Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 May 1;181(5):1635–1642. doi: 10.1084/jem.181.5.1635

Pancreatic islet beta cells drive T cell-immune responses in the nonobese diabetic mouse model

PMCID: PMC2192008  PMID: 7722443

Abstract

The role of autoantigens and that of target organs in which tissue lesions develop remains elusive in most spontaneous models of autoimmune diseases. Whether the presence of target autoantigens is required for the recruitment of autoreactive lymphocytes is unknown in most cases. To evaluate the importance of islet cells in the development of autoimmunity in the nonobese diabetic (NOD) mouse, we generated beta cell-deprived mice by injecting a high dose of alloxan, a toxic agent specific for beta cells. In contrast with spleen cells from 6-mo-old naive NOD mice which transfer diabetes in irradiated 8-mo- old male recipients, spleen cells from age-matched NOD mice which received a single injection of alloxan at 3 wk of age did not transfer diabetes. With the exception of the ability to transfer diabetes, beta cell-deprived NOD mice showed maintained immune competence. Furthermore, sialitis developed with the expected intensity and prevalence in beta cell-deprived mice. Already committed "diabetogenic" spleen cells collected from spontaneously diabetic mice also showed a reduced capacity to transfer diabetes after their removal from the diabetic mice and transient "parking" in beta cell-deprived mice. Taken together, our data bring evidence that involvement of autoreactive T cells detected by the capacity to transfer diabetes requires the presence of target beta cells.

Full Text

The Full Text of this article is available as a PDF (1.8 MB).

