Clinical potential of antigen-specific therapies in type 1 diabetes

Review of Diabetic Studies

Volumn 9, Issue 4, 2012, Pages 328-337

  Coppieters, Ken T ^a   Sehested Hansen, Birgit ^b   von Herrath, Matthias G ^a,c  

^a NOVO NORDISK INC   (United States)

^b NOVO NORDISK A S   (Denmark)

^c LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY   (United States)

Author keywords

DiaPep277; HSP60; Immune tolerance; Nasal antigen; Oral antigen; Regulatory T cell; Type 1 diabetes

Indexed keywords

CHAPERONIN 60; DIAPEP 277; GLUTAMATE DECARBOXYLASE; INSULIN; PLACEBO; UNCLASSIFIED DRUG;

ANTIGEN PRESENTING CELL; ANTIGEN SPECIFICITY; CD4+ T LYMPHOCYTE; DISEASE ASSOCIATION; DISEASE EXACERBATION; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERANCE; FOLLOW UP; HUMAN; IMMUNE RESPONSE; IMMUNOMODULATION; IMMUNOPATHOLOGY; IMMUNOSUPPRESSIVE TREATMENT; INSULIN DEPENDENT DIABETES MELLITUS; LOW DRUG DOSE; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROGNOSIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RISK BENEFIT ANALYSIS; T LYMPHOCYTE ACTIVATION; TREATMENT OUTCOME;

EID: 84879529122     PISSN: 16136071     EISSN: 16140575     Source Type: Journal    
DOI: 10.1900/RDS.2012.9.328     Document Type: Review

References (90)

