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Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1995 Oct;102(1):152–158. doi: 10.1111/j.1365-2249.1995.tb06649.x

HLA-DR-restricted T cell lines from newly diagnosed type 1 diabetic patients specific for insulinoma and normal islet beta cell proteins: lack of reactivity to glutamic acid decarboxylase.

G C Huang 1, J Tremble 1, E Bailyes 1, S D Arden 1, T Kaye 1, A M McGregor 1, J P Banga 1
PMCID: PMC1553330  PMID: 7554382

Abstract

T cells reacting with pancreatic islet beta cell proteins play a pivotal role in the pathogenesis of type 1 diabetes in experimental animal models and man, although the islet cell autoantigens against which these T cells are directed remain to be characterized. We have previously shown the presence of disease-related antigens residing in the transplantable RIN insulinoma membranes which are recognized by T cells from diabetic NOD mice. We now report on the establishment of CD4+, T cell lines reacting with insulinoma membranes from six newly diagnosed type 1 diabetic patients. Detailed examination of T cell lines from two patients revealed that both the lines continued to react with normal islet cell proteins and, interestingly, were also stimulated by antigens present in brain microsomes. The two T cell lines showed reactivity with different molecular weight proteins of the insulinoma membranes and both the lines were histocompatibility-linked antigen (HLA)-DR restricted. Although the insulinoma membrane preparation is known to contain glutamic acid decarboxylase (GAD), none of the six T cell lines proliferates in response to purified GAD. These T cell lines will be valuable in characterizing novel islet beta cell antigens which are likely to be implicated in type 1 diabetes.

