Insulin: a critical autoantigen and potential therapeutic agent in Type 1 diabetes

References

• Turner R, Stratton I, Horton V et al. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in Type 2 diabetes. UK Prospective Diabetes Study Group. Lancet350(9087), 1288–1293 (1997).
   PubMed Web of Science ®Google Scholar
• Steele C, Hagopian WA, Gitelman S et al. Insulin secretion in Type 1 diabetes. Diabetes53(2), 426–433 (2004).
   PubMed Web of Science ®Google Scholar
• Meier JJ, Bhushan A, Butler AE, Rizza RA, Butler PC. Sustained β cell apoptosis in patients with long-standing Type 1 diabetes: indirect evidence for islet regeneration? Diabetologia48(11), 2221–2228 (2005).
   PubMed Web of Science ®Google Scholar
• Pugliese A. Genetics of Type 1 diabetes. Endocrinol. Metab. Clin. North Am.33(1), 1–16, vii (2004).
   PubMed Web of Science ®Google Scholar
• Concannon P, Erlich HA, Julier C et al. Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families. Diabetes54(10), 2995–3001 (2005).
   PubMed Web of Science ®Google Scholar
• Pugliese A. The insulin gene in Type 1 diabetes. IUBMB. Life57(7), 463–468 (2005).
   PubMedGoogle Scholar
• Bottazzo GF, Florin-Christensen A, Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet2(7892), 1279–1283 (1974).
   PubMed Web of Science ®Google Scholar
• Gorsuch AN, Spencer KM, Lister J et al. Evidence for a long prediabetic period in Type I (insulin-dependent) diabetes mellitus. Lancet2(8260–8261), 1363–1365 (1981).
   PubMed Web of Science ®Google Scholar
• Decochez K, Tits J, Coolens JL et al. High frequency of persisting or increasing islet-specific autoantibody levels after diagnosis of Type 1 diabetes presenting before 40 years of age. The Belgian Diabetes Registry. Diabetes Care23(6), 838–844 (2000).
   PubMed Web of Science ®Google Scholar
• Krischer JP, Cuthbertson DD, Yu L et al. Screening strategies for the identification of multiple antibody-positive relatives of individuals with Type 1 diabetes. J. Clin. Endocrinol. Metab.88(1), 103–108 (2003).
   PubMed Web of Science ®Google Scholar
• Hampe CS, Hammerle LP, Bekris L et al. Recognition of glutamic acid decarboxylase (GAD) by autoantibodies from different GAD antibody-positive phenotypes. J. Clin. Endocrinol. Metab.85(12), 4671–4679 (2000).
   PubMed Web of Science ®Google Scholar
• Serreze DV and Silveira PA. The role of B lymphocytes as key antigen-presenting cells in the development of T cell-mediated autoimmune Type 1 diabetes. Curr. Dir. Autoimmun.6, 212–227 (2003).
   PubMedGoogle Scholar
• Tree TI, Peakman M. Autoreactive T cells in human Type 1 diabetes. Endocrinol. Metab. Clin. North Am.33(1), 113–133 (2004).
   PubMedGoogle Scholar
• Foulis AK. The pathology of the endocrine pancreas in Type 1 (insulin-dependent) diabetes mellitus. APMIS104(3), 161–167 (1996).
   PubMedGoogle Scholar
• Rabinovitch A. Immunoregulation by cytokines in autoimmune diabetes. Adv. Exp. Med. Biol.520, 159–193 (2003).
   PubMedGoogle Scholar
• Lieberman SM, DiLorenzo TP. A comprehensive guide to antibody and T-cell responses in Type 1 diabetes. Tissue Antigens62(5), 359–377 (2003).
   PubMedGoogle Scholar
• George SK, Preda I, Avagyan S et al. Immunokinetics of autoreactive CD4 T cells in blood: a reporter for the "hit-and-run" autoimmune attack on pancreas and diabetes progression. J. Autoimmun. 23(2), 151–160 (2004).
   PubMedGoogle Scholar
• Conrad B, Weidmann E, Trucco G et al. Evidence for superantigen involvement in insulin-dependent diabetes mellitus aetiology. Nature371(6495), 351–355 (1994).
   PubMed Web of Science ®Google Scholar
• Imagawa A, Hanafusa T, Tamura S et al. Pancreatic biopsy as a procedure for detecting in situ autoimmune phenomena in Type 1 diabetes: close correlation between serological markers and histological evidence of cellular autoimmunity. Diabetes50(6), 1269–1273 (2001).
