Antigen-specific regulatory T cells and low dose of IL-2 in treatment of type 1 diabetes

Frontiers in Immunology

Volumn 6, Issue JAN, 2016, Pages

  Pham, Minh N ^a,b   Von Herrath, Matthias G ^a   Vela, Jose Luis ^a  

^a NOVO NORDISK INC   (United States)

^b PACIFIC NORTHWEST RESEARCH INSTITUTE   (United States)

Author keywords

Antigen specific therapy; Immune biomarker; Low dose interleukin 2; Regulatory T cell; Type 1 diabetes

Indexed keywords

BIOLOGICAL MARKER; INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR; INTERLEUKIN 2 RECEPTOR ALPHA; PROTEIN BCL 2;

ALOPECIA AREATA; ANTIGEN FUNCTION; ANTIGEN SPECIFICITY; AUTOIMMUNITY; DRUG EFFICACY; HUMAN; IMMUNOREGULATION; IMMUNOSUPPRESSIVE TREATMENT; INSULIN DEPENDENT DIABETES MELLITUS; LOW DRUG DOSE; NEOPLASM; REGULATORY T LYMPHOCYTE; REVIEW; T LYMPHOCYTE ACTIVATION;

EID: 84958206640     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2015.00651     Document Type: Review

References (86)

1. Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science (1976) 193:1007-8. doi: 10.1126/science.181845
2. Bayer AL, Pugliese A, Malek TR. The IL-2/IL-2R system: from basic science to therapeutic applications to enhance immune regulation. Immunol Res (2013) 57:197-209. doi:10.1007/s12026-013-8452-5
3. Klatzmann D, Abbas AK. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol (2015) 15:283-94. doi:10.1038/nri3823
4. Hanzly M, Aboumohamed A, Yarlagadda N, Creighton T, Digiorgio L, Fredrick A, et al. High-dose interleukin-2 therapy for metastatic renal cell carcinoma: a contemporary experience. Urology (2014) 83:1129-34. doi:10.1016/j.urology.2014.02.005
5. Thomas JS, Kabbinavar F. Metastatic clear cell renal cell carcinoma: a review of current therapies and novel immunotherapies. Crit Rev Oncol Hematol (2015) 96(3):527-33. doi:10.1016/j.critrevonc.2015.07.009
6. Bindon C, Czerniecki M, Ruell P, Edwards A, McCarthy WH, Harris R, et al. Clearance rates and systemic effects of intravenously administered interleukin 2 (IL-2) containing preparations in human subjects. Br J Cancer (1983) 47:123-33. doi:10.1038/bjc.1983.15
7. Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA (1994) 271:907-13. doi:10.1001/jama.1994.03510360033032
8. Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol (2003) 21:3127-32. doi:10.1200/JCO.2003.02.122
9. Alric L, Thebault S, Peron JM, Balard P, Metivier S, Pipy B, et al. Pilot study of interferon-alpha-ribavirin-interleukin-2 for treatment of nonresponder patients with severe liver disease infected by hepatitis C virus genotype 1. J Viral Hepat (2006) 13:139-44. doi:10.1111/j.1365-2893.2005.00694.x
10. Grinberg-Bleyer Y, Baeyens A, You S, Elhage R, Fourcade G, Gregoire S, et al. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J Exp Med (2010) 207:1871-8. doi:10.1084/jem.20100209
11. Ohl K, Wiener A, Schippers A, Wagner N, Tenbrock K. Interleukin-2 treatment reverses effects of cAMP-responsive element modulator alpha-over-expressing T cells in autoimmune-prone mice. Clin Exp Immunol (2015) 181:76-86. doi:10.1111/cei.12629
12. Pilon CB, Petillon S, Naserian S, Martin GH, Badoual C, Lang P, et al. Administration of low doses of IL-2 combined to rapamycin promotes allogeneic skin graft survival in mice. Am J Transplant (2014) 14:2874-82. doi:10.1111/ajt.12944
13. Rabinovitch A, Suarez-Pinzon WL, Shapiro AM, Rajotte RV, Power R. Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice. Diabetes (2002) 51:638-45. doi:10.2337/diabetes.51.3.638
14. Tang Q, Adams JY, Penaranda C, Melli K, Piaggio E, Sgouroudis E, et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity (2008) 28:687-97. doi:10.1016/j.immuni.2008.03.016
15. Hartemann A, Bensimon G, Payan CA, Jacqueminet S, Bourron O, Nicolas N, et al. Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol (2013) 1:295-305. doi:10.1016/S2213-8587(13)70113-X
16. Rosenzwajg M, Churlaud G, Mallone R, Six A, Derian N, Chaara W, et al. Low-dose interleukin-2 fosters a dose-dependent regulatory T cell tuned milieu in T1D patients. J Autoimmun (2015) 58:48-58. doi:10.1016/j.jaut.2015.01.001
17. Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med (2011) 365:2067-77. doi:10.1056/NEJMoa1105143. Correction: N Engl J Med (2014) 370:786.
18. Humrich JY, von Spee-Mayer C, Siegert E, Alexander T, Hiepe F, Radbruch A, et al. Rapid induction of clinical remission by low-dose interleukin-2 in a patient with refractory SLE. Ann Rheum Dis (2015) 74:791-2. doi:10.1136/annrheumdis-2014-206506
19. Matsuoka K, Koreth J, Kim HT, Bascug G, McDonough S, Kawano Y, et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med (2013) 5:179ra43. doi:10.1126/scitranslmed.3005265
20. Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP III, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med (2011) 365:2055-66. doi:10.1056/NEJMoa1108188
21. Castela E, Le DF, Butori C, Ticchioni M, Hofman P, Bahadoran P, et al. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol (2014) 150:748-51. doi:10.1001/jamadermatol.2014.504
22. Ludvigsson J, Cheramy M, Axelsson S, Pihl M, Akerman L, Casas R. GAD-treatment of children and adolescents with recent-onset type 1 diabetes preserves residual insulin secretion after 30 months. Diabetes Metab Res Rev (2014) 30:405-14. doi:10.1002/dmrr.2503