1. Coppieters KT, von Herrath MG. Histopathology of type 1 diabetes: old paradigms and new insights. Rev Diabet Stud 2009. 6(2):85-96.
2. Coppieters KT, Dotta F, Amirian N, Campbell PD, Kay TW, Atkinson MA, Roep BO, von Herrath MG. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med 2012. 209(1):51-60.
3. Skowera A, Ellis RJ, Varela-Calvino R, Arif S, Huang GC, Van-Krinks C, Zaremba A, Rackham C, Allen JS, Tree TI, et al. CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope. J Clin Invest 2008. 118(10):3390-3402.
4. Tyden G, Reinholt FP, Sundkvist G, Bolinder J. Recurrence of autoimmune diabetes mellitus in recipients of cadaveric pancreatic grafts. N Engl J Med 1996. 335(12):860-863.
5. Feutren G, Papoz L, Assan R, Vialettes B, Karsenty G, Vexiau P, Du RH, Rodier M, Sirmai J, Lallemand A, et al. Cyclosporin increases the rate and length of remissions in insulin-dependent diabetes of recent onset. Results of a multicentre double-blind trial. Lancet 1986. 2(8499):119-124.
6. Harrison LC, Colman PG, Dean B, Baxter R, Martin FI. Increase in remission rate in newly diagnosed type I diabetic subjects treated with azathioprine. Diabetes 1985. 34(12):1306-1308.
7. Cyclosporin-induced remission of IDDM after early intervention. Association of 1 yr of cyclosporin treatment with enhanced insulin secretion. The Canadian-European Randomized Control Trial Group. Diabetes 1988. 37(11):1574-1582.
8. Parving HH, Tarnow L, Nielsen FS, Rossing P, Mandrup-Poulsen T, Osterby R, Nerup J. Cyclosporine nephrotoxicity in type 1 diabetic patients. A 7-year follow-up study. Diabetes Care 1999. 22(3):478-483.
9. Voltarelli JC, Couri CE, Stracieri AB, Oliveira MC, Moraes DA, Pieroni F, Coutinho M, Malmegrim KC, Foss-Freitas MC, Simoes BP, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 2007. 297(14):1568-1576.
10. Orban T, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Marks JB, Monzavi R, et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet 2011. 378(9789):412-419.
11. Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R, Gottlieb PA, Marks JB, McGee PF, Moran AM, et al. Rituximab, Blymphocyte depletion, and preservation of beta-cell function. N Engl J Med 2009. 361(22):2143-2152.
12. Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002. 346(22):1692-1698.
13. Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, Gorus F, Goldman M, Walter M, Candon S, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005. 352(25):2598-2608.
14. Keymeulen B, Candon S, Fafi-Kremer S, Ziegler A, Leruez-Ville M, Mathieu C, Vandemeulebroucke E, Walter M, Crenier L, Thervet E, et al. Transient Epstein-Barr virus reactivation in CD3 monoclonal antibodytreated patients. Blood 2010. 115(6):1145-1155.
15. Sherry N, Hagopian W, Ludvigsson J, Jain SM, Wahlen J, Ferry RJ, Jr., Bode B, Aronoff S, Holland C, Carlin D, et al. Teplizumab for treatment of type 1 diabetes (Protege study): 1-year results from a randomised, placebo-controlled trial. Lancet 2011. 378(9790):487-497.
16. Chatenoud L, Thervet E, Primo J, Bach JF. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci USA 1994. 91(1):123-127.
17. von Herrath MG, Coon B, Wolfe T, Chatenoud L. Nonmitogenic CD3 antibody reverses virally induced (rat insulin promoter-lymphocytic choriomeningitis virus) autoimmune diabetes without impeding viral clearance. J Immunol 2002. 168(2):933-941.
18. Lenschow DJ, Ho SC, Sattar H, Rhee L, Gray G, Nabavi N, Herold KC, Bluestone JA. Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse. J Exp Med 1995. 181(3):1145-1155.
19. Yang XD, Tisch R, Singer SM, Cao ZA, Liblau RS, Schreiber RD, McDevitt HO. Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. J Exp Med 1994. 180(3):995-1004.
20. Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 1994. 265(5176):1237-1240.
21. Fujihashi K, Dohi T, Rennert PD, Yamamoto M, Koga T, Kiyono H, McGhee JR. Peyer's patches are required for oral tolerance to proteins. Proc Natl Acad Sci USA 2001. 98(6):3310-3315.
22. von Herrath MG, Harrison LC. Antigen-induced regulatory T cells in autoimmunity. Nat Rev Immunol 2003. 3(3):223-232.
23. Tree TI, Lawson J, Edwards H, Skowera A, Arif S, Roep BO, Peakman M. Naturally arising human CD4 T-cells that recognize islet autoantigens and secrete interleukin-10 regulate proinflammatory T-cell responses via linked suppression. Diabetes 2010. 59(6):1451-1460.
24. Coppieters KT, Amirian N, von Herrath MG. Incidental CD8 T cell reactivity against caspase-cleaved apoptotic self-antigens from ubiquitously expressed proteins in islets from prediabetic human leucocyte antigen-A2 transgenic non-obese diabetic mice. Clin Exp Immunol 2011. 165(2):155-162.