Selected References

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

  1. Adams T. E., Alpert S., Hanahan D. Non-tolerance and autoantibodies to a transgenic self antigen expressed in pancreatic beta cells. Nature. 1987 Jan 15;325(6101):223–228. doi: 10.1038/325223a0. [DOI] [PubMed] [Google Scholar]
  2. Atkinson M. A., Maclaren N. K., Luchetta R. Insulitis and diabetes in NOD mice reduced by prophylactic insulin therapy. Diabetes. 1990 Aug;39(8):933–937. doi: 10.2337/diab.39.8.933. [DOI] [PubMed] [Google Scholar]
  3. BILLINGHAM R. E., BRENT L., MEDAWAR P. B. Actively acquired tolerance of foreign cells. Nature. 1953 Oct 3;172(4379):603–606. doi: 10.1038/172603a0. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Boitard C., Bendelac A., Richard M. F., Carnaud C., Bach J. F. Prevention of diabetes in nonobese diabetic mice by anti-I-A monoclonal antibodies: transfer of protection by splenic T cells. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9719–9723. doi: 10.1073/pnas.85.24.9719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. Bronze M. S., Beachey E. H., Dale J. B. Protective and heart-crossreactive epitopes located within the NH2 terminus of type 19 streptococcal M protein. J Exp Med. 1988 Jun 1;167(6):1849–1859. doi: 10.1084/jem.167.6.1849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brown T. R., Sundick R. S., Dhar A., Sheth D., Bagchi N. Uptake and metabolism of iodine is crucial for the development of thyroiditis in obese strain chickens. J Clin Invest. 1991 Jul;88(1):106–111. doi: 10.1172/JCI115265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cohen P. L., Eisenberg R. A. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol. 1991;9:243–269. doi: 10.1146/annurev.iy.09.040191.001331. [DOI] [PubMed] [Google Scholar]
  10. Dale J. B., Beachey E. H. Sequence of myosin-crossreactive epitopes of streptococcal M protein. J Exp Med. 1986 Nov 1;164(5):1785–1790. doi: 10.1084/jem.164.5.1785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gotfredsen C. F., Buschard K., Frandsen E. K. Reduction of diabetes incidence of BB Wistar rats by early prophylactic insulin treatment of diabetes-prone animals. Diabetologia. 1985 Dec;28(12):933–935. doi: 10.1007/BF00703140. [DOI] [PubMed] [Google Scholar]
  12. Gottlieb P. A., Handler E. S., Appel M. C., Greiner D. L., Mordes J. P., Rossini A. A. Insulin treatment prevents diabetes mellitus but not thyroiditis in RT6-depleted diabetes resistant BB/Wor rats. Diabetologia. 1991 May;34(5):296–300. doi: 10.1007/BF00404999. [DOI] [PubMed] [Google Scholar]
  13. Goverman J., Woods A., Larson L., Weiner L. P., Hood L., Zaller D. M. Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell. 1993 Feb 26;72(4):551–560. doi: 10.1016/0092-8674(93)90074-z. [DOI] [PubMed] [Google Scholar]
  14. Gray D., Matzinger P. T cell memory is short-lived in the absence of antigen. J Exp Med. 1991 Nov 1;174(5):969–974. doi: 10.1084/jem.174.5.969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Heath W. R., Allison J., Hoffmann M. W., Schönrich G., Hämmerling G., Arnold B., Miller J. F. Autoimmune diabetes as a consequence of locally produced interleukin-2. Nature. 1992 Oct 8;359(6395):547–549. doi: 10.1038/359547a0. [DOI] [PubMed] [Google Scholar]
  16. Hutchings P., Rosen H., O'Reilly L., Simpson E., Gordon S., Cooke A. Transfer of diabetes in mice prevented by blockade of adhesion-promoting receptor on macrophages. Nature. 1990 Dec 13;348(6302):639–642. doi: 10.1038/348639a0. [DOI] [PubMed] [Google Scholar]
  17. Kappler J. W., Roehm N., Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987 Apr 24;49(2):273–280. doi: 10.1016/0092-8674(87)90568-x. [DOI] [PubMed] [Google Scholar]
  18. Kappler J. W., Staerz U., White J., Marrack P. C. Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex. Nature. 1988 Mar 3;332(6159):35–40. doi: 10.1038/332035a0. [DOI] [PubMed] [Google Scholar]
  19. Lacy P. E., Kostianovsky M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes. 1967 Jan;16(1):35–39. doi: 10.2337/diab.16.1.35. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. McCullagh P. Interception of the development of self tolerance in fetal lambs. Eur J Immunol. 1989 Aug;19(8):1387–1392. doi: 10.1002/eji.1830190806. [DOI] [PubMed] [Google Scholar]
  22. Miyazaki A., Hanafusa T., Yamada K., Miyagawa J., Fujino-Kurihara H., Nakajima H., Nonaka K., Tarui S. Predominance of T lymphocytes in pancreatic islets and spleen of pre-diabetic non-obese diabetic (NOD) mice: a longitudinal study. Clin Exp Immunol. 1985 Jun;60(3):622–630. [PMC free article] [PubMed] [Google Scholar]
  23. Nikolić-Zugić J., Bevan M. J. Role of self-peptides in positively selecting the T-cell repertoire. Nature. 1990 Mar 1;344(6261):65–67. doi: 10.1038/344065a0. [DOI] [PubMed] [Google Scholar]
  24. Nossal G. J. Immunologic tolerance: collaboration between antigen and lymphokines. Science. 1989 Jul 14;245(4914):147–153. doi: 10.1126/science.2526369. [DOI] [PubMed] [Google Scholar]
  25. O'Reilly L. A., Hutchings P. R., Crocker P. R., Simpson E., Lund T., Kioussis D., Takei F., Baird J., Cooke A. Characterization of pancreatic islet cell infiltrates in NOD mice: effect of cell transfer and transgene expression. Eur J Immunol. 1991 May;21(5):1171–1180. doi: 10.1002/eji.1830210512. [DOI] [PubMed] [Google Scholar]
