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. 1996 Oct 15;98(8):1851–1859. doi: 10.1172/JCI118986

Prevention of adoptively transferred diabetes in nonobese diabetic mice with IL-10-transduced islet-specific Th1 lymphocytes. A gene therapy model for autoimmune diabetes.

M Moritani 1, K Yoshimoto 1, S Ii 1, M Kondo 1, H Iwahana 1, T Yamaoka 1, T Sano 1, N Nakano 1, H Kikutani 1, M Itakura 1
PMCID: PMC507625  PMID: 8878437

Abstract

Four pancreatic islet-specific CD4+ helper T (Th) 1 (Th1) clones and two Th1 clones transduced with an SRalpha promoter-linked murine IL-10 (mIL-10) cDNA of 2.0-6.0 x 10(6) cells were adoptively transferred to nonobese diabetic (NOD) mice at age 8 d. Cyclophosphamide (CY) was administered at age 37 d (plus CY), and the incidence of diabetes and the histological grade of insulitis were examined at age 47 d. After the adoptive transfer of IL-10-transduced Th1 cells, polymerase chain reaction (PCR) and reverse-transcription (RT)-PCR detected the neo gene and the retrovirus vector-mediated IL-10 mRNA in situ in recipient islets, respectively. RT-PCR detected the decrease of IFN-gamma mRNA relative to IL-10 mRNA in IL-10-transduced Th1 clones in vitro and also in recipient islets. All four wild type Th1 clones plus CY induced the insulitis grade of 2.75 and diabetes in 66% of recipient NOD mice. IL-10-transduced two Th1 clones plus CY induced periinsulitis with the grade of 1.43 and diabetes in 8.0%. The 1:1 mixture of wild type Th1 cells and IL-10-transduced Th1 cells plus CY induced periinsulitis with the grade of 1.85 and diabetes in 20%. The suppression of diabetes through decreasing IFN-gamma mRNA by the tissue-specific delivery of IL-10 to pancreatic islets with IL-10-transduced Th1 cells affords us the starting basis to develop the gene therapy for autoimmune diabetes.

