Processing and presentation of (pro)-insulin in the MHC class II pathway: The generation of antigen-based immunomodulators in the context of type 1 diabetes mellitus

Diabetes/Metabolism Research and Reviews

Volumn 26, Issue 4, 2010, Pages 227-238

  Burster, Timo ^a   Boehm, Bernhard O ^a  

^a UNIVERSITY HOSPITAL ULM   (Germany)

Author keywords

Altered peptide ligands; Antigen processing; Proteases

Indexed keywords

ALTERED PEPTIDE LIGAND; AUTOANTIGEN; CATHEPSIN; EPITOPE; IMMUNOMODULATING AGENT; LIGAND; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; PEPTIDE; PROINSULIN; PROTEINASE; UNCLASSIFIED DRUG;

ANTIGEN PRESENTATION; ANTIGEN PRESENTING CELL; AUTOIMMUNITY; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; DENDRITIC CELL; HUMAN; INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE ACTIVATION;

ANIMALS; ANTIGEN PRESENTATION; CATHEPSINS; DENDRITIC CELLS; DESENSITIZATION, IMMUNOLOGIC; DIABETES MELLITUS, TYPE 1; HISTOCOMPATIBILITY ANTIGENS CLASS II; HUMANS; IMMUNOLOGIC FACTORS; LYMPHOCYTE ACTIVATION; MAJOR HISTOCOMPATIBILITY COMPLEX; PEPTIDE FRAGMENTS; PROINSULIN; T-LYMPHOCYTES, REGULATORY;

EID: 77952777466     PISSN: 15207552     EISSN: 15207560     Source Type: Journal    
DOI: 10.1002/dmrr.1090     Document Type: Review

References (141)

1. Tisch R, McDevitt H. Insulin-dependent diabetes mellitus. Cell 1996; 85: 291-297.
2. Adorini L, Muller S, Cardinaux F, Lehmann PV, Falcioni F, Nagy ZA. In vivo competition between self peptides and foreign antigens in T-cell activation. Nature 1988; 334: 623-625.
3. Degano M, Garcia KC, Apostolopoulos V, Rudolph MG, Teyton L, Wilson IA. A functional hot spot for antigen recognition in a superagonist TCR/MHC complex. Immunity 2000; 12: 251-261.
4. Sakai K, Zamvil SS, Mitchell DJ, Hodgkinson S, Rothbard JB, Steinman L. Prevention of experimental encephalomyelitis with peptides that block interaction of T cells with major histocompatibility complex proteins. Proc Natl Acad Sci U S A 1989; 86: 9470-9474.
5. Wraith DC, Smilek DE, Mitchell DJ, Steinman L, McDevitt HO. Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy. Cell 1989; 59:247-255.
6. Weber MS, Prod'homme T, Youssef S, et al. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat Med 2007; 13: 935-943.
7. Nicholson LB, Greer JM, Sobel RA, Lees MB, Kuchroo VK. An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity 1995; 3: 397-405.
8. Teitelbaum D, Aharoni R, Arnon R, Sela M. Specific inhibition of the T-cell response to myelin basic protein by the synthetic copolymer Cop 1. Proc Natl Acad Sci U S A 1988; 85: 9724-9728.
9. Crowe PD, Qin Y, Conlon PJ, Antel JP. NBI-5788, an altered MBP83-99 peptide, induces a T-helper 2-like immune response in multiple sclerosis patients. Ann Neurol 2000; 48: 758-765.
10. Kappos L, Comi G, Panitch H, et al. The Altered Peptide Ligand in Relapsing MS Study Group. Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. Nat Med 2000; 6: 1176-1182.
11. Bielekova B, Goodwin B, Richert N, et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med 2000; 6: 1167-1175.
12. Hoglund P, Mintern J, Waltzinger C, Heath W, Benoist C, Mathis D. Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes. J Exp Med 1999; 189: 331-339.
13. Mohan JF, Levisetti MG, Calderon B, Herzog JW, Petzold SJ, Unanue ER. Unique autoreactive T cells recognize insulin peptides generated within the islets of Langerhans in autoimmune diabetes. Nat Immunol 2010; 11: 350-354.
14. 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 2001; 107: 555-564. (Pubitemid 32205177)
15. Allen JS, Pang K, Skowera A, et al. Plasmacytoid dendritic cells are proportionally expanded at diagnosis of type 1 diabetes and enhance islet autoantigen presentation to T-cells through immune complex capture. Diabetes 2009; 58: 138-145.
16. Reijonen H, Daniels TL, Lernmark A, Nepom GT. GAD65-specific autoantibodies enhance the presentation of an immunodominant T-cell epitope from GAD65. Diabetes 2000; 49: 1621-1626.
17. Eisenbarth GS. Type I diabetes mellitus. A chronic autoimmune disease. N Engl JMed 1986; 314: 1360-1368. (Pubitemid 16122469)
18. Wegmann DR, Norbury-Glaser M, Daniel D. Insulin-specific T cells are a predominant component of islet infiltrates in pre-diabetic NOD mice. Eur J Immunol 1994; 24: 1853-1857.
19. 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. Diabetes 1999; 48: 460-468. (Pubitemid 29106857)
20. Roep BO. The role of T-cells in the pathogenesis of Type 1 diabetes: from cause to cure. Diabetologia 2003; 46: 305-321.
21. Lieberman SM, DiLorenzo TP. A comprehensive guide to antibody and T-cell responses in type 1 diabetes. Tissue Antigens 2003; 62: 359-377.
22. Anderson MS, Bluestone JA. The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 2005; 23: 447-485.
23. Calderon B, Suri A, Miller MJ, Unanue ER. Dendritic cells in islets of Langerhans constitutively present beta cell-derived peptides bound to their class II MHC molecules. Proc Natl Acad Sci U S A 2008; 105: 6121-6126.
24. Vendrame F, Pileggi A, Laughlin E, et al. 3rd Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, associated with autoantibodies and pathogenic autoreactive CD4 T-cells. Diabetes 2010; 59: 947-957.
25. Mandrup-Poulsen T. The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia 1996; 39: 1005-1029.
26. Donath MY, Storling J, Berchtold LA, Billestrup N, Mandrup-Poulsen T. Cytokines and beta-cell biology: from concept to clinical translation. Endocr Rev 2008; 29: 334-350.
27. Eizirik DL, Mandrup-Poulsen T. A choice of death - the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia 2001; 44: 2115-2133.
28. Nerup J, Mandrup-Poulsen T, Molvig J, Helqvist S, Wogensen L, Egeberg J. Mechanisms of pancreatic beta-cell destruction in type I diabetes. Diabetes Care 1988; 11(Suppl 1): 16-23. (Pubitemid 19005572)
29. Burster T, Macmillan H, Hou T, Boehm BO, Mellins ED. Cathepsin G: roles in antigen presentation and beyond. Mol Immunol 2010; 47: 658-665.
30. Colbert JD, Matthews SP, Miller G,Watts C. Diverse regulatory roles for lysosomal proteases in the immune response. Eur J Immunol 2009; 39: 2955-2965.
31. Fiebiger E, Meraner P, Weber E, et al. Cytokines regulate proteolysis in major histocompatibility complex class II-dependent antigen presentation by dendritic cells. J Exp Med 2001; 193: 881-892.
32. Reich M, Spindler KD, Burret M, Kalbacher H, Boehm BO, Burster T. Cathepsin A is expressed in primary human antigenpresenting cells. Immunol Lett 2010; 128: 143-147.
33. Rehault S, Brillard-Bourdet M, Juliano MA, Juliano L, Gauthier F, Moreau T. New, sensitive fluorogenic substrates for human cathepsin G based on the sequence of serpin-reactive site loops. J Biol Chem 1999; 274: 13810-13817. (Pubitemid 129518677)
34. Wysocka M, Legowska A, Bulak E, et al. New chromogenic substrates of human neutrophil cathepsin G containing non-natural aromatic amino acid residues in position P(1) selected by combinatorial chemistry methods. Mol Divers 2007; 11: 93-99.
35. Chapman HA. Endosomal proteolysis and MHC class II function. Curr Opin Immunol 1998; 10: 93-102.
36. Ruckrich T, Brandenburg J, Cansier A, et al. Specificity of human cathepsin S determined by processing of peptide substrates and MHC class II-associated invariant chain. Biol Chem 2006; 387: 1503-1511.
37. Arnold D, Keilholz W, Schild H, Dumrese T, Stevanovic S, Rammensee HG. Substrate specificity of cathepsins D and E determined by N-terminal and C-terminal sequencing of peptide pools. Eur J Biochem 1997; 249: 171-179. (Pubitemid 27432611)
38. Watts C, Matthews SP, Mazzeo D, Manoury B, Moss CX. Asparaginyl endopeptidase: case history of a class II MHC compartment protease. Immunol Rev 2005; 207: 218-228.
39. Schwarz G, Brandenburg J, Reich M, Burster T, Driessen C, Kalbacher H. Characterization of legumain. Biol Chem 2002; 383: 1813-1816.
40. Cezari MH, Puzer L, Juliano MA, Carmona AK, Juliano L. Cathepsin B carboxydipeptidase specificity analysis using internally quenched fluorescent peptides. Biochem J 2002; 368: 365-369.
41. Devanathan G, Turnbull JL, Ziomek E, Purisima EO, Menard R, Sulea T. Carboxy-monopeptidase substrate specificity of human cathepsin X. Biochem Biophys Res Commun 2005; 329: 445-452.
42. Kawamura Y, Matoba T, Hata T, Doi E. Substrate specificities of cathepsin A,L and A,S from pig kidney. J Biochem 1977; 81: 435-441. (Pubitemid 8078735)
43. Rothe M, Dodt J. Studies on the aminopeptidase activity of rat cathepsin H. Eur J Biochem 1992; 210: 759-764.
44. Takahashi T, Dehdarani AH, Tang J. Porcine spleen cathepsin H hydrolyzes oligopeptides solely by aminopeptidase activity. J Biol Chem 1988; 263: 10952-10957.
45. Maynard J, Petersson K, Wilson DH, et al. Structure of an autoimmune T cell receptor complexed with class II peptide-MHC: insights into MHC bias and antigen specificity. Immunity 2005; 22: 81-92.
46. Maehr R,Mintern JD, Herman AE, et al. Cathepsin L is essential for onset of autoimmune diabetes in NOD mice. J Clin Invest 2005; 115: 2934-2943.
47. Hsing LC, Kirk EA, McMillen TS, et al. Roles for cathepsins S, L, and B in insulitis and diabetes in the NOD mouse. J Autoimmun 2010; 34: 96-104.
48. Kwok WW, Nepom GT, Raymond FC. HLA-DQ polymorphisms are highly selective for peptide binding interactions. J Immunol 1995; 155: 2468-2476.
49. Lee KH, Wucherpfennig KW, Wiley DC. Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat Immunol 2001; 2: 501-507.
50. 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 2001; 107: 173-180. (Pubitemid 32096833)
51. Suri A, Levisetti MG, Unanue ER. Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity? Curr Opin Immunol 2008; 20: 105-110.
52. Rammensee HG, Friede T, Stevanoviic S. MHC ligands and peptide motifs: first listing. Immunogenetics 1995; 41: 178-228.
53. Moustakas AK, Papadopoulos GK. Use of MHC II structural features in the design of vaccines for organ-specific autoimmune diseases. Curr Pharm Des 2009; 15: 3262-3273.
54. Day SL, Ramsland PA, Apostolopoulos V. Non-canonical peptides bound to MHC. Curr Pharm Des 2009; 15: 3274-3282.
55. Wucherpfennig KW, Call MJ, Deng L, Mariuzza R. Structural alterations in peptide-MHC recognition by self-reactive T cell receptors. Curr Opin Immunol 2009; 21: 590-595.
56. Jones EY, Fugger L, Strominger JL, Siebold C. MHC class II proteins and disease: a structural perspective. Nat Rev Immunol 2006; 6: 271-282.
57. Burster T, Marin-Esteban V, Boehm BO, et al. Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions. Biochem Pharmacol 2007; 74: 1514-1523.
58. Wegmann DR, Eisenbarth GS. It's insulin. J Autoimmun 2000; 15: 286-291.
59. Jasinski JM, Eisenbarth GS. Insulin as a primary autoantigen for type 1A diabetes. Clin Dev Immunol 2005; 12: 181-186.
60. Nakayama M, Abiru N, Moriyama H, et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 2005; 435: 220-223.
61. 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. Nat Med 1999; 5: 1026-1031.
62. Wong FS, Moustakas AK, Wen L, Papadopoulos GK, Janeway CA. Analysis of structure and function relationships of an autoantigenic peptide of insulin bound to H-2K(d) that stimulates CD8 T cells in insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A 2002; 99: 5551-5556.
63. Levisetti MG, Suri A, Petzold SJ, Unanue ER. The insulin-specific T cells of nonobese diabetic mice recognize a weak MHC-binding segment in more than one form. J Immunol 2007; 178: 6051-6057. (Pubitemid 46717384)
64. 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. Diabetes 2002; 51: 2126-2134. (Pubitemid 34729017)
65. Kent SC, Chen Y, Clemmings SM, et al. Loss of IL-4 secretion from human type 1a diabetic pancreatic draining lymph node NKT cells. J Immunol 2005; 175: 4458-4464. (Pubitemid 41361982)
66. Mannering SI, Pang SH, Williamson NA, et al. The A-chain of insulin is a hot-spot for CD4+ T cell epitopes in human type 1 diabetes. Clin Exp Immunol 2009; 156: 226-231.
67. Mannering SI, Harrison LC, Williamson NA, et al. The insulin A-chain epitope recognized by human T cells is posttranslationally modified. J Exp Med 2005; 202: 1191-1197.
68. Simone E, Daniel D, Schloot N, et al. T cell receptor restriction of diabetogenic autoimmune NOD T cells. Proc Natl Acad Sci U S A 1997; 94: 2518-2521.
69. Durinovic-Bello I, Boehm BO, Ziegler AG. Predominantly recognized proinsulin T helper cell epitopes in individuals with and without islet cell autoimmunity. J Autoimmun 2002; 18: 55-66.
70. Durinovic-Bello I, Rosinger S, Olson JA, et al. DRB1 x 0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype. Proc Natl Acad Sci U S A 2006; 103: 11683-11688.
71. Endl J, Rosinger S, Schwarz B, et al. Coexpression of CD25 and OX40 (CD134) receptors delineates autoreactive T-cells in type 1 diabetes. Diabetes 2006; 55: 50-60.
72. Di Lorenzo TP, Peakman M, Roep BO. Translational mini-review series on type 1 diabetes: systematic analysis of T cell epitopes in autoimmune diabetes. Clin Exp Immunol 2007; 148: 1-16.
73. Arif S, Tree TI, Astill TP, et al. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest 2004; 113: 451-463.