  26. Ohashi P. S., Oehen S., Buerki K., Pircher H., Ohashi C. T., Odermatt B., Malissen B., Zinkernagel R. M., Hengartner H. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell. 1991 Apr 19;65(2):305–317. doi: 10.1016/0092-8674(91)90164-t. [DOI] [PubMed] [Google Scholar]
  27. Okamoto M., Murakami M., Shimizu A., Ozaki S., Tsubata T., Kumagai S., Honjo T. A transgenic model of autoimmune hemolytic anemia. J Exp Med. 1992 Jan 1;175(1):71–79. doi: 10.1084/jem.175.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Oldstone M. B. Molecular mimicry and autoimmune disease. Cell. 1987 Sep 11;50(6):819–820. doi: 10.1016/0092-8674(87)90507-1. [DOI] [PubMed] [Google Scholar]
  29. Oldstone M. B., Nerenberg M., Southern P., Price J., Lewicki H. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell. 1991 Apr 19;65(2):319–331. doi: 10.1016/0092-8674(91)90165-u. [DOI] [PubMed] [Google Scholar]
  30. Owen R. D. IMMUNOGENETIC CONSEQUENCES OF VASCULAR ANASTOMOSES BETWEEN BOVINE TWINS. Science. 1945 Oct 19;102(2651):400–401. doi: 10.1126/science.102.2651.400. [DOI] [PubMed] [Google Scholar]
  31. Palmer J. P., Asplin C. M., Clemons P., Lyen K., Tatpati O., Raghu P. K., Paquette T. L. Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science. 1983 Dec 23;222(4630):1337–1339. doi: 10.1126/science.6362005. [DOI] [PubMed] [Google Scholar]
  32. Pontes de Carvalho L. C., Templeman J., Wick G., Roitt I. M. The role of self-antigen in the development of autoimmunity in Obese strain chickens with spontaneous autoallergic thyroiditis. J Exp Med. 1982 May 1;155(5):1255–1266. doi: 10.1084/jem.155.5.1255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. ROSE N. R., WITEBSKY E. Studies on organ specificity. V. Changes in the thyroid glands of rabbits following active immunization with rabbit thyroid extracts. J Immunol. 1956 Jun;76(6):417–427. [PubMed] [Google Scholar]
  34. 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]
  35. Rerup C. C. Drugs producing diabetes through damage of the insulin secreting cells. Pharmacol Rev. 1970 Dec;22(4):485–518. [PubMed] [Google Scholar]
  36. Ricordi C., Lacy P. E. Renal subcapsular xenotransplantation of purified porcine islets. Transplantation. 1987 Nov;44(5):721–723. [PubMed] [Google Scholar]
  37. Rossini A. A., Like A. A., Chick W. L., Appel M. C., Cahill G. F., Jr Studies of streptozotocin-induced insulitis and diabetes. Proc Natl Acad Sci U S A. 1977 Jun;74(6):2485–2489. doi: 10.1073/pnas.74.6.2485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. SIMONSEN M. Graft versus host reactions. Their natural history, and applicability as tools of research. Prog Allergy. 1962;6:349–467. [PubMed] [Google Scholar]
  39. 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]
  40. Sarvetnick N., Shizuru J., Liggitt D., Martin L., McIntyre B., Gregory A., Parslow T., Stewart T. Loss of pancreatic islet tolerance induced by beta-cell expression of interferon-gamma. Nature. 1990 Aug 30;346(6287):844–847. doi: 10.1038/346844a0. [DOI] [PubMed] [Google Scholar]
  41. Seligmann M., Brouet J. C. Antibody activity of human myeloma globulins. Semin Hematol. 1973 Apr;10(2):163–177. [PubMed] [Google Scholar]
  42. Sha W. C., Nelson C. A., Newberry R. D., Kranz D. M., Russell J. H., Loh D. Y. Positive and negative selection of an antigen receptor on T cells in transgenic mice. Nature. 1988 Nov 3;336(6194):73–76. doi: 10.1038/336073a0. [DOI] [PubMed] [Google Scholar]
  43. 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]
  44. Signore A., Pozzilli P., Gale E. A., Andreani D., Beverley P. C. The natural history of lymphocyte subsets infiltrating the pancreas of NOD mice. Diabetologia. 1989 May;32(5):282–289. doi: 10.1007/BF00265543. [DOI] [PubMed] [Google Scholar]
  45. Sinha A. A., Lopez M. T., McDevitt H. O. Autoimmune diseases: the failure of self tolerance. Science. 1990 Jun 15;248(4961):1380–1388. doi: 10.1126/science.1972595. [DOI] [PubMed] [Google Scholar]
  46. Smith S. C., Allen P. M. Expression of myosin-class II major histocompatibility complexes in the normal myocardium occurs before induction of autoimmune myocarditis. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9131–9135. doi: 10.1073/pnas.89.19.9131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Strasser A., Whittingham S., Vaux D. L., Bath M. L., Adams J. M., Cory S., Harris A. W. Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8661–8665. doi: 10.1073/pnas.88.19.8661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. TRIPLETT E. L. On the mechanism of immunologic self recognition. J Immunol. 1962 Oct;89:505–510. [PubMed] [Google Scholar]
  49. Tochino Y. The NOD mouse as a model of type I diabetes. Crit Rev Immunol. 1987;8(1):49–81. [PubMed] [Google Scholar]
  50. Tsao B. P., Ohnishi K., Cheroutre H., Mitchell B., Teitell M., Mixter P., Kronenberg M., Hahn B. H. Failed self-tolerance and autoimmunity in IgG anti-DNA transgenic mice. J Immunol. 1992 Jul 1;149(1):350–358. [PubMed] [Google Scholar]
  51. 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]
  52. Wiedenmann B., Franke W. W. Identification and localization of synaptophysin, an integral membrane glycoprotein of Mr 38,000 characteristic of presynaptic vesicles. Cell. 1985 Jul;41(3):1017–1028. doi: 10.1016/s0092-8674(85)80082-9. [DOI] [PubMed] [Google Scholar]
  53. von Boehmer H. Developmental biology of T cells in T cell-receptor transgenic mice. Annu Rev Immunol. 1990;8:531–556. doi: 10.1146/annurev.iy.08.040190.002531. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES