REFERENCES

1. Gillespie KM. Type 1 diabetes: pathogenesis and prevention. CMAJ. 2006;175:165-70.

2. Norris JM, Johnson RK, Stene LC. Type 1 diabetes-early life origins and changing epidemiology. Lancet Diabetes Endocrinol. 2020;8:226-38.

3. Gregory GA, Robinson TIG, Linklater SE, et al; International Diabetes Federation Diabetes Atlas Type 1 Diabetes in Adults Special Interest Group. Global incidence, prevalence, and mortality of type 1 diabetes in 2021 with projection to 2040: a modelling study. Lancet Diabetes Endocrinol. 2022;10:741-60.

4. World Obesity Federation. World Obesity Atlas 2023. Available from: https://www.aafp.org/pubs/afp/issues/2018/0801/p154.html. [Last accessed on 26 Mar 2025].

5. Riddell MC, Peters AL. Exercise in adults with type 1 diabetes mellitus. Nat Rev Endocrinol. 2023;19:98-111.

6. Holt RIG, DeVries JH, Hess-Fischl A, et al. The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2021;64:2609-52.

7. Lind M, Svensson AM, Kosiborod M, et al. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med. 2014;371:1972-82.

8. Hughes JW, Riddlesworth TD, DiMeglio LA, Miller KM, Rickels MR, McGill JB; T1D Exchange Clinic Network. Autoimmune diseases in children and adults with type 1 diabetes from the T1D exchange clinic registry. J Clin Endocrinol Metab. 2016;101:4931-7.

9. Milluzzo A, Falorni A, Brozzetti A, et al. Risk for coexistent autoimmune diseases in familial and sporadic type 1 diabetes is related to age at diabetes onset. Endocr Pract. 2021;27:110-7.

10. Hughes JW, Bao YK, Salam M, et al. Late-onset T1DM and older age predict risk of additional autoimmune disease. Diabetes Care. 2019;42:32-8.

11. Diabetes Association Professional Practice Committee. 2. Diagnosis and classification of diabetes: standards of care in diabetes-2024. Diabetes Care. 2024;47:S20-42.

12. Bluestone JA, Buckner JH, Herold KC. Immunotherapy: building a bridge to a cure for type 1 diabetes. Science. 2021;373:510-6.

13. Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature. 2010;464:1293-300.

14. Wagner DH Jr. Overlooked mechanisms in type 1 diabetes etiology: how unique costimulatory molecules contribute to diabetogenesis. Front Endocrinol. 2017;8:208.

15. Goswami TK, Singh M, Dhawan M, et al. Regulatory T cells (Tregs) and their therapeutic potential against autoimmune disorders - advances and challenges. Hum Vaccin Immunother. 2022;18:2035117.

16. Brusko TM, Wasserfall CH, Clare-Salzler MJ, Schatz DA, Atkinson MA. Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes. Diabetes. 2005;54:1407-14.

17. Burrack AL, Martinov T, Fife BT. T cell-mediated beta cell destruction: autoimmunity and alloimmunity in the context of type 1 diabetes. Front Endocrinol. 2017;8:343.

18. Pinheiro MM, Pinheiro FMM, Garo ML, et al. Prevention and treatment of type 1 diabetes: in search of the ideal combination therapy targeting multiple immunometabolic pathways. Metab Target Organ Damage. 2024;4:19.

19. Bettini M, Bettini ML. Function, failure, and the future potential of tregs in type 1 diabetes. Diabetes. 2021;70:1211-9.

20. Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature. 1953;172:603-6.

21. Weigle W, Mitchison N. Immunological tolerance. Progress in immunology. Elsevier; 1971. pp. 1467-70.

22. Sullivan JA, AlAdra DP, Olson BM, McNeel DG, Burlingham WJ. Infectious tolerance as seen with 2020 vision: the role of IL-35 and extracellular vesicles. Front Immunol. 2020;11:1867.

23. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057-61.

24. Zhao H, Liao X, Kang Y. Tregs: where we are and what comes next? Front Immunol. 2017;8:1578.

25. Georgiev P, Charbonnier LM, Chatila TA. Regulatory T cells: the many faces of Foxp3. J Clin Immunol. 2019;39:623-40.

26. Baecher-Allan C, Viglietta V, Hafler DA. Human CD4+CD25+ regulatory T cells. Semin Immunol. 2004;16:89-98.

27. Thornton AM, Korty PE, Tran DQ, et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol. 2010;184:3433-41.

28. Su H, Longhi MS, Wang P, Vergani D, Ma Y. Human CD4+CD25highCD127low/neg regulatory T cells. In: Mitry RR, Hughes RD, Editors. Human cell culture protocols. Totowa: Humana Press; 2012. pp. 287-99.