   PubMed Web of Science ®Google Scholar
• Gianani R, Putnam A, Still T et al. Initial results of screening of non-diabetic organ donors for expression of islet autoantibodies. J. Clin. Endocrinol. Metab. (2006) (Epub ahead of print).
   PubMedGoogle Scholar
• Pugliese A, Allende G, Laughlin E et al. Recurrence of autoantibodies and autoreactive T cells in patients with Type 1 diabetes following pancreas transplantation. Diabetes53(Suppl. 2), A69 (2004).
   Google Scholar
• Palmer JP, Asplin CM, Clemons P et al. Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science222(4630), 1337–1339 (1983).
   PubMed Web of Science ®Google Scholar
• Vardi P, Dib SA, Tuttleman M et al. Competitive insulin autoantibody assay. Prospective evaluation of subjects at high risk for development of type I diabetes mellitus. Diabetes36(11), 1286–1291 (1987).
   PubMed Web of Science ®Google Scholar
• Vardi P, Ziegler AG, Mathews JH et al. Concentration of insulin autoantibodies at onset of type I diabetes. Inverse log-linear correlation with age. Diabetes Care11(9), 736–739 (1988).
   PubMed Web of Science ®Google Scholar
• Ziegler R, Alper CA, Awdeh ZL et al. Specific association of HLA-DR4 with increased prevalence and level of insulin autoantibodies in first-degree relatives of patients with type I diabetes. Diabetes40(6), 709–714 (1991).
   PubMedGoogle Scholar
• Pugliese A, Bugawan T, Moromisato R et al. Two subsets of HLA-DQA1 alleles mark phenotypic variation in levels of insulin autoantibodies in first degree relatives at risk for insulin-dependent diabetes. J. Clin. Invest.93(6), 2447–2452 (1994).
   PubMedGoogle Scholar
• Yu L, Rewers M, Gianani R et al. Antiislet autoantibodies usually develop sequentially rather than simultaneously. J. Clin. Endocrinol. Metab.81(12), 4264–4267 (1996).
   PubMed Web of Science ®Google Scholar
• Bonifacio E, Scirpoli M, Kredel K, Fuchtenbusch M, Ziegler AG. Early autoantibody responses in prediabetes are IgG1 dominated and suggest antigen-specific regulation. J. Immunol.163(1), 525–532 (1999).
   PubMedGoogle Scholar
• Ziegler AG, Hummel M, Schenker M, Bonifacio E. Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with Type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. Diabetes48(3), 460–468 (1999).
   PubMed Web of Science ®Google Scholar
• Yu L, Robles DT, Abiru N et al. Early expression of antiinsulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes. Proc. Natl. Acad. Sci. USA97(4), 1701–1706 (2000).
   PubMed Web of Science ®Google Scholar
• Colman PG, McNair P, Margetts H et al. The Melbourne Pre-Diabetes Study: prediction of Type 1 diabetes mellitus using antibody and metabolic testing. Med. J. Aust.169(2), 81–84 (1998).
   PubMedGoogle Scholar
• Achenbach P, Koczwara K, Knopff A et al. Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to Type 1 diabetes. J. Clin. Invest.114(4), 589–597 (2004).
   PubMedGoogle Scholar
• Aoki CA, Borchers AT, Ridgway WM et al. NOD mice and autoimmunity. Med. J. Aust.4(6), 373–379 (2005).
   Google Scholar
• Trudeau JD, Kelly-Smith C, Verchere CB et al. Prediction of spontaneous autoimmune diabetes in NOD mice by quantification of autoreactive T cells in peripheral blood. J. Clin. Invest.111(2), 217–223 (2003).
   PubMed Web of Science ®Google Scholar
• Chen W, Bergerot I, Elliott JF et al. Evidence that a peptide spanning the B-C junction of proinsulin is an early autoantigen epitope in the pathogenesis of Type 1 diabetes. J. Immunol.167(9), 4926–4935 (2001).
   PubMedGoogle Scholar
• Daniel D, Gill RG, Schloot N, Wegmann D. Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice. Eur. J. Immunol.25, 1056–1062 (1995).
