoxic T lymphocytes in nonobese diabetic mice.
    J Immunol. 1989 Aug 15;143(4):1155-62 PMID: 2663991
  8. Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone.
    Science. 1990 Sep 21;249(4975):1433-6 PMID: 2205920
  9. The role of CD4+ and CD8+ T cells in the destruction of islet grafts by spontaneously diabetic mice.
    Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):527-31 PMID: 1899142
  10. Cells mediating allograft rejection.
    Transplantation. 1991 Jun;51(6):1141-51 PMID: 1675502
  11. Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin.
    Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10252-6 PMID: 1946445
  12. Prevention of recurrence of IDDM in islet-transplanted diabetic NOD mice by adjuvant immunotherapy.
    Diabetes. 1992 Jan;41(1):114-7 PMID: 1727730
  13. Interleukin-10.
    Annu Rev Immunol. 1993;11:165-90 PMID: 8386517
  14. Differential regulation of murine T lymphocyte subsets.
    Annu Rev Immunol. 1993;11:29-48 PMID: 8476563
  15. Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice.
    J Exp Med. 1993 Jul 1;178(1):87-99 PMID: 8315397
  16. Presentation of beta-cell antigens to CD4+ and CD8+ T cells of non-obese diabetic mice.
    J Immunol. 1993 Aug 1;151(3):1723-30 PMID: 8101546
  17. The interleukin-12 subunit p40 specifically inhibits effects of the interleukin-12 heterodimer.
    Eur J Immunol. 1993 Sep;23(9):2202-8 PMID: 8103745
  18. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming.
    Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10188-92 PMID: 7901851
  19. Production of interleukin 10 by islet cells accelerates immune-mediated destruction of beta cells in nonobese diabetic mice.
    J Exp Med. 1994 Apr 1;179(4):1379-84 PMID: 8145050
  20. Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM. Therapeutic intervention by immunostimulation?
    Diabetes. 1994 May;43(5):613-21 PMID: 8168635
  21. Recombinant human IL-10 prevents the onset of diabetes in the nonobese diabetic mouse.
    Clin Immunol Immunopathol. 1994 May;71(2):169-75 PMID: 8181185
  22. Adoptive immunotherapy with murine tumor-specific T lymphocytes engineered to secrete interleukin 2.
    Cancer Res. 1994 Nov 15;54(22):5757-60 PMID: 7525049
  23. Analysis of cytokine mRNA expression in syngeneic islet grafts of NOD mice: interleukin 2 and interferon gamma mRNA expression correlate with graft rejection and interleukin 10 with graft survival.
    Diabetologia. 1994 Aug;37(8):833-7 PMID: 7988786
  24. Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice.
    J Exp Med. 1995 Feb 1;181(2):817-21 PMID: 7836934
  25. Mouse interleukin-12 (IL-12) p40 homodimer: a potent IL-12 antagonist.
    Eur J Immunol. 1995 Jan;25(1):200-6 PMID: 7843232
  26. Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-gamma transcription.
    J Clin Invest. 1995 Feb;95(2):628-34 PMID: 7860747
  27. Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses.
    J Virol. 1995 Apr;69(4):2004-15 PMID: 7884845
  28. Transgenic expression of IL-10 in pancreatic islet A cells accelerates autoimmune insulitis and diabetes in non-obese diabetic mice.
    Int Immunol. 1994 Dec;6(12):1927-36 PMID: 7696210
  29. IFN-gamma gene expression in pancreatic islet-infiltrating mononuclear cells correlates with autoimmune diabetes in nonobese diabetic mice.
    J Immunol. 1995 May 1;154(9):4874-82 PMID: 7722337
  30. T helper cell subsets in insulin-dependent diabetes.
    Science. 1995 May 26;268(5214):1185-8 PMID: 7761837
  31. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity.
    Annu Rev Immunol. 1995;13:251-76 PMID: 7612223
  32. Prolonged survival of pancreatic islet allografts mediated by adenovirus immunoregulatory transgenes.
    Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6947-51 PMID: 7624350
  33. Suppression of insulitis in non-obese diabetic (NOD) mice by oral insulin administration is associated with selective expression of interleukin-4 and -10, transforming growth factor-beta, and prostaglandin-E.
    Am J Pathol. 1995 Nov;147(5):1193-9 PMID: 7485382
  34. Insulin-dependent diabetes mellitus.
    Cell. 1996 May 3;85(3):291-7 PMID: 8616883
  35. Interleukin-12 gene expression is associated with rapid development of diabetes mellitus in non-obese diabetic mice.
    Diabetologia. 1996 Jan;39(1):119-22 PMID: 8720612
  36. Local production of the p40 subunit of interleukin 12 suppresses T-helper 1-mediated immune responses and prevents allogeneic myoblast rejection.
    Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9085-9 PMID: 8799158
  37. High dose oral tolerance in ovalbumin TCR-transgenic mice: systemic neutralization of IL-12 augments TGF-beta secretion and T cell apoptosis.
    J Immunol. 1996 Sep 15;157(6):2348-57 PMID: 8805632
  38. Prevention of adoptively transferred diabetes in nonobese diabetic mice with IL-10-transduced islet-specific Th1 lymphocytes. A gene therapy model for autoimmune diabetes.
    J Clin Invest. 1996 Oct 15;98(8):1851-9 PMID: 8878437
  39. Functional diversity of helper T lymphocytes.
    Nature. 1996 Oct 31;383(6603):787-93 PMID: 8893001
  40. Interleukin 12 mRNA expression in islets correlates with beta-cell destruction in NOD mice.
    J Autoimmun. 1996 Oct;9(5):645-51 PMID: 8933280
  41. Aerosol insulin induces regulatory CD8 gamma delta T cells that prevent murine insulin-dependent diabetes.
    J Exp Med. 1996 Dec 1;184(6):2167-74 PMID: 8976172
  42. A noncytolytic IL-10/Fc fusion protein prevents diabetes, blocks autoimmunity, and promotes suppressor phenomena in NOD mice.
    J Immunol. 1997 May 1;158(9):4507-13 PMID: 9127018
  43. Regulation of transforming growth factor-beta production by interleukin-12.
    Eur J Immunol. 1997 May;27(5):1213-20 PMID: 9174613
  44. Molecular role of TGF-beta, secreted from a new type of CD4+ suppressor T cell, NY4.2, in the prevention of autoimmune IDDM in NOD mice.
    J Autoimmun. 1997 Jun;10(3):299-307 PMID: 9218758
  45. Suppression of cyclophosphamide induced diabetes development and pancreatic Th1 reactivity in NOD mice treated with the interleukin (IL)-12 antagonist IL-12(p40)2.
    Diabetologia. 1997 Jun;40(6):641-6 PMID: 9222642
  46. Expression of adenoviral E3 transgenes in beta cells prevents autoimmune diabetes.
    Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9808-13 PMID: 9275207
  47. Deviation of pancreas-infiltrating cells to Th2 by interleukin-12 antagonist administration inhibits autoimmune diabetes.
    Eur J Immunol. 1997 Sep;27(9):2330-9 PMID: 9341777
  48. Construction of nondefective adenovirus type 5 bearing a 2.8-kilobase hepatitis B virus DNA near the right end of its genome.
    J Virol. 1985 Jun;54(3):711-9 PMID: 3999192
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI2675
Published
1998-11-15
Pages
1807-14
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC509130
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI2675 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: [email protected]

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