23. Pozzilli P, Crino A, Schiaffini R, Manfrini S, Fioriti E, Coppolino G, et al. A 2-year pilot trial of continuous subcutaneous insulin infusion versus intensive insulin therapy in patients with newly diagnosed type 1 diabetes (IMDIAB 8). Diabetes Technol Ther (2003) 5:965-74. doi:10.1089/152091503322641006
24. Skyler JS, Krischer JP, Wolfsdorf J, Cowie C, Palmer JP, Greenbaum C, et al. Effects of oral insulin in relatives of patients with type 1 diabetes: the diabetes prevention trial-type 1. Diabetes Care (2005) 28:1068-76. doi:10.2337/diacare.28.5.1068
25. 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) 32:2036-40. doi:10.2337/dc09-0449
26. von Herrath MG, Korsgren O, Atkinson MA. Factors impeding the discovery of an intervention-based treatment for type 1 diabetes. Clin Exp Immunol (2015). doi:10.1111/cei.12656
27. Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, et al. Structure and expression of a cloned cDNA for human interleukin-2. 1983. Biotechnology (1992) 24:304-9.
28. Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol (2012) 12:180-90. doi:10.1038/nri3156
29. Powell JD, Ragheb JA, Kitagawa-Sakakida S, Schwartz RH. Molecular regulation of interleukin-2 expression by CD28 co-stimulation and anergy. Immunol Rev (1998) 165:287-300. doi:10.1111/j.1600-065X.1998.tb01246.x
30. Cheng LE, Ohlen C, Nelson BH, Greenberg PD. Enhanced signaling through the IL-2 receptor in CD8+ T cells regulated by antigen recognition results in preferential proliferation and expansion of responding CD8+ T cells rather than promotion of cell death. Proc Natl Acad Sci U S A (2002) 99:3001-6. doi:10.1073/pnas.052676899
31. Malek TR, Castro I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity (2010) 33:153-65. doi:10.1016/j.immuni.2010.08.004
32. Rickert M, Boulanger MJ, Goriatcheva N, Garcia KC. Compensatory energetic mechanisms mediating the assembly of signaling complexes between interleukin-2 and its alpha, beta, and gamma(c) receptors. J Mol Biol (2004) 339:1115-28. doi:10.1016/j.jmb.2004.04.038
33. Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA. Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A (2006) 103:2788-93. doi:10.1073/pnas.0511161103
34. Wang X, Rickert M, Garcia KC. Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors. Science (2005) 310:1159-63. doi:10.1126/science.1117893
35. Friedmann MC, Migone TS, Russell SM, Leonard WJ. Different interleukin 2 receptor beta-chain tyrosines couple to at least two signaling pathways and synergistically mediate interleukin 2-induced proliferation. Proc Natl Acad Sci U S A (1996) 93:2077-82. doi:10.1073/pnas.93.5.2077
36. Wuest TY, Willette-Brown J, Durum SK, Hurwitz AA. The influence of IL-2 family cytokines on activation and function of naturally occurring regulatory T cells. J Leukoc Biol (2008) 84:973-80. doi:10.1189/jlb.1107778
37. Sadlack B, Lohler J, Schorle H, Klebb G, Haber H, Sickel E, et al. Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur J Immunol (1995) 25:3053-9. doi:10.1002/eji.1830251111
38. Suzuki H, Kundig TM, Furlonger C, Wakeham A, Timms E, Matsuyama T, et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science (1995) 268:1472-6. doi:10.1126/science.7770771
39. Thornton AM, Donovan EE, Piccirillo CA, Shevach EM. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J Immunol (2004) 172:6519-23. doi:10.4049/jimmunol.172.11.6519
40. Todd JA. Etiology of type 1 diabetes. Immunity (2010) 32:457-67. doi:10.1016/j.immuni.2010.04.001
41. Garg G, Tyler JR, Yang JH, Cutler AJ, Downes K, Pekalski M, et al. Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function. J Immunol (2012) 188:4644-53. doi:10.4049/jimmunol.1100272
42. Hulme MA, Wasserfall CH, Atkinson MA, Brusko TM. Central role for interleukin-2 in type 1 diabetes. Diabetes (2012) 61:14-22. doi:10.2337/db11-1213
43. Kitas GD, Salmon M, Farr M, Gaston JS, Bacon PA. Deficient interleukin 2 production in rheumatoid arthritis: association with active disease and systemic complications. Clin Exp Immunol (1988) 73:242-9.
44. Lieberman LA, Tsokos GC. The IL-2 defect in systemic lupus erythematosus disease has an expansive effect on host immunity. J Biomed Biotechnol (2010) 2010:740619. doi:10.1155/2010/740619