   PubMed Web of Science ®Google Scholar
• Wong FS, Karttunen J, Dumont C et al. Identification of an MHC class I-restricted autoantigen in Type 1 diabetes by screening an organ-specific cDNA library. Nature Med.5(9), 1026–1031 (1999).
   PubMed Web of Science ®Google Scholar
• Liu E, Abiru N, Moriyama H, Miao D, Eisenbarth GS. Induction of insulin autoantibodies and protection from diabetes with subcutaneous insulin B:9–23 peptide without adjuvant. Ann. NY Acad. Sci.958, 224–227 (2002).
   PubMed Web of Science ®Google Scholar
• Moriyama H, Wen L, Abiru N et al. Induction and acceleration of insulitis/diabetes in mice with a viral mimic (polyinosinic-polycytidylic acid) and an insulin self-peptide. Proc. Natl Acad. Sci. USA99(8), 5539–5544 (2002).
   PubMed Web of Science ®Google Scholar
• Abiru N, Maniatis AK, Yu L et al. Peptide and major histocompatibility complex-specific breaking of humoral tolerance to native insulin with the B9–23 peptide in diabetes-prone and normal mice. Diabetes50(6), 1274–1281 (2001).
   PubMed Web of Science ®Google Scholar
• Rudy G, Stone N, Harrison LC et al. Similar peptides from two β cell autoantigens, proinsulin and glutamic acid decarboxylase, stimulate T cells of individuals at risk for insulin-dependent diabetes. Mol. Med.1(6), 625–633 (1995).
   PubMed Web of Science ®Google Scholar
• Durinovic-Bello I, Boehm BO, Ziegler AG. Predominantly recognized proinsulin T helper cell epitopes in individuals with and without islet cell autoimmunity. J. Autoimmun.18(1), 55–66 (2002).
   PubMedGoogle Scholar
• Narendran P, Williams AJ, Elsegood K, Leech NJ, Dayan CM. Humoral and cellular immune responses to proinsulin in adults with newly diagnosed Type 1 diabetes. Diabetes Metab. Res. Rev.19(1), 52–59 (2003).
   PubMed Web of Science ®Google Scholar
• Alleva DG, Crowe PD, Jin L et al. A disease-associated cellular immune response in Type 1 diabetics to an immunodominant epitope of insulin. J. Clin. Invest.107(2), 173–180 (2001).
   PubMed Web of Science ®Google Scholar
• Toma A, Haddouk S, Briand JP et al. Recognition of a subregion of human proinsulin by class I-restricted T cells in Type 1 diabetic patients. Proc. Natl Acad. Sci. USA102(30), 10581–10586 (2005).
   PubMed Web of Science ®Google Scholar
• Hassainya Y, Garcia-Pons F, Kratzer R et al. Identification of naturally processed HLA-A2-restricted proinsulin epitopes by reverse immunology. Diabetes54(7), 2053–2059 (2005).
   PubMed Web of Science ®Google Scholar
• Kent SC, Chen Y, Bregoli L et al. Expanded T cells from pancreatic lymph nodes of Type 1 diabetic subjects recognize an insulin epitope. Nature435(7039), 224–228 (2005).
   PubMed Web of Science ®Google Scholar
• Mannering SI, Harrison LC, Williamson NA et al. The insulin A-chain epitope recognized by human T cells is posttranslationally modified. J. Exp. Med.202(9), 1191–1197 (2005).
   PubMed Web of Science ®Google Scholar
• Solimena M. Vesicular autoantigens of Type 1 diabetes. Diabetes Metab. Rev.14(3), 227–240 (1998).
   PubMedGoogle Scholar
• Harashima S, Clark A, Christie MR, Notkins AL. The dense core transmembrane vesicle protein IA-2 is a regulator of vesicle number and insulin secretion. Proc. Natl Acad. Sci. USA102(24), 8704–8709 (2005).
   PubMedGoogle Scholar
• Yang J, Danke NA, Berger D et al. Islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD4+ T cells in human subjects. J. Immunol.176(5), 2781–2789 (2006).
   PubMed Web of Science ®Google Scholar
• Araki E, Oyadomari S, Mori M. Impact of endoplasmic reticulum stress pathway on pancreatic β-cells and diabetes mellitus. Exp. Biol. Med. (Maywood)228(10), 1213–1217 (2003).