74. Manoury B, Mazzeo D, Fugger L, et al. Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP. Nat Immunol 2002; 3: 169-174.
75. Manoury B, Hewitt EW, Morrice N, Dando PM, Barrett AJ, Watts C. An asparaginyl endopeptidase processes a microbial antigen for class II MHC presentation. Nature 1998; 396: 695-699.
76. Burster T, Beck A, Tolosa E, et al. Differential processing of autoantigens in lysosomes from human monocyte-derived and peripheral blood dendritic cells. J Immunol 2005; 175: 5940-5949. (Pubitemid 41508079)
77. Burster T, Beck A, Tolosa E, et al. Cathepsin G, and not the asparagine-specific endoprotease, controls the processing of myelin basic protein in lysosomes from human B lymphocytes. J Immunol 2004; 172: 5495-5503. (Pubitemid 38542050)
78. Reich M, Lesner A, Legowska A, et al. Application of specific cell permeable cathepsin G inhibitors resulted in reduced antigen processing in primary dendritic cells. Mol Immunol 2009; 46: 2994-2999.
79. Stoeckle C, Sommandas V, Adamopoulou E, et al. Cathepsin G is differentially expressed in primary human antigen-presenting cells. Cell Immunol 2009; 255: 41-45.
80. Matthews SP, Werber I, Deussing J, Peters C, Reinheckel T, Watts C. Distinct protease requirements for antigen presentation in vitro and in vivo. J Immunol 2010; 184: 2423-2431.
81. Sercarz EE, Lehmann PV, Ametani A, Benichou G, Miller A, Moudgil K. Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol 1993; 11: 729-766. (Pubitemid 23115022)
82. Delovitch TL, Semple JW, Naquet P, et al. Pathways of processing of insulin by antigen-presenting cells. Immunol Rev 1988; 106: 195-222. (Pubitemid 19001508)
83. Naquet P, Ellis J, Singh B, Hodges RS, Delovitch TL. Processing and presentation of insulin. I. Analysis of immunogenic peptides and processing requirements for insulin A loop-specific T cells. J Immunol 1987; 139: 3955-3963. (Pubitemid 18013683)
84. Lang Y, Forquet F, Speck E, Blum J, Delovitch TL. Major histocompatibility complex class II molecules function as a template for the processing of a partially processed insulin peptide into a T-cell epitope. Diabetes 1996; 45: 1711-1719. (Pubitemid 26398950)
85. Nishioku T, Hashimoto K, Yamashita K, et al. Involvement of cathepsin E in exogenous antigen processing in primary cultured murine microglia. J BiolChem 2002; 277: 4816-4822.
86. Blow AM, Barrett AJ. Action of human cathepsin G on the oxidized B chain of insulin. Biochem J 1977; 161: 17-19. (Pubitemid 8008812)
87. Vasiljeva O, Dolinar M, Turk V, Turk B. Recombinant human cathepsin H lacking the mini chain is an endopeptidase. Biochemistry 2003; 42: 13522-13528.
88. Anderton SM, Wraith DC. Selection and fine-tuning of the autoimmune T-cell repertoire. Nat Rev Immunol 2002; 2: 487-498.
89. Bettini M, Vignali DA. Regulatory T cells and inhibitory cytokines in autoimmunity. Curr Opin Immunol 2009; 21: 612-618.
90. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986; 136: 2348-2357. (Pubitemid 16136806)
91. Trinchieri G, Peritt D, Gerosa F. Acute induction and priming for cytokine production in lymphocytes. Cytokine Growth Factor Rev 1996; 7: 123-132.
92. Lafaille JJ. The role of helper T cell subsets in autoimmune diseases. Cytokine Growth Factor Rev 1998; 9: 139-151.
93. Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J ExpMed 2005; 201: 233-240.
94. Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 2007; 8: 345-350.
95. O'Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 2010; 327: 1098-1102.
96. Liu X, Leung S, Wang C, et al. Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease. Nat Med 2010; 16: 191-197.
97. Romagnani S, Maggi E, Liotta F, Cosmi L, Annunziato F. Properties and origin of human Th17 cells. Mol Immunol 2009; 47: 3-7.
98. Mensah-Brown EP, Shahin A, Al-Shamisi M, Wei X, Lukic ML. IL-23 leads to diabetes induction after subdiabetogenic treatment with multiple low doses of streptozotocin. Eur J Immunol 2006; 36: 216-223.