45. Linker-Israeli M, Bakke AC, Kitridou RC, Gendler S, Gillis S, Horwitz DA. Defective production of interleukin 1 and interleukin 2 in patients with systemic lupus erythematosus (SLE). J Immunol (1983) 130:2651-5.
46. Plagnol V, Howson JM, Smyth DJ, Walker N, Hafler JP, Wallace C, et al. Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases. PLoS Genet (2011) 7:e1002216. doi:10.1371/journal.pgen.1002216
47. Chen Q, Kim YC, Laurence A, Punkosdy GA, Shevach EM. IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3+ T cells in vivo. J Immunol (2011) 186:6329-37. doi:10.4049/jimmunol.1100061
48. Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med (1985) 313:1485-92. doi:10.1056/NEJM198512053132327
49. Lentsch AB, Miller FN, Edwards MJ. Mechanisms of leukocyte-mediated tissue injury induced by interleukin-2. Cancer Immunol Immunother (1999) 47:243-8. doi:10.1007/s002620050527
50. Mitra S, Ring AM, Amarnath S, Spangler JB, Li P, Ju W, et al. Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps. Immunity (2015) 42:826-38. doi:10.1016/j.immuni.2015.04.018
51. Spangler JB, Tomala J, Luca VC, Jude KM, Dong S, Ring AM, et al. Antibodies to interleukin-2 elicit selective T cell subset potentiation through distinct conformational mechanisms. Immunity (2015) 42:815-25. doi:10.1016/j.immuni.2015.04.015
52. Churlaud G, Jimenez V, Ruberte J, Amadoudji ZM, Fourcade G, Gottrand G, et al. Sustained stimulation and expansion of Tregs by IL2 control autoimmunity without impairing immune responses to infection, vaccination and cancer. Clin Immunol (2014) 151:114-26. doi:10.1016/j.clim.2014.02.003
53. Long SA, Rieck M, Sanda S, Bollyky JB, Samuels PL, Goland R, et al. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function. Diabetes (2012) 61:2340-8. doi:10.2337/db12-0049
54. Luczynski W, Wawrusiewicz-Kurylonek N, Stasiak-Barmuta A, Urban R, Ilendo E, Urban M, et al. Diminished expression of ICOS, GITR and CTLA-4 at the mRNA level in T regulatory cells of children with newly diagnosed type 1 diabetes. Acta Biochim Pol (2009) 56(2):361-70.
55. Schlaak JF, Schramm C, Radecke K, Zum Buschenfelde KH, Gerken G. Sustained suppression of HCV replication and inflammatory activity after interleukin-2 therapy in patients with HIV/hepatitis C virus coinfection. J Acquir Immune Defic Syndr (2002) 29:145-8. doi:10.1097/00042560-200202010-00006
56. Velilla PA, Shata MT, Lages CS, Ying J, Fichtenbaum CJ, Chougnet C. Effect of low-dose IL-2 immunotherapy on frequency and phenotype of regulatory T cells and NK cells in HIV/HCV-coinfected patients. AIDS Res Hum Retroviruses (2008) 24:52-61. doi:10.1089/aid.2007.0180
57. Kennedy-Nasser AA, Ku S, Castillo-Caro P, Hazrat Y, Wu MF, Liu H, et al. Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory T cells without diminishing antiviral and antileukemic activity. Clin Cancer Res (2014) 20:2215-25. doi:10.1158/1078-0432.CCR-13-3205
58. Gilhar A, Etzioni A, Paus R. Alopecia areata. N Engl J Med (2012) 366:1515-25. doi:10.1056/NEJMra1103442
59. Gilhar A, Shalaginov R, Assy B, Serafimovich S, Kalish RS. Alopecia areata is a T-lymphocyte mediated autoimmune disease: lesional human T-lymphocytes transfer alopecia areata to human skin grafts on SCID mice. J Investig Dermatol Symp Proc (1999) 4:207-10. doi:10.1038/sj.jidsp.5640212
60. Han YM, Sheng YY, Xu F, Qi SS, Liu XJ, Hu RM, et al. Imbalance of T-helper 17 and regulatory T cells in patients with alopecia areata. J Dermatol (2015) 42(10):981-8. doi:10.1111/1346-8138.12978
61. Tang Q. Therapeutic window of interleukin-2 for autoimmune diseases. Diabetes (2015) 64:1912-3. doi:10.2337/db15-0188
62. Yu A, Snowhite I, Vendrame F, Rosenzwajg M, Klatzmann D, Pugliese A, et al. Selective IL-2 responsiveness of regulatory T cells through multiple intrinsic mechanisms supports the use of low-dose IL-2 therapy in type 1 diabetes. Diabetes (2015) 64:2172-83. doi:10.2337/db14-1322
63. Kosmaczewska A. Low-dose interlekin-2 therapy: a driver of an imbalance between immune tolerance and autoimmunity. Int J Mol Sci (2014) 15(10):18574-92. doi:10.3390/ijms151018574
64. Harrison LC, Wentworth JM, Zhang Y, Bandala-Sanchez E, Bohmer RM, Neale AM, et al. Antigen-based vaccination and prevention of type 1 diabetes. Curr Diab Rep (2013) 13:616-23. doi:10.1007/s11892-013-0415-7