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Selected References

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  1. Bendelac A., Carnaud C., Boitard C., Bach J. F. Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. J Exp Med. 1987 Oct 1;166(4):823–832. doi: 10.1084/jem.166.4.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Campbell I. L., Kay T. W., Oxbrow L., Harrison L. C. Essential role for interferon-gamma and interleukin-6 in autoimmune insulin-dependent diabetes in NOD/Wehi mice. J Clin Invest. 1991 Feb;87(2):739–742. doi: 10.1172/JCI115055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Castaño L., Eisenbarth G. S. Type-I diabetes: a chronic autoimmune disease of human, mouse, and rat. Annu Rev Immunol. 1990;8:647–679. doi: 10.1146/annurev.iy.08.040190.003243. [DOI] [PubMed] [Google Scholar]
  4. Danos O., Mulligan R. C. Safe and efficient generation of recombinant retroviruses with amphotropic and ecotropic host ranges. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6460–6464. doi: 10.1073/pnas.85.17.6460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Debray-Sachs M., Carnaud C., Boitard C., Cohen H., Gresser I., Bedossa P., Bach J. F. Prevention of diabetes in NOD mice treated with antibody to murine IFN gamma. J Autoimmun. 1991 Apr;4(2):237–248. doi: 10.1016/0896-8411(91)90021-4. [DOI] [PubMed] [Google Scholar]
  6. Fitch F. W., McKisic M. D., Lancki D. W., Gajewski T. F. Differential regulation of murine T lymphocyte subsets. Annu Rev Immunol. 1993;11:29–48. doi: 10.1146/annurev.iy.11.040193.000333. [DOI] [PubMed] [Google Scholar]
  7. Harada M., Makino S. Promotion of spontaneous diabetes in non-obese diabetes-prone mice by cyclophosphamide. Diabetologia. 1984 Dec;27(6):604–606. doi: 10.1007/BF00276978. [DOI] [PubMed] [Google Scholar]
  8. Haskins K., McDuffie M. Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science. 1990 Sep 21;249(4975):1433–1436. doi: 10.1126/science.2205920. [DOI] [PubMed] [Google Scholar]
  9. Haskins K., Portas M., Bergman B., Lafferty K., Bradley B. Pancreatic islet-specific T-cell clones from nonobese diabetic mice. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8000–8004. doi: 10.1073/pnas.86.20.8000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jacob C. O., Aiso S., Michie S. A., McDevitt H. O., Acha-Orbea H. Prevention of diabetes in nonobese diabetic mice by tumor necrosis factor (TNF): similarities between TNF-alpha and interleukin 1. Proc Natl Acad Sci U S A. 1990 Feb;87(3):968–972. doi: 10.1073/pnas.87.3.968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Katz J. D., Benoist C., Mathis D. T helper cell subsets in insulin-dependent diabetes. Science. 1995 May 26;268(5214):1185–1188. doi: 10.1126/science.7761837. [DOI] [PubMed] [Google Scholar]
  12. Kawakami Y., Yamaoka T., Hirochika R., Yamashita K., Itakura M., Nakauchi H. Somatic gene therapy for diabetes with an immunological safety system for complete removal of transplanted cells. Diabetes. 1992 Aug;41(8):956–961. doi: 10.2337/diab.41.8.956. [DOI] [PubMed] [Google Scholar]
  13. LaFace D. M., Peck A. B. Reciprocal allogeneic bone marrow transplantation between NOD mice and diabetes-nonsusceptible mice associated with transfer and prevention of autoimmune diabetes. Diabetes. 1989 Jul;38(7):894–901. doi: 10.2337/diab.38.7.894. [DOI] [PubMed] [Google Scholar]
  14. Lee M. S., Wogensen L., Shizuru J., Oldstone M. B., Sarvetnick N. Pancreatic islet production of murine interleukin-10 does not inhibit immune-mediated tissue destruction. J Clin Invest. 1994 Mar;93(3):1332–1338. doi: 10.1172/JCI117092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mandrup-Poulsen T., Bendtzen K., Nielsen J. H., Bendixen G., Nerup J. Cytokines cause functional and structural damage to isolated islets of Langerhans. Allergy. 1985 Aug;40(6):424–429. doi: 10.1111/j.1398-9995.1985.tb02681.x. [DOI] [PubMed] [Google Scholar]
  16. McDaniel M. L., Hughes J. H., Wolf B. A., Easom R. A., Turk J. W. Descriptive and mechanistic considerations of interleukin 1 and insulin secretion. Diabetes. 1988 Oct;37(10):1311–1315. doi: 10.2337/diab.37.10.1311. [DOI] [PubMed] [Google Scholar]
  17. Miller B. J., Appel M. C., O'Neil J. J., Wicker L. S. Both the Lyt-2+ and L3T4+ T cell subsets are required for the transfer of diabetes in nonobese diabetic mice. J Immunol. 1988 Jan 1;140(1):52–58. [PubMed] [Google Scholar]
  18. Morgenstern J. P., Land H. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 1990 Jun 25;18(12):3587–3596. doi: 10.1093/nar/18.12.3587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Moritani M., Yoshimoto K., Tashiro F., Hashimoto C., Miyazaki J., Ii S., Kudo E., Iwahana H., Hayashi Y., Sano T. 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):1927–1936. doi: 10.1093/intimm/6.12.1927. [DOI] [PubMed] [Google Scholar]
  20. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  21. Mosmann T. R. Properties and functions of interleukin-10. Adv Immunol. 1994;56:1–26. [PubMed] [Google Scholar]