   PubMed Web of Science ®Google Scholar
• Oyadomari S, Araki E, Mori M. Endoplasmic reticulum stress-mediated apoptosis in pancreatic β-cells. Apoptosis7(4), 335–345 (2002).
   PubMed Web of Science ®Google Scholar
• Allen JR, Nguyen LX, Sargent KE et al. High ER stress in β-cells stimulates intracellular degradation of misfolded insulin. Biochemistry Biophysics Res. Commun.324(1), 166–170 (2004).
   PubMedGoogle Scholar
• Devaskar SU, Singh BS, Carnaghi LR, Rajakumar PA, Giddings SJ. Insulin II gene expression in rat central nervous system. Regulatory Peptides48, 55–63 (1993).
   PubMed Web of Science ®Google Scholar
• Taha A, Budd GC, Pansky B. Preproinsulin messenger ribonucleic acid in the rat adrenal gland. Ann. Clin. Lab. Sci.23(6), 469–476 (1993).
   PubMedGoogle Scholar
• Budd GC, Pansky B, Glatzer L. Preproinsulin mRNA in the rat eye. Invest. Ophthalmol. Vis. Sci.34(2), 463–469 (1993).
   PubMedGoogle Scholar
• Giddings SJ, King CD, Harman KW, Flood JF, Carnaghi LR. Allele specific inactivation of insulin 1 and 2, in the mouse yolk, indicates imprinting. Nature Genetics6, 310–313 (1994).
   PubMed Web of Science ®Google Scholar
• Kendzierski KS, Pansky B, Budd GC, Saffran M. Evidence for biosynthesis of preproinsulin in gut of rat. Endocrine13(3), 353–359 (2000).
   PubMedGoogle Scholar
• Pugliese A. Central and peripheral autoantigen presentation in immune tolerance. Immunology111, 138–146 (2004).
   PubMedGoogle Scholar
• Pugliese A, Brown D, Garza D et al. Self-antigen-presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organs. J. Clin. Invest.107(5), 555–564 (2001).
   PubMedGoogle Scholar
• Diez J, Park Y, Zeller M et al. Differential splicing of the IA-2 mRNA in pancreas and lymphoid organs as a permissive genetic mechanism for autoimmunity against the IA-2 Type 1 diabetes autoantigen. Diabetes50(4), 895–900 (2001).
   PubMed Web of Science ®Google Scholar
• Garcia CA, Prabakar KR, Diez J et al. Dendritic cells in human thymus and periphery display a proinsulin epitope in a transcription-dependent, capture-independent fashion. J. Immunol.175(4), 2111–2122 (2005).
   PubMedGoogle Scholar
• Gotter J, Brors B, Hergenhahn M, Kyewski B. Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J. Exp. Med.199(2), 155–166 (2004).
   PubMed Web of Science ®Google Scholar
• Pugliese A, Zeller M, Fernandez AJ et al. The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for Type 1 diabetes. Nat. Genetics15(3), 293–297 (1997).
   PubMed Web of Science ®Google Scholar
• Vafiadis P, Bennett ST, Todd JA et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat. Genetics15(3), 289–292 (1997).
   PubMed Web of Science ®Google Scholar
• Bennett ST, Todd JA. Human Type 1 diabetes and the insulin gene: principles of mapping polygenes. Annu. Rev. Genetics30, 343–370 (1996).
   PubMed Web of Science ®Google Scholar
• Pugliese A, Zeller M, Fernandez A Jr et al. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for Type 1 diabetes. Nat. Genet.15, 293–297 (1997).
   PubMed Web of Science ®Google Scholar
• Chentoufi AA, Polychronakos C. Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes. Diabetes51(5), 1383–1390 (2002).
   PubMed Web of Science ®Google Scholar
• Brimnes MK, Jensen T, Jorgensen TN et al. Low expression of insulin in the thymus of non-obese diabetic mice. J. Autoimmun.19(4), 203–213 (2002).
   PubMedGoogle Scholar
• French MB, Allison J, Cram DS et al. Transgenic expression of mouse proinsulin II prevents diabetes in nonobese diabetic mice. Diabetes46(1), 34–39 (1997).
   PubMedGoogle Scholar
• Thebault-Baumont K, Dubois-Laforgue D, Krief P et al. Acceleration of Type 1 diabetes mellitus in proinsulin 2-deficient NOD mice. J. Clin. Invest.111(6), 851–857 (2003).