29. Dai Z, Zhang S, Xie Q, et al. Natural CD8+CD122+ T cells are more potent in suppression of allograft rejection than CD4+CD25+ regulatory T cells. Am J Transplant. 2014;14:39-48.

30. Yadav M, Louvet C, Davini D, et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med. 2012;209:1713-22, S1.

31. Cai J, Wang D, Zhang G, Guo X. The role of PD-1/PD-L1 axis in Treg development and function: implications for cancer immunotherapy. Onco Targets Ther. 2019;12:8437-45.

32. Huang CT, Workman CJ, Flies D, et al. Role of LAG-3 in regulatory T cells. Immunity. 2004;21:503-13.

33. Schmitt EG, Williams CB. Generation and function of induced regulatory T cells. Front Immunol. 2013;4:152.

34. Workman CJ, Szymczak-Workman AL, Collison LW, Pillai MR, Vignali DA. The development and function of regulatory T cells. Cell Mol Life Sci. 2009;66:2603-22.

35. Shevach EM, Thornton AM. tTregs, pTregs, and iTregs: similarities and differences. Immunol Rev. 2014;259:88-102.

36. Shevach EM, Tran DQ, Davidson TS, Andersson J. The critical contribution of TGF-beta to the induction of Foxp3 expression and regulatory T cell function. Eur J Immunol. 2008;38:915-7.

37. Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of treg-mediated T cell suppression. Front Immunol. 2012;3:51.

38. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383:69-82.

39. Ikegami H, Noso S, Babaya N, Kawabata Y. Genetics and pathogenesis of type 1 diabetes: prospects for prevention and intervention. J Diabetes Investig. 2011;2:415-20.

40. Rewers M, Ludvigsson J. Environmental risk factors for type 1 diabetes. Lancet. 2016;387:2340-8.

41. Diabetes Care 2018. pp. 1887-94. Redondo MJ, Geyer S, Steck AK, et al; Type 1 Diabetes TrialNet Study Group. A type 1 diabetes genetic risk score predicts progression of islet autoimmunity and development of type 1 diabetes in individuals at risk. Diabetes Care. 2018;41:1887-94.

42. Klak M, Gomółka M, Kowalska P, et al. Type 1 diabetes: genes associated with disease development. Cent Eur J Immunol. 2020;45:439-53.

43. Morran MP, Vonberg A, Khadra A, Pietropaolo M. Immunogenetics of type 1 diabetes mellitus. Mol Aspects Med. 2015;42:42-60.

44. Lehuen A, Diana J, Zaccone P, Cooke A. Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol. 2010;10:501-13.

45. Scherm MG, Wyatt RC, Serr I, Anz D, Richardson SJ, Daniel C. Beta cell and immune cell interactions in autoimmune type 1 diabetes: how they meet and talk to each other. Mol Metab. 2022;64:101565.

46. Roep BO. The role of T-cells in the pathogenesis of Type 1 diabetes: from cause to cure. Diabetologia. 2003;46:305-21.

47. Ilonen J, Lempainen J, Veijola R. The heterogeneous pathogenesis of type 1 diabetes mellitus. Nat Rev Endocrinol. 2019;15:635-50.

48. Leete P, Willcox A, Krogvold L, et al. Differential insulitic profiles determine the extent of β-cell destruction and the age at onset of type 1 diabetes. Diabetes. 2016;65:1362-9.

49. Li Y, Liu Y, Chu CQ. Th17 cells in type 1 diabetes: role in the pathogenesis and regulation by gut microbiome. Mediators Inflamm. 2015;2015:638470.

50. Walker LS, von Herrath M. CD4 T cell differentiation in type 1 diabetes. Clin Exp Immunol. 2016;183:16-29.

51. Smith MJ, Cambier JC, Gottlieb PA. Endotypes in T1D: B lymphocytes and early onset. Curr Opin Endocrinol Diabetes Obes. 2020;27:225-30.

52. Wong FS, Wen L. B cells in autoimmune diabetes. Rev Diabet Stud. 2005;2:121-35.

53. Zóka A, Műzes G, Somogyi A, et al. Altered immune regulation in type 1 diabetes. Clin Dev Immunol. 2013;2013:254874.

54. Okubo Y, Torrey H, Butterworth J, Zheng H, Faustman DL. Treg activation defect in type 1 diabetes: correction with TNFR2 agonism. Clin Transl Immunology. 2016;5:e56.

55. Hull CM, Peakman M, Tree TIM. Regulatory T cell dysfunction in type 1 diabetes: what’s broken and how can we fix it? Diabetologia. 2017;60:1839-50.