99. Jain R, Tartar DM, Gregg RK, et al. Innocuous IFNgamma induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production. J Exp Med 2008; 205: 207-218.
100. Bending D, De La Pena H, Veldhoen M, et al. Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Invest 2009; 119: 565-572.
101. Martin-Orozco N, Chung Y, Chang SH, Wang YH, Dong C. Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur J Immunol 2009; 39: 216-224.
102. Han G, Wang R, Chen G, et al. Interleukin-17-producing gammadelta(+) T cells protect NOD mice from type 1 diabetes through a mechanism involving transforming growth factorbeta. Immunology 2009; 129: 197-206.
103. Brusko TM, Putnam AL, Bluestone JA. Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol Rev 2008; 223: 371-390.
104. Peng Y, Laouar Y, Li MO, Green EA, Flavell RA. TGF-beta regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc Natl Acad Sci U S A 2004; 101: 4572-4577.
105. Luo X, Tarbell KV, Yang H, et al. Dendritic cells with TGF-beta1 differentiate naive CD4+CD25- T cells into islet-protective Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A 2007; 104: 2821-2826.
106. Sgouroudis E, Piccirillo CA. Control of type 1 diabetes by CD4+Foxp3+ regulatory T cells: lessons from mouse models and implications for human disease. Diabetes Metab Res Rev 2009; 25: 208-218.
107. Miyara M, Yoshioka Y, Kitoh A, et al. Functional delineation and differentiation dynamics of human CD4+T cells expressing the FoxP3 transcription factor. Immunity 2009; 30: 899-911.
108. Wraith DC. Therapeutic peptide vaccines for treatment of autoimmune diseases. Immunol Lett 2009; 122: 134-136.
109. Weldon JE, Xiang L, Chertov O, et al. A protease-resistant immunotoxin against CD22 with greatly increased activity against CLL and diminished animal toxicity. Blood 2009; 113: 3792-3800.
110. Ludvigsson J. Therapy with GAD in diabetes. Diabetes Metab Res Rev 2009; 25: 307-315.
111. Katsara M, Tselios T, Deraos S, et al. Round and round we go: cyclic peptides in disease. Curr Med Chem 2006; 13: 2221-2232.
112. Lamont AG, Powell MF, Colon SM, Miles C, Grey HM, Sette A. The use of peptide analogs with improved stability and MHC binding capacity to inhibit antigen presentation in vitro and in vivo. J Immunol 1990; 144: 2493-2498. (Pubitemid 20136648)
113. Bolin DR, Swain AL, Sarabu R, et al. Peptide and peptide mimetic inhibitors of antigen presentation by HLA-DR class II MHC molecules. Design, structure-activity relationships, and X-ray crystal structures. J Med Chem 2000; 43: 2135-2148.
114. Falcioni F, Ito K, Vidovic D, et al. Peptidomimetic compounds that inhibit antigen presentation by autoimmune disease-associated class II major histocompatibility molecules. Nat Biotechnol. 1999; 17: 562-567.
115. Engering A, Lefkovits I, Pieters J. Analysis of subcellular organelles involved in major histocompatibility complex (MHC) class II-restricted antigen presentation by electrophoresis. Electrophoresis 1997; 18: 2523-2530.
116. Tan MC, Mommaas AM, Drijfhout JW, et al.Mannose receptor-mediated uptake of antigens strongly enhances HLA class II-restricted antigen presentation by cultured dendritic cells. Eur J Immunol 1997; 27: 2426-2435.
117. Sheng KC, Kalkanidis M, Pouniotis DS, et al. Delivery of antigen using a novel mannosylated dendrimer potentiates immunogenicity in vitro and in vivo. Eur J Immunol 2008; 38: 424-436.
118. Agnes MC, Tan A, Jordens R, et al. Strongly increased efficiency of altered peptide ligands by mannosylation. Int Immunol 1998; 10: 1299-1304.
119. Lernmark A. Glutamic acid decarboxylase - gene to antigen to disease. J Intern Med 1996; 240: 259-277. (Pubitemid 26388855)
120. Tilz GP, Dausset J, Wiltgen M. The diabetic antigen Glutamic Acid Decarboxylase (GAD 65) in the human peripheral blood. Int Arch Allergy Immunol 2009; 152: 184-194.