   PubMedGoogle Scholar
• Moriyama H, Abiru N, Paronen J et al. Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse. Proc. Natl Acad. Sci. USA100(18), 10376–10381 (2003).
   PubMedGoogle Scholar
• Jaeckel E, Lipes MA, von Boehmer H. Recessive tolerance to preproinsulin 2 reduces but does not abolish Type 1 diabetes. Nat. Immunol.5(10), 1028–1035 (2004).
   PubMedGoogle Scholar
• Abiru N, Wegmann D, Kawasaki E et al. Dual overlapping peptides recognized by insulin peptide B:9–23 T cell receptor AV13S3 T cell clones of the NOD mouse. J. Autoimmun.14(3), 231–237 (2000).
   PubMedGoogle Scholar
• Nakayama M, Abiru N, Moriyama H et al. Prime role for an insulin epitope in the development of Type 1 diabetes in NOD mice. Nature435(7039), 220–223 (2005).
   PubMed Web of Science ®Google Scholar
• Nakayama M, Babaya N, Miao D et al. Thymic expression of mutated B16:A preproinsulin messenger RNA does not reverse acceleration of NOD diabetes associated with insulin 2 (thymic expressed insulin) knockout. J. Autoimmun.25(3), 193–198 (2005).
   PubMedGoogle Scholar
• Dogra RS, Vaidyanathan P, Prabakar KR et al. Alternative splicing of G6PC2, the gene coding for the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), results in differential expression in human thymus and spleen compared with pancreas. Diabetologia (2006) (Epub).
   PubMedGoogle Scholar
• Kralovicova J, Gaunt TR, Rodriguez S et al. Variants in the human insulin gene that affect pre-mRNA splicing: is -23HphI a functional single nucleotide polymorphism at IDDM2? Diabetes55(1), 260–264 (2006).
   PubMed Web of Science ®Google Scholar
• Kubosaki A, Miura J, Notkins AL. IA-2 is not required for the development of diabetes in NOD mice. Diabetologia47(1), 149–150 (2004).
   PubMed Web of Science ®Google Scholar
• Jaeckel E, Klein L, Martin-Orozco N, von Boehmer H. Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase. J. Exp. Med.197(12), 1635–1644 (2003).
   PubMed Web of Science ®Google Scholar
• Geng L, Solimena M, Flavell RA, Sherwin RS, Hayday AC. Widespread expression of an autoantigen-GAD65 transgene does not tolerize non-obese diabetic mice and can exacerbate disease. Proc. Natl Acad. Sci. USA95(17), 10055–10060 (1998).
   PubMedGoogle Scholar
• Kash SF, Condie BG, Baekkeskov S. Glutamate decarboxylase and GABA in pancreatic islets: lessons from knock-out mice. Horm. Metab. Res.31(5), 340–344 (1999).
   PubMed Web of Science ®Google Scholar
• Muir A, Schatz D, Maclaren N. Antigen-specific immunotherapy: oral tolerance and subcutaneous immunization in the treatment of insulin-dependent diabetes. Diabetes Metab. Rev.9(4), 279–287 (1993).
   PubMed Web of Science ®Google Scholar
• Bergerot I, Fabien N, Maguer V, Thivolet C. Oral administration of human insulin to NOD mice generates CD4+ T cells that suppress adoptive transfer of diabetes. J. Autoimmun.7(5), 655–663 (1994).
   PubMedGoogle Scholar
• Maron R, Guerau-de-Arellano M, Zhang X, Weiner HL. Oral administration of insulin to neonates suppresses spontaneous and cyclophosphamide induced diabetes in the NOD mouse. J. Autoimmun.16(1), 21–28 (2001).
   PubMed Web of Science ®Google Scholar
• Atkinson M, Maclaren N, Luchetta R, Burr I. Insulitis and diabetes in NOD mice reduced by prophylactic insulin therapy. Diabetes39, 933–937 (1990).
   PubMed Web of Science ®Google Scholar
• Harrison LC, Dempsey-Collier M, Kramer DR, Takahashi K. Aerosol insulin induces regulatory CD8 γδ T cells that prevent murine insulin-dependent diabetes. J. Exp. Med.184(6), 2167–2174 (1996).
   PubMedGoogle Scholar
• Martinez NR, Augstein P, Moustakas AK et al. Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide. J. Clin. Invest.111(9), 1365–1371 (2003).