25. Brusko T, Wasserfall C, McGrail K, Schatz R, Viener HL, Schatz D, Haller M, Rockell J, Gottlieb P, Clare-Salzler M, et al. No alterations in the frequency of FOXP3+ regulatory T-cells in type 1 diabetes. Diabetes 2007. 56(3):604-612.
26. Long SA, Rieck M, Sanda S, Bollyky JB, Samuels PL, Goland R, Ahmann A, Rabinovitch A, Aggarwal S, Phippard D, et al. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function. Diabetes 2012. 61(9):2340-2348.
27. Nagler-Anderson C, Bober LA, Robinson ME, Siskind GW, Thorbecke GJ. Suppression of type II collagen-induced arthritis by intragastric administration of soluble type II collagen. Proc Natl Acad Sci USA 1986. 83(19):7443-7446.
28. Higgins PJ, Weiner HL. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein and its fragments. J Immunol 1988. 140(2):440-445.
29. Zhang ZJ, Davidson L, Eisenbarth G, Weiner HL. Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci USA 1991. 88(22):10252-10256.
30. Harrison LC, Dempsey-Collier M, Kramer DR, Takahashi K. Aerosol insulin induces regulatory CD8 gamma delta T cells that prevent murine insulin-dependent diabetes. J Exp Med 1996. 184(6):2167-2174.
31. Tian J, Atkinson MA, Clare-Salzler M, Herschenfeld A, Forsthuber T, Lehmann PV, Kaufman DL. Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulindependent diabetes. J Exp Med 1996. 183(4):1561-1567.
32. Atkinson MA, Maclaren NK, Luchetta R. Insulitis and diabetes in NOD mice reduced by prophylactic insulin therapy. Diabetes 1990. 39(8):933-937.
33. Bellmann K, Kolb H, Rastegar S, Jee P, Scott FW. Potential risk of oral insulin with adjuvant for the prevention of Type I diabetes: a protocol effective in NOD mice may exacerbate disease in BB rats. Diabetologia 1998. 41(7):844-847.
34. Krishnamoorthy G, Saxena A, Mars LT, Domingues HS, Mentele R, Ben-Nun A, Lassmann H, Dornmair K, Kurschus FC, Liblau RS, et al. Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis. Nat Med 2009. 15(6):626-632.
35. Macfarlane GJ, El-Metwally A, De SV, Ernst E, Dowds GL, Moots RJ. Evidence for the efficacy of complementary and alternative medicines in the management of rheumatoid arthritis: a systematic review. Rheumatology.(Oxford) 2011. 50(9):1672-1683.
36. Weiner HL, Mackin GA, Matsui M, Orav EJ, Khoury SJ, Dawson DM, Hafler DA. Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science 1993. 259(5099):1321-1324.
37. Mamchak AA, Manenkova Y, Leconet W, Zheng Y, Chan JR, Stokes CL, Shoda LK, von HM, Bresson D. Preexisting autoantibodies predict efficacy of oral insulin to cure autoimmune diabetes in combination with anti-CD3. Diabetes 2012. 61(6):1490-1499.
38. Thrower SL, James L, Hall W, Green KM, Arif S, Allen JS, Van-Krinks C, Lozanoska-Ochser B, Marquesini L, Brown S, et al. Proinsulin peptide immunotherapy in type 1 diabetes: report of a first-in-man Phase I safety study. Clin Exp Immunol 2009. 155(2):156-165.
39. Orban T, Farkas K, Jalahej H, Kis J, Treszl A, Falk B, Reijonen H, Wolfsdorf J, Ricker A, Matthews JB, et al. Autoantigen-specific regulatory T cells induced in patients with type 1 diabetes mellitus by insulin B-chain immunotherapy. J Autoimmun 2010. 34(4):408-415.
40. Huurman VA, van der Meide PE, Duinkerken G, Willemen S, Cohen IR, Elias D, Roep BO. Immunological efficacy of heat shock protein 60 peptide Dia-Pep277 therapy in clinical type I diabetes. Clin Exp Immunol 2008. 152(3):488-497.
41. Velthuis JH, Unger WW, Abreu JR, Duinkerken G, Franken K, Peakman M, Bakker AH, Reker-Hadrup S, Keymeulen B, Drijfhout JW, et al. Simultaneous detection of circulating autoreactive CD8+ T-cells specific for different islet cell-associated epitopes using combinatorial MHC multimers. Diabetes 2010. 59(7):1721-1730.
42. Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, Yu L, Wegmann DR, Hutton JC, Elliott JF, et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 2005. 435(7039):220-223.
43. von Herrath MG, Dyrberg T, Oldstone MB. Oral insulin treatment suppresses virus-induced antigen-specific destruction of beta cells and prevents autoimmune diabetes in transgenic mice. J Clin Invest 1996. 98(6):1324-1331.
44. Petersen JS, Bregenholt S, Apostolopolous V, Homann D, Wolfe T, Hughes A, De JK, Wang M, Dyrberg T, von Herrath MG. Coupling of oral human or porcine insulin to the B subunit of cholera toxin (CTB) overcomes critical antigenic differences for prevention of type I diabetes. Clin Exp Immunol 2003. 134(1):38-45.
45. Homann D, Dyrberg T, Petersen J, Oldstone MB, von Herrath MG. Insulin in oral immune tolerance: a one-amino acid change in the B chain makes the difference. J Immunol 1999. 163(4):1833-1838.
46. Skyler JS, Krischer JP, Wolfsdorf J, Cowie C, Palmer JP, Greenbaum C, Cuthbertson D, Rafkin-Mervis LE, Chase HP, Leschek E. Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial - Type 1. Diabetes Care 2005. 28(5):1068-1076.
47. Pozzilli P, Pitocco D, Visalli N, Cavallo MG, Buzzetti R, Crino A, Spera S, Suraci C, Multari G, Cervoni M, et al. No effect of oral insulin on residual beta-cell function in recent-onset type I diabetes (the IMDIAB VII). IMDIAB Group. Diabetologia 2000. 43(8):1000-1004.
48. Chaillous L, Lefevre H, Thivolet C, Boitard C, Lahlou N, Atlan-Gepner C, Bouhanick B, Mogenet A, Nicolino M, Carel JC, et al. Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Diabete Insuline Orale group. Lancet 2000. 356(9229):545-549.
49. Ergun-Longmire B, Marker J, Zeidler A, Rapaport R, Raskin P, Bode B, Schatz D, Vargas A, Rogers D, Schwartz S, et al. Oral insulin therapy to prevent progression of immune-mediated (type 1) diabetes. Ann N Y Acad Sci 2004. 1029:260-277.
50. Fousteri G, Chan JR, Zheng Y, Whiting C, Dave A, Bresson D, Croft M, von Herrath M. Virtual optimization of nasal insulin therapy predicts immunization frequency to be crucial for diabetes protection. Diabetes 2010. 59(12):3148-3158.
51. Harrison LC, Honeyman MC, Steele CE, Stone NL, Sarugeri E, Bonifacio E, Couper JJ, Colman PG. Pancreatic beta-cell function and immune responses to insulin after administration of intranasal insulin to humans at risk for type 1 diabetes. Diabetes Care 2004. 27(10):2348-2355.
52. Nanto-Salonen K, Kupila A, Simell S, Siljander H, Salonsaari T, Hekkala A, Korhonen S, Erkkola R, Sipila JI, Haavisto L, et al. Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial. Lancet 2008. 372(9651):1746-1755.
53. Fourlanos S, Perry C, Gellert SA, Martinuzzi E, Mallone R, Butler J, Colman PG, Harrison LC. Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes. Diabetes 2011. 60(4):1237-1245.
54. Achenbach P, Barker J, Bonifacio E. Modulating the natural history of type 1 diabetes in children at high genetic risk by mucosal insulin immunization. Curr Diab Rep 2008. 8(2):87-93.
55. Keller RJ, Eisenbarth GS, Jackson RA. Insulin prophylaxis in individuals at high risk of type I diabetes. Lancet 1993. 341(8850):927-928.
56. Bowman MA, Campbell L, Darrow BL, Ellis TM, Suresh A, Atkinson MA. Immunological and metabolic effects of prophylactic insulin therapy in the NOD-scid/scid adoptive transfer model of IDDM. Diabetes 1996. 45(2):205-208.
57. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002. 346(22):1685-1691.
58. Walter M, Philotheou A, Bonnici F, Ziegler AG, Jimenez R. No effect of the altered peptide ligand NBI-6024 on beta-cell residual function and insulin needs in new-onset type 1 diabetes. Diabetes Care 2009. 32(11):2036-2040.
59. Bielekova B, Goodwin B, Richert N, Cortese I, Kondo T, Afshar G, Gran B, Eaton J, Antel J, Frank JA, 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(10):1167-1175.
60. Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, De CP. Identification of the 64K autoantigen in insulindependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 1990. 347(6289):151-156.
61. Velloso LA, Kampe O, Hallberg A, Christmanson L, Betsholtz C, Karlsson FA. Demonstration of GAD-65 as the main immunogenic isoform of glutamate decarboxylase in type 1 diabetes and determination of autoantibodies using a radioligand produced by eukaryotic expression. J Clin Invest 1993. 91(5):2084-2090.
62. De Aizpurua HJ, Wilson YM, Harrison LC. Glutamic acid decarboxylase autoantibodies in preclinical insulindependent diabetes. Proc Natl Acad Sci USA 1992. 89(20):9841-9845.
63. Solimena M, Folli F, Aparisi R, Pozza G, De CP. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990. 322(22):1555-1560.
64. Lohmann T, Hawa M, Leslie RD, Lane R, Picard J, Londei M. Immune reactivity to glutamic acid decarboxylase 65 in stiffman syndrome and type 1 diabetes mellitus. Lancet 2000. 356(9223):31-35.
65. Tisch R, Yang XD, Singer SM, Liblau RS, Fugger L, McDevitt HO. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 1993. 366(6450):72-75.
66. Petersen JS, Karlsen AE, Markholst H, Worsaae A, Dyrberg T, Michelsen B. Neonatal tolerization with glutamic acid decarboxylase but not with bovine serum albumin delays the onset of diabetes in NOD mice. Diabetes 1994. 43(12):1478-1484.
67. Tisch R, Wang B, Weaver DJ, Liu B, Bui T, Arthos J, Serreze DV. Antigen-specific mediated suppression of beta cell autoimmunity by plasmid DNA vaccination. J Immunol 2001. 166(3):2122-2132.
68. Ludvigsson J. Therapy with GAD in diabetes. Diabetes Metab Res Rev 2009. 25(4):307-315.