  22. Nakano N., Kikutani H., Nishimoto H., Kishimoto T. T cell receptor V gene usage of islet beta cell-reactive T cells is not restricted in non-obese diabetic mice. J Exp Med. 1991 May 1;173(5):1091–1097. doi: 10.1084/jem.173.5.1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pennline K. J., Roque-Gaffney E., Monahan M. Recombinant human IL-10 prevents the onset of diabetes in the nonobese diabetic mouse. Clin Immunol Immunopathol. 1994 May;71(2):169–175. doi: 10.1006/clin.1994.1068. [DOI] [PubMed] [Google Scholar]
  24. Powrie F., Coffman R. L. Cytokine regulation of T-cell function: potential for therapeutic intervention. Immunol Today. 1993 Jun;14(6):270–274. doi: 10.1016/0167-5699(93)90044-L. [DOI] [PubMed] [Google Scholar]
  25. Pukel C., Baquerizo H., Rabinovitch A. Destruction of rat islet cell monolayers by cytokines. Synergistic interactions of interferon-gamma, tumor necrosis factor, lymphotoxin, and interleukin 1. Diabetes. 1988 Jan;37(1):133–136. doi: 10.2337/diab.37.1.133. [DOI] [PubMed] [Google Scholar]
  26. Rapoport M. J., Jaramillo A., Zipris D., Lazarus A. H., Serreze D. V., Leiter E. H., Cyopick P., Danska J. S., Delovitch T. L. 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. doi: 10.1084/jem.178.1.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Romagnani S. Human TH1 and TH2 subsets: regulation of differentiation and role in protection and immunopathology. Int Arch Allergy Immunol. 1992;98(4):279–285. doi: 10.1159/000236199. [DOI] [PubMed] [Google Scholar]
  28. Rosenberg S. A., Anderson W. F., Blaese M., Hwu P., Yannelli J. R., Yang J. C., Topalian S. L., Schwartzentruber D. J., Weber J. S., Ettinghausen S. E. The development of gene therapy for the treatment of cancer. Ann Surg. 1993 Oct;218(4):455–464. doi: 10.1097/00000658-199310000-00006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sarvetnick N., Liggitt D., Pitts S. L., Hansen S. E., Stewart T. A. Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell. 1988 Mar 11;52(5):773–782. doi: 10.1016/0092-8674(88)90414-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Seino H., Takahashi K., Satoh J., Zhu X. P., Sagara M., Masuda T., Nobunaga T., Funahashi I., Kajikawa T., Toyota T. Prevention of autoimmune diabetes with lymphotoxin in NOD mice. Diabetes. 1993 Mar;42(3):398–404. doi: 10.2337/diab.42.3.398. [DOI] [PubMed] [Google Scholar]
  31. Selden R. F., Skoskiewicz M. J., Howie K. B., Russell P. S., Goodman H. M. Implantation of genetically engineered fibroblasts into mice: implications for gene therapy. Science. 1987 May 8;236(4802):714–718. doi: 10.1126/science.3472348. [DOI] [PubMed] [Google Scholar]
  32. Serreze D. V., Hamaguchi K., Leiter E. H. Immunostimulation circumvents diabetes in NOD/Lt mice. J Autoimmun. 1989 Dec;2(6):759–776. doi: 10.1016/0896-8411(89)90003-6. [DOI] [PubMed] [Google Scholar]
  33. Serreze D. V., Leiter E. H., Worthen S. M., Shultz L. D. NOD marrow stem cells adoptively transfer diabetes to resistant (NOD x NON)F1 mice. Diabetes. 1988 Feb;37(2):252–255. doi: 10.2337/diab.37.2.252. [DOI] [PubMed] [Google Scholar]
  34. Stewart T. A., Hultgren B., Huang X., Pitts-Meek S., Hully J., MacLachlan N. J. Induction of type I diabetes by interferon-alpha in transgenic mice. Science. 1993 Jun 25;260(5116):1942–1946. doi: 10.1126/science.8100367. [DOI] [PubMed] [Google Scholar]
  35. Takebe Y., Seiki M., Fujisawa J., Hoy P., Yokota K., Arai K., Yoshida M., Arai N. SR alpha promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat. Mol Cell Biol. 1988 Jan;8(1):466–472. doi: 10.1128/mcb.8.1.466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wicker L. S., Miller B. J., Mullen Y. Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Diabetes. 1986 Aug;35(8):855–860. doi: 10.2337/diab.35.8.855. [DOI] [PubMed] [Google Scholar]
  37. Wogensen L., Lee M. S., Sarvetnick N. 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):1379–1384. doi: 10.1084/jem.179.4.1379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wong F. S., Visintin I., Wen L., Flavell R. A., Janeway C. A., Jr CD8 T cell clones from young nonobese diabetic (NOD) islets can transfer rapid onset of diabetes in NOD mice in the absence of CD4 cells. J Exp Med. 1996 Jan 1;183(1):67–76. doi: 10.1084/jem.183.1.67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Yang X. D., Tisch R., Singer S. M., Cao Z. A., Liblau R. S., Schreiber R. D., McDevitt H. O. Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. J Exp Med. 1994 Sep 1;180(3):995–1004. doi: 10.1084/jem.180.3.995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Yasunami R., Bach J. F. Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice. Eur J Immunol. 1988 Mar;18(3):481–484. doi: 10.1002/eji.1830180325. [DOI] [PubMed] [Google Scholar]
  41. Zielasek J., Burkart V., Naylor P., Goldstein A., Kiesel U., Kolb H. Interleukin-2-dependent control of disease development in spontaneously diabetic BB rats. Immunology. 1990 Feb;69(2):209–214. [PMC free article] [PubMed] [Google Scholar]

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