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. 1995 Jun;95(6):2979–2985. doi: 10.1172/JCI118006

In vivo activity and in vitro specificity of CD4+ Th1 and Th2 cells derived from the spleens of diabetic NOD mice.

D Healey 1, P Ozegbe 1, S Arden 1, P Chandler 1, J Hutton 1, A Cooke 1
PMCID: PMC295987  PMID: 7769140

Abstract

CD4+ T cell lines were generated from the spleens of diabetic NOD mice against crude membrane preparations derived from a rat insulinoma. Adoptive transfer of these lines into neonatal mice confirms that overt diabetes is induced by gamma-IFN-secreting Th1 cells, whereas transfer of IL-4-secreting Th2 cells resulted in a nondestructive peri-islet insulitis. Analysis of the antigens recognized by individual T cell clones from the Th1 line included reactivity against an insulinoma membrane fraction enriched in proteins of approximately 38 kD. Immune responses to the same antigen preparation have been associated with T cell clones derived from human insulin-dependent diabetes mellitus. The specificity of Th2 cells includes reactivity to a fraction enriched in proteins of 30 kD. The data suggest that in insulin-dependent diabetes mellitus the balance between beta cell destruction, associated with intra-islet infiltration, and nondestructive (potential protective) peri-islet insulitis may depend on both the antigens recognized, and the prevailing cytokine environment.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bergman B., Haskins K. Islet-specific T-cell clones from the NOD mouse respond to beta-granule antigen. Diabetes. 1994 Feb;43(2):197–203. doi: 10.2337/diab.43.2.197. [DOI] [PubMed] [Google Scholar]
  2. Boitard C., Yasunami R., Dardenne M., Bach J. F. T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice. J Exp Med. 1989 May 1;169(5):1669–1680. doi: 10.1084/jem.169.5.1669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chatenoud L., Ferran C., Bach J. F. In-vivo anti-CD3 treatment of autoimmune patients. Lancet. 1989 Jul 15;2(8655):164–164. doi: 10.1016/s0140-6736(89)90226-2. [DOI] [PubMed] [Google Scholar]
  4. Chatenoud L., Thervet E., Primo J., Bach J. F. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):123–127. doi: 10.1073/pnas.91.1.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chick W. L., Warren S., Chute R. N., Like A. A., Lauris V., Kitchen K. C. A transplantable insulinoma in the rat. Proc Natl Acad Sci U S A. 1977 Feb;74(2):628–632. doi: 10.1073/pnas.74.2.628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Elias D., Reshef T., Birk O. S., van der Zee R., Walker M. D., Cohen I. R. Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3088–3091. doi: 10.1073/pnas.88.8.3088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Feutren G., Papoz L., Assan R., Vialettes B., Karsenty G., Vexiau P., Du Rostu H., Rodier M., Sirmai J., Lallemand A. Cyclosporin increases the rate and length of remissions in insulin-dependent diabetes of recent onset. Results of a multicentre double-blind trial. Lancet. 1986 Jul 19;2(8499):119–124. doi: 10.1016/s0140-6736(86)91943-4. [DOI] [PubMed] [Google Scholar]
  8. Fowell D., Mason D. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J Exp Med. 1993 Mar 1;177(3):627–636. doi: 10.1084/jem.177.3.627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gelber C., Paborsky L., Singer S., McAteer D., Tisch R., Jolicoeur C., Buelow R., McDevitt H., Fathman C. G. Isolation of nonobese diabetic mouse T-cells that recognize novel autoantigens involved in the early events of diabetes. Diabetes. 1994 Jan;43(1):33–39. doi: 10.2337/diab.43.1.33. [DOI] [PubMed] [Google Scholar]
  10. Harada M., Makino S. Suppression of overt diabetes in NOD mice by anti-thymocyte serum or anti-Thy 1, 2 antibody. Jikken Dobutsu. 1986 Oct;35(4):501–504. doi: 10.1538/expanim1978.35.4_501. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. 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]
  13. Hutchings P. R., Cooke A. The transfer of autoimmune diabetes in NOD mice can be inhibited or accelerated by distinct cell populations present in normal splenocytes taken from young males. J Autoimmun. 1990 Apr;3(2):175–185. doi: 10.1016/0896-8411(90)90139-j. [DOI] [PubMed] [Google Scholar]