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Selected References

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  1. Atkinson M. A., Bowman M. A., Campbell L., Darrow B. L., Kaufman D. L., Maclaren N. K. Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes. J Clin Invest. 1994 Nov;94(5):2125–2129. doi: 10.1172/JCI117567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Atkinson M. A., Kaufman D. L., Campbell L., Gibbs K. A., Shah S. C., Bu D. F., Erlander M. G., Tobin A. J., Maclaren N. K. Response of peripheral-blood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes. Lancet. 1992 Feb 22;339(8791):458–459. doi: 10.1016/0140-6736(92)91061-c. [DOI] [PubMed] [Google Scholar]
  3. Atkinson M. A., Maclaren N. K. Islet cell autoantigens in insulin-dependent diabetes. J Clin Invest. 1993 Oct;92(4):1608–1616. doi: 10.1172/JCI116745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baekkeskov S., Aanstoot H. J., Christgau S., Reetz A., Solimena M., Cascalho M., Folli F., Richter-Olesen H., De Camilli P., Camilli P. D. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature. 1990 Sep 13;347(6289):151–156. doi: 10.1038/347151a0. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Bieg S., Bailyes E. M., Yassin N., Amann J., Herberg L., McGregor A. M., Scherbaum W. A., Banga J. P. A multiplicity of protein antigens in subcellular fractions of rat insulinoma tissue are able to stimulate T cells obtained from non-obese diabetic mice. Diabetologia. 1993 May;36(5):385–390. doi: 10.1007/BF00402272. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Durinovic-Bellò I., Steinle A., Ziegler A. G., Schendel D. J. HLA-DQ-restricted, islet-specific T-cell clones of a type I diabetic patient. T-cell receptor sequence similarities to insulitis-inducing T-cells of nonobese diabetic mice. Diabetes. 1994 Nov;43(11):1318–1325. doi: 10.2337/diab.43.11.1318. [DOI] [PubMed] [Google Scholar]
  9. Ewins D. L., Barnett P. S., Ratanachaiyavong S., Sharrock C., Lanchbury J., McGregor A. M., Banga J. P. Antigen-specific T cell recognition of affinity-purified and recombinant thyroid peroxidase in autoimmune thyroid disease. Clin Exp Immunol. 1992 Oct;90(1):93–98. doi: 10.1111/j.1365-2249.1992.tb05838.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ewins D. L., Barnett P. S., Tomlinson R. W., McGregor A. M., Banga J. P. Mapping epitope specificities of monoclonal antibodies to thyroid peroxidase using recombinant antigen preparations. Autoimmunity. 1992;11(3):141–149. doi: 10.3109/08916939209035148. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Gillard B. K., Thomas J. W., Nell L. J., Marcus D. M. Antibodies against ganglioside GT3 in the sera of patients with type I diabetes mellitus. J Immunol. 1989 Jun 1;142(11):3826–3832. [PubMed] [Google Scholar]
  13. Harcourt G. C., Sommer N., Rothbard J., Willcox H. N., Newsom-Davis J. A juxta-membrane epitope on the human acetylcholine receptor recognized by T cells in myasthenia gravis. J Clin Invest. 1988 Oct;82(4):1295–1300. doi: 10.1172/JCI113729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hutton J. C. The insulin secretory granule. Diabetologia. 1989 May;32(5):271–281. doi: 10.1007/BF00265542. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Keller R. J. Cellular immunity to human insulin in individuals at high risk for the development of type I diabetes mellitus. J Autoimmun. 1990 Jun;3(3):321–327. doi: 10.1016/0896-8411(90)90150-q. [DOI] [PubMed] [Google Scholar]
  17. Lee D. S., Tian J., Phan T., Kaufman D. L. Cloning and sequence analysis of a murine cDNA encoding glutamate decarboxylase (GAD65). Biochim Biophys Acta. 1993 Oct 19;1216(1):157–160. doi: 10.1016/0167-4781(93)90056-j. [DOI] [PubMed] [Google Scholar]
  18. Martin R., Jaraquemada D., Flerlage M., Richert J., Whitaker J., Long E. O., McFarlin D. E., McFarland H. F. Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals. J Immunol. 1990 Jul 15;145(2):540–548. [PubMed] [Google Scholar]
  19. Muschel R., Khoury G., Reid L. M. Regulation of insulin mRNA abundance and adenylation: dependence on hormones and matrix substrata. Mol Cell Biol. 1986 Jan;6(1):337–341. doi: 10.1128/mcb.6.1.337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Olerup O., Zetterquist H. HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens. 1992 May;39(5):225–235. doi: 10.1111/j.1399-0039.1992.tb01940.x. [DOI] [PubMed] [Google Scholar]
  21. Petersen J. S., Hejnaes K. R., Moody A., Karlsen A. E., Marshall M. O., Høier-Madsen M., Boel E., Michelsen B. K., Dyrberg T. Detection of GAD65 antibodies in diabetes and other autoimmune diseases using a simple radioligand assay. Diabetes. 1994 Mar;43(3):459–467. doi: 10.2337/diab.43.3.459. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Roep B. O., Kallan A. A., De Vries R. R. Beta-cell antigen-specific lysis of macrophages by CD4 T-cell clones from newly diagnosed IDDM patient. A putative mechanism of T-cell-mediated autoimmune islet cell destruction. Diabetes. 1992 Nov;41(11):1380–1384. doi: 10.2337/diab.41.11.1380. [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. Sheehy M. J. HLA and insulin-dependent diabetes. A protective perspective. Diabetes. 1992 Feb;41(2):123–129. doi: 10.2337/diab.41.2.123. [DOI] [PubMed] [Google Scholar]
  26. Sheehy M. J., Scharf S. J., Rowe J. R., Neme de Gimenez M. H., Meske L. M., Erlich H. A., Nepom B. S. A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles. J Clin Invest. 1989 Mar;83(3):830–835. doi: 10.1172/JCI113965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Todd J. A. Genetic analysis of susceptibility to type 1 diabetes. Springer Semin Immunopathol. 1992;14(1):33–58. doi: 10.1007/BF00197131. [DOI] [PubMed] [Google Scholar]
  29. Van Vliet E., Roep B. O., Meulenbroek L., Bruining G. J., De Vries R. R. Human T cell clones with specificity for insulinoma cell antigens. Eur J Immunol. 1989 Jan;19(1):213–216. doi: 10.1002/eji.1830190136. [DOI] [PubMed] [Google Scholar]
  30. Velloso L. A., Kämpe O., Eizirik D. L., Hallberg A., Andersson A., Karlsson F. A. Human autoantibodies react with glutamic acid decarboxylase antigen in human and rat but not in mouse pancreatic islets. Diabetologia. 1993 Jan;36(1):39–46. doi: 10.1007/BF00399091. [DOI] [PubMed] [Google Scholar]

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