65. Peakman M, von HM. Antigen-specific immunotherapy for type 1 diabetes: maximizing the potential. Diabetes (2010) 59:2087-93. doi:10.2337/db10-0630
66. Sarikonda G, Sachithanantham S, Manenkova Y, Kupfer T, Posgai A, Wasserfall C, et al. Transient B-cell depletion with anti-CD20 in combination with proinsulin DNA vaccine or oral insulin: immunologic effects and efficacy in NOD mice. PLoS One (2013) 8:e54712. doi:10.1371/journal.pone.0054712
67. Diabetes Prevention Trial-Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med (2002) 346(22):1685-91. doi:10.1056/NEJMoa012350
68. Nanto-Salonen K, Kupila A, Simell S, Siljander H, Salonsaari T, Hekkala A, 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) 372:1746-55. doi:10.1016/S0140-6736(08)61309-4
69. Thrower SL, James L, Hall W, Green KM, Arif S, Allen JS, et al. Proinsulin peptide immunotherapy in type 1 diabetes: report of a first-in-man phase I safety study. Clin Exp Immunol (2009) 155:156-65. doi:10.1111/j.1365-2249.2008.03814.x
70. Bonifacio E, Ziegler AG, Klingensmith G, Schober E, Bingley PJ, Rottenkolber M, et al. Effects of high-dose oral insulin on immune responses in children at high risk for type 1 diabetes: the Pre-POINT randomized clinical trial. JAMA (2015) 313:1541-9. doi:10.1001/jama.2015.2928
71. 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):269-75. doi:10.1002/dmrr.691
72. Huurman VA, van der Meide PE, Duinkerken G, Willemen S, Cohen IR, Elias D, et al. Immunological efficacy of heat shock protein 60 peptide DiaPep277 therapy in clinical type I diabetes. Clin Exp Immunol (2008) 152(3):488-97. doi:10.1111/j.1365-2249.2008.03656.x
73. 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):1749-53. doi:10.1016/S0140-6736(01)06801-5
74. Axelsson S, Hjorth M, Akerman L, Ludvigsson J, Casas R. Early induction of GAD(65)-reactive Th2 response in type 1 diabetic children treated with alum-formulated GAD(65). Diabetes Metab Res Rev (2010) 26(7):559-68. doi:10.1002/dmrr.1126
75. Ludvigsson J, Krisky D, Casas R, Battelino T, Castaño L, Greening J, et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N Engl J Med (2012) 366(5):433-42. doi:10.1056/NEJMoa1107096
76. Hjorth M, Axelsson S, Rydén A, Faresjö M, Ludvigsson J, Casas R. GAD-alum treatment induces GAD65-specific CD4+CD25highFOXP3+ cells in type 1 diabetic patients. Clin Immunol (2011) 138(1):117-26. doi:10.1016/j.clim.2010.10.004
77. Ryden AK, Wesley JD, Coppieters KT, Von Herrath MG. Non-antigenic and antigenic interventions in type 1 diabetes. Hum Vaccin Immunother (2014) 10:838-46. doi:10.4161/hv.26890
78. Bollyky JB, Xu P, Butte AJ, Wilson DM, Beam CA, Greenbaum CJ. Heterogeneity in recent-onset type 1 diabetes-a clinical trial perspective. Diabetes Metab Res Rev (2015) 31:588-94. doi:10.1002/dmrr.2643
79. Greenbaum CJ, Beam CA, Boulware D, Gitelman SE, Gottlieb PA, Herold KC, et al. Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite Type 1 Diabetes TrialNet data. Diabetes (2012) 61:2066-73. doi:10.2337/db11-1538
80. Lachin JM, McGee P, Palmer JP. Impact of C-peptide preservation on metabolic and clinical outcomes in the diabetes control and complications trial. Diabetes (2014) 63:739-48. doi:10.2337/db13-0881
81. Eisenbarth GS. Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med (1986) 314(21):1360-8. doi:10.1056/NEJM198605223142106
82. Campbell-Thompson ML, Kaddis JS, Wasserfall C, Haller MJ, Pugliese A, Schatz DA, et al. The influence of type 1 diabetes on pancreatic weight. Diabetologia (2016) 59(1):217-21. doi:10.1007/s00125-015-3752-z
83. Purohit S, She JX. Biomarkers for type 1 diabetes. Int J Clin Exp Med (2008) 1(2):98-116.
84. Rekers NV, von Herrath MG, Wesley JD. Immunotherapies and immune biomarkers in Type 1 diabetes: a partnership for success. Clin Immunol (2015) 161(1):37-43. doi:10.1016/j.clim.2015.05.021
85. Tooley JE, Herold KC. Biomarkers in type 1 diabetes: application to the clinical trial setting. Curr Opin Endocrinol Diabetes Obes (2014) 21:287-92. doi:10.1097/MED.0000000000000076
86. Odegard JM, Nepom GT, Wambre E. Biomarkers for antigen immunotherapy in allergy and type 1 diabetes. Clin Immunol (2015) 161(1):44-50. doi:10.1016/j.clim.2015.05.023