  14. Hutchings P. R., Simpson E., O'Reilly L. A., Lund T., Waldmann H., Cooke A. The involvement of Ly2+ T cells in beta cell destruction. J Autoimmun. 1990 Apr;3 (Suppl 1):101–109. doi: 10.1016/s0896-8411(09)90018-x. [DOI] [PubMed] [Google Scholar]
  15. Hutchings P., O'Reilly L., Parish N. M., Waldmann H., Cooke A. The use of a non-depleting anti-CD4 monoclonal antibody to re-establish tolerance to beta cells in NOD mice. Eur J Immunol. 1992 Jul;22(7):1913–1918. doi: 10.1002/eji.1830220735. [DOI] [PubMed] [Google Scholar]
  16. Hutton J. C., Penn E. J., Peshavaria M. Isolation and characterisation of insulin secretory granules from a rat islet cell tumour. Diabetologia. 1982 Oct;23(4):365–373. doi: 10.1007/BF00253746. [DOI] [PubMed] [Google Scholar]
  17. Kaufman D. L., Clare-Salzler M., Tian J., Forsthuber T., Ting G. S., Robinson P., Atkinson M. A., Sercarz E. E., Tobin A. J., Lehmann P. V. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature. 1993 Nov 4;366(6450):69–72. doi: 10.1038/366069a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Liu G. Y., Baker D., Fairchild S., Figueroa F., Quartey-Papafio R., Tone M., Healey D., Cooke A., Turk J. L., Wraith D. C. Complete characterization of the expressed immune response genes in Biozzi AB/H mice: structural and functional identity between AB/H and NOD A region molecules. Immunogenetics. 1993;37(4):296–300. doi: 10.1007/BF00187458. [DOI] [PubMed] [Google Scholar]
  19. Makino S., Kunimoto K., Muraoka Y., Mizushima Y., Katagiri K., Tochino Y. Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu. 1980 Jan;29(1):1–13. doi: 10.1538/expanim1978.29.1_1. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. 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]
  23. Roep B. O., Arden S. D., de Vries R. R., Hutton J. C. T-cell clones from a type-1 diabetes patient respond to insulin secretory granule proteins. Nature. 1990 Jun 14;345(6276):632–634. doi: 10.1038/345632a0. [DOI] [PubMed] [Google Scholar]
  24. Roep B. O., Kallan A. A., Hazenbos W. L., Bruining G. J., Bailyes E. M., Arden S. D., Hutton J. C., de Vries R. R. T-cell reactivity to 38 kD insulin-secretory-granule protein in patients with recent-onset type 1 diabetes. Lancet. 1991 Jun 15;337(8755):1439–1441. doi: 10.1016/0140-6736(91)93127-u. [DOI] [PubMed] [Google Scholar]
  25. Shehadeh N. N., LaRosa F., Lafferty K. J. Altered cytokine activity in adjuvant inhibition of autoimmune diabetes. J Autoimmun. 1993 Jun;6(3):291–300. doi: 10.1006/jaut.1993.1025. [DOI] [PubMed] [Google Scholar]
  26. Shizuru J. A., Taylor-Edwards C., Banks B. A., Gregory A. K., Fathman C. G. Immunotherapy of the nonobese diabetic mouse: treatment with an antibody to T-helper lymphocytes. Science. 1988 Apr 29;240(4852):659–662. doi: 10.1126/science.2966437. [DOI] [PubMed] [Google Scholar]
  27. Sopwith A. M., Hutton J. C., Naber S. P., Chick W. L., Hales C. N. Insulin secretion by a transplantable rat islet cell tumour. Diabetologia. 1981 Sep;21(3):224–229. doi: 10.1007/BF00252658. [DOI] [PubMed] [Google Scholar]
  28. Tisch R., Yang X. D., Singer S. M., Liblau R. S., Fugger L., McDevitt H. O. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature. 1993 Nov 4;366(6450):72–75. doi: 10.1038/366072a0. [DOI] [PubMed] [Google Scholar]
  29. Wegmann D. R., Shehadeh N., Lafferty K. J., Norbury-Glaser M., Gill R. G., Daniel D. Establishment of islet-specific T-cell lines and clones from islet isografts placed in spontaneously diabetic NOD mice. J Autoimmun. 1993 Oct;6(5):517–527. doi: 10.1006/jaut.1993.1043. [DOI] [PubMed] [Google Scholar]
  30. Wogensen L., Huang X., Sarvetnick N. Leukocyte extravasation into the pancreatic tissue in transgenic mice expressing interleukin 10 in the islets of Langerhans. J Exp Med. 1993 Jul 1;178(1):175–185. doi: 10.1084/jem.178.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. 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]
  32. 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]

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