69. Agardh CD, Cilio CM, Lethagen A, Lynch K, Leslie RD, Palmer M, Harris RA, Robertson JA, Lernmark A. Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes. J Diabetes Complications 2005. 19(4):238-246.
70. Agardh CD, Lynch K, Palmer M, Link K, Lernmark A. GAD65 vaccination significantly reduces insulin dependence at five years follow-up in a dose escalating study in adult-onset autoimmune diabetes patients. Diabetologia 2008. 51:S230-S230.
71. Ludvigsson J, Faresjo M, Hjorth M, Axelsson S, Cheramy M, Pihl M, Vaarala O, Forsander G, Ivarsson S, Johansson C, et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med 2008. 359(18):1909-1920.
72. Ludvigsson J, Hjorth M, Cheramy M, Axelsson S, Pihl M, Forsander G, Nilsson NO, Samuelsson BO, Wood T, Aman J, et al. Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial. Diabetologia 2011. 54(3):634-640.
73. Hjorth M, Axelsson S, Ryden A, Faresjo M, Ludvigsson J, Casas R. GAD-alum treatment induces GAD65-specific CD4+CD25highFOXP3+ cells in type 1 diabetic patients. Clin Immunol 2011. 138(1):117-126.
74. Axelsson S, Hjorth M, Ludvigsson J, Casas R. Decreased GAD(65)-specific Th1/Tc1 phenotype in children with Type 1 diabetes treated with GAD-alum. Diabet Med 2012. 29(10):1272-1278.
75. Axelsson S, Cheramy M, Hjorth M, Pihl M, Akerman L, Martinuzzi E, Mallone R, Ludvigsson J, Casas R. Long-lasting immune responses 4 years after GAD-alum treatment in children with type 1 diabetes. Plos One 2011. 6(12):e29008.
76. Wherrett DK, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Herold KC, Marks JB, et al. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised doubleblind trial. Lancet 2011. 378(9788):319-327.
77. Ludvigsson J, Krisky D, Casas R, Battelino T, Castano L, Greening J, Kordonouri O, Otonkoski T, Pozzilli P, Robert JJ, et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N Engl J Med 2012. 366(5):433-442.
78. Elias D, Markovits D, Reshef T, van der Zee R, Cohen IR. Induction and therapy of autoimmune diabetes in the non-obese diabetic (NOD/Lt) mouse by a 65-kDa heat shock protein. Proc Natl Acad Sci USA 1990. 87(4):1576-1580.
79. Elias D, Reshef T, Birk OS, van der Zee R, Walker MD, Cohen IR. Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein. Proc Natl Acad Sci USA 1991. 88(8):3088-3091.
80. Elias D, Cohen IR. Peptide therapy for diabetes in NOD mice. Lancet 1994. 343(8899):704-706.
81. Elias D, Marcus H, Reshef T, Ablamunits V, Cohen IR. Induction of diabetes in standard mice by immunization with the p277 peptide of a 60-kDa heat shock protein. Eur J Immunol 1995. 25(10):2851-2857.
82. Abulafia-Lapid R, Elias D, Raz I, Keren-Zur Y, Atlan H, Cohen IR. T cell proliferative responses of type 1 diabetes patients and healthy individuals to human hsp60 and its peptides. J Autoimmun 1999. 12(2):121-129.
83. 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(9295):1749-1753.
84. Raz I, Avron A, Tamir M, Metzger M, Symer L, Eldor R, Cohen IR, Elias D. Treatment of new-onset type 1 diabetes with peptide DiaPep277 is safe and associated with preserved beta-cell function: extension of a randomized, double-blind, phase II trial. Diabetes Metab Res Rev 2007. 23(4):292-298.
85. Zanin-Zhorov A, Cahalon L, Tal G, Margalit R, Lider O, Cohen IR. Heat shock protein 60 enhances CD4+ CD25+ regulatory T cell function via innate TLR2 signaling. J Clin Invest 2006. 116(7):2022-2032.
86. Huurman VA, Decochez K, Mathieu C, Cohen IR, Roep BO. Therapy with the hsp60 peptide DiaPep277 in C-peptide positive type 1 diabetes patients. Diabetes Metab Res Rev 2007. 23(4):269-275.
87. Lazar L, Ofan R, Weintrob N, Avron A, Tamir M, Elias D, Phillip M, Josefsberg Z. Heat-shock protein peptide DiaPep277 treatment in children with newly diagnosed type 1 diabetes: a randomised, double-blind phase II study. Diabetes Metab Res Rev 2007. 23(4):286-291.
88. Schloot NC, Meierhoff G, Lengyel C, Vandorfi G, Takacs J, Panczel P, Barkai L, Madacsy L, Oroszlan T, Kovacs P, et al. Effect of heat shock protein peptide DiaPep277 on beta-cell function in paediatric and adult patients with recent-onset diabetes mellitus type 1: two prospective, randomized, double-blind phase II trials. Diabetes Metab Res Rev 2007. 23(4):276-285.
89. Buzzetti R, Cernea S, Petrone A, Capizzi M, Spoletini M, Zampetti S, Guglielmi C, Venditti C, Pozzilli P. C-peptide response and HLA genotypes in subjects with recent-onset type 1 diabetes after immunotherapy with DiaPep277: an exploratory study. Diabetes 2011. 60(11):3067-3072.
90. von Herrath M. Combination therapies for type 1 diabetes: why not now? Immunotherapy 2010. 2(3):289-291.