121. Baekkeskov S, Aanstoot HJ, Christgau S, et al. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 1990; 347: 151-156. (Pubitemid 120028931)
122. Yoon JW, Yoon CS, Lim HW, et al. Control of autoimmune diabetes in NOD mice by GAD expression or suppression in beta cells. Science 1999; 284: 1183-1187.
123. Boehm BO, Rosinger S, Sauer G, et al. Protease-resistant human GAD-derived altered peptide ligands decrease TNF-alpha and IL-17 production in peripheral blood cells from patients with type 1 diabetes mellitus. Mol Immunol 2009; 46: 2576-2584.
124. Raz I, Eldor R, Naparstek Y. Immune modulation for prevention of type 1 diabetes mellitus. Trends Biotechnol. 2005; 23: 128-134.
125. Raz I, Elias D, Avron A, Tamir M, Metzger M, Cohen IR. Beta-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial. Lancet 2001; 358: 1749-1753.
126. Elias D, Avron A, Tamir M, Raz I. DiaPep277 preserves endogenous insulin production by immunomodulation in type 1 diabetes. Ann N Y Acad Sci 2006; 1079: 340-344.
127. Hurtenbach U, Lier E, Adorini L, Nagy ZA. Prevention of autoimmune diabetes in non-obese diabetic mice by treatment with a class II major histocompatibility complex-blocking peptide. J ExpMed 1993; 177: 1499-1504. (Pubitemid 23117142)
128. Sai P, Rivereau AS, Granier C, Haertle T, Martignat L. Immunization of non-obese diabetic (NOD) mice with glutamic acid decarboxylase-derived peptide 524-543 reduces cyclophosphamide-accelerated diabetes. Clin Exp Immunol 1996; 105: 330-337. (Pubitemid 26246954)
129. Geluk A, van Meijgaarden KE, Roep BO, Ottenhoff TH. Altered peptide ligands of islet autoantigen Imogen 38 inhibit antigen specific T cell reactivity in human type-1 diabetes. J Autoimmun 1998; 11: 353-361.
130. Nepom GT, Lippolis JD, White FM, et al. Identification and modulation of a naturally processed T cell epitope from the diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65). Proc Natl Acad Sci U S A 2001; 98: 1763-1768.
131. Masewicz SA, Papadopoulos GK, Swanson E, Moriarity L, Moustakas AK, Nepom GT. Modulation of T cell response to hGAD65 peptide epitopes. Tissue Antigens 2002; 59: 101-112.
132. 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 2003; 4: 2.
133. Leech MD, Chung CY, Culshaw A, Anderton SM. Peptide-based immunotherapy of experimental autoimmune encephalomyelitis without anaphylaxis. Eur J Immunol 2007; 37: 3576-3581.
134. Zhang L, Nakayama M, Eisenbarth GS. Insulin as an autoantigen in NOD/human diabetes. Curr Opin Immunol 2008; 20: 111-118.
135. van Aalst D, Kalbacher H, Palesch D, et al. A proinsulin74-90-derived protease-resistant, altered peptide ligand increases TGF-β 1 secretion in PBMC from patients with type 1 diabetes mellitus. J Leukoc Biol 2010; PMID 20110445.
136. Windhagen A, Scholz C, Hollsberg P, Fukaura H, Sette A, Hafler DA. Modulation of cytokine patterns of human autoreactive T cell clones by a single amino acid substitution of their peptide ligand. Immunity 1995; 2: 373-380.
137. Paas-Rozner M, Sela M, Mozes E. The nature of the active suppression of responses associated with experimental autoimmune myasthenia gravis by a dual altered peptide ligand administered by different routes. Proc Natl Acad Sci U S A 2001; 98: 12642-12647.
138. Szabo G, Mandrekar P, Girouard L, Catalano D. Regulation of human monocyte functions by acute ethanol treatment: decreased tumor necrosis factor-alpha, interleukin-1 beta and elevated interleukin-10, and transforming growth factor-beta production. Alcohol Clin Exp Res 1996; 20: 900-907. (Pubitemid 26282325)
139. Lau AH, Szabo G, Thomson AW. Antigen-presenting cells under the influence of alcohol. Trends Immunol 2009; 30: 13-22.
140. Lu Y, Boehm J, Nichol L, Trucco M, Ringquist S. Multiplex HLA-typing by pyrosequencing. Methods Mol Biol 2009; 496: 89-114.
141. Bluestone JA, Tang Q, Sedwick CE. T regulatory cells in autoimmune diabetes: past challenges, future prospects. J Clin Immunol 2008; 28: 677-684.