   PubMedGoogle Scholar
• Daniel D, Wegmann DR. Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9–23). Proc. Natl Acad. Sci. USA93(2), 956–960 (1996).
   PubMed Web of Science ®Google Scholar
• Alleva DG, Gaur A, Jin L et al. Immunological characterization and therapeutic activity of an altered-peptide ligand, NBI-6024, based on the immunodominant Type 1 diabetes autoantigen insulin B-chain (9–23) peptide. Diabetes51(7), 2126–2134 (2002).
   PubMed Web of Science ®Google Scholar
• Liu E, Moriyama H, Abiru N et al. Anti-peptide autoantibodies and fatal anaphylaxis in NOD mice in response to insulin self-peptides B:9–23 and B:13–23. J. Clin. Invest.110(7), 1021–1027 (2002).
   PubMed Web of Science ®Google Scholar
• Pedotti R, Sanna M, Tsai M et al. Severe anaphylactic reactions to glutamic acid decarboxylase (GAD) self peptides in NOD mice that spontaneously develop autoimmune Type 1 diabetes mellitus. BMC. Immunol.4(1), 2 (2003).
   PubMedGoogle Scholar
• Hanninen A, Braakhuis A, Heath WR, Harrison LC. Mucosal antigen primes diabetogenic cytotoxic T-lymphocytes regardless of dose or delivery route. Diabetes50(4), 771–775 (2001).
   PubMed Web of Science ®Google Scholar
• Keller RJ, Eisenbarth GS, Jackson RA. Insulin prophylaxis in individuals at high risk of type I diabetes. Lancet341(8850), 927–928 (1993).
   PubMed Web of Science ®Google Scholar
• Diabetes Prevention Trial - Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with Type 1 diabetes mellitus. N. Engl. J. Med.346(22), 1685–1691 (2002).
   PubMed Web of Science ®Google Scholar
• Karounos DG, Goes SU, Bryson JS. Dose of insulin is a critical factor in the prevention of Type 1 diabetes in NOD mice. Diabetes52(Suppl. 1), A276 (2003).
   Google Scholar
• Skyler JS, Krischer JP, Wolfsdorf J et al. Effects of oral insulin in relatives of patients with Type 1 diabetes: The Diabetes Prevention Trial-Type 1. Diabetes Care28(5), 1068–1076 (2005).
   PubMed Web of Science ®Google Scholar
• Faria AM and Weiner HL. Oral tolerance. Immunol. Rev.206, 232–259 (2005).
   PubMed Web of Science ®Google Scholar
• Maruyama T, Shimada A, Kanatsuka A et al. Multicenter prevention trial of slowly progressive Type 1 diabetes with small dose of insulin (the Tokyo study): preliminary report. Ann. NY Acad. Sci.1005, 362–369 (2003).
   PubMedGoogle Scholar
• Hanninen A and Harrison LC. γδ T cells as mediators of mucosal tolerance: the autoimmune diabetes model. Immunol. Rev.173, 109–119 (2000).
   PubMed Web of Science ®Google Scholar
• Harrison LC, Honeyman MC, Steele CE et al. Pancreatic β-cell function and immune responses to insulin after administration of intranasal insulin to humans at risk for Type 1 diabetes. Diabetes Care27(10), 2348–2355 (2004).
   PubMed Web of Science ®Google Scholar
• Alleva DG, Maki RA, Putnam AL et al. Immunomodulation in Type 1 diabetes by NBI-6024, an altered peptide ligand of the insulin B epitope. Scand. J. Immunol.63(1), 59–69 (2006).
   PubMed Web of Science ®Google Scholar
• Herold KC, Hagopian W, Auger JA et al. Anti-CD3 monoclonal antibody in new-onset Type 1 diabetes mellitus. N. Engl. J. Med.346(22), 1692–1698 (2002).
   PubMed Web of Science ®Google Scholar
• Keymeulen B, Vandemeulebroucke E, Ziegler AG et al. Insulin needs after CD3-antibody therapy in new-onset Type 1 diabetes. N. Engl. J. Med.352(25), 2598–2608 (2005).
   PubMed Web of Science ®Google Scholar
• Raz I, Elias D, Avron A et al. β-cell function in new-onset Type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, Phase II trial. Lancet358(9295), 1749–1753 (2001).
   PubMed Web of Science ®Google Scholar