56. Belle TL, Coppieters KT, von Herrath MG. Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev. 2011;91:79-118.

57. Visperas A, Vignali DA. Are regulatory T cells defective in type 1 diabetes and can we fix them? J Immunol. 2016;197:3762-70.

58. Greenbaum CJ, Speake C, Krischer J, et al. Strength in numbers: opportunities for enhancing the development of effective treatments for type 1 diabetes-the TrialNet experience. Diabetes. 2018;67:1216-25.

59. Li Z, Li D, Tsun A, Li B. FOXP3+ regulatory T cells and their functional regulation. Cell Mol Immunol. 2015;12:558-65.

60. Baecher-Allan CM, Hafler DA. The purification and functional analysis of human CD4+CD25high regulatory T cells. Curr Protoc Immunol. 2006;Chapter 7:7.4B.1-12.

61. Devaud C, Darcy PK, Kershaw MH. Foxp3 expression in T regulatory cells and other cell lineages. Cancer Immunol Immunother. 2014;63:869-76.

62. Caramalho Í, Nunes-Cabaço H, Foxall RB, Sousa AE. Regulatory T-cell development in the human thymus. Front Immunol. 2015;6:395.

63. Harris F, Berdugo YA, Tree T. IL-2-based approaches to Treg enhancement. Clin Exp Immunol. 2023;211:149-63.

64. Busse D, de la Rosa M, Hobiger K, et al. Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments. Proc Natl Acad Sci U S A. 2010;107:3058-63.

65. Park JH, Lee KH, Jeon B, et al. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: a systematic review. Autoimmun Rev. 2020;19:102526.

66. Gao X, Liu H, Ding G, et al. Complement C3 deficiency prevent against the onset of streptozotocin-induced autoimmune diabetes involving expansion of regulatory T cells. Clin Immunol. 2011;140:236-43.

67. Mathisen AF, Vacaru AM, Unger L, et al. Molecular profiling of NOD mouse islets reveals a novel regulator of insulitis onset. Sci Rep. 2024;14:14669.

68. Grinberg-Bleyer Y, Baeyens A, You 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.

69. D’Alise AM, Auyeung V, Feuerer M, et al. The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors. Proc Natl Acad Sci U S A. 2008;105:19857-62.

70. Zhao Y, Lin B, Darflinger R, Zhang Y, Holterman MJ, Skidgel RA. Human cord blood stem cell-modulated regulatory T lymphocytes reverse the autoimmune-caused type 1 diabetes in nonobese diabetic (NOD) mice. PLoS One. 2009;4:e4226.

71. Tarbell KV, Petit L, Zuo X, et al. Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med. 2007;204:191-201.

72. Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM. CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med. 2004;199:1467-77.

73. Cheatem D, Ganesh BB, Gangi E, Vasu C, Prabhakar BS. Modulation of dendritic cells using granulocyte-macrophage colony-stimulating factor (GM-CSF) delays type 1 diabetes by enhancing CD4+CD25+ regulatory T cell function. Clin Immunol. 2009;131:260-70.

74. Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI. Defective suppressor function in CD4+CD25+ T-cells from patients with type 1 diabetes. Diabetes. 2005;54:92-9.

75. Haseda F, Imagawa A, Murase-Mishiba Y, Terasaki J, Hanafusa T. CD4+ CD45RA- FoxP3high activated regulatory T cells are functionally impaired and related to residual insulin-secreting capacity in patients with type 1 diabetes. Clin Exp Immunol. 2013;173:207-16.

76. Glisic-Milosavljevic S, Wang T, Koppen M, et al. Dynamic changes in CD4+ CD25+high T cell apoptosis after the diagnosis of type 1 diabetes. Clin Exp Immunol. 2007;150:75-82.

77. Glisic-Milosavljevic S, Waukau J, Jailwala P, et al. At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD4+CD25+ T-cell fraction. PLoS One. 2007;2:e146.

78. Long SA, Cerosaletti K, Bollyky PL, et al. Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4+CD25+ regulatory T-cells of type 1 diabetic subjects. Diabetes. 2010;59:407-15.

79. Garg G, Tyler JR, Yang JH, 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.

80. McClymont SA, Putnam AL, Lee MR, et al. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J Immunol. 2011;186:3918-26.

81. Marwaha AK, Crome SQ, Panagiotopoulos C, et al. Cutting edge: increased IL-17-secreting T cells in children with new-onset type 1 diabetes. J Immunol. 2010;185:3814-8.

82. Huang Q, Zhu J. Regulatory T cell-based therapy in type 1 diabetes: latest breakthroughs and evidence. Int Immunopharmacol. 2024;140:112724.

83. Ghobadinezhad F, Ebrahimi N, Mozaffari F, et al. The emerging role of regulatory cell-based therapy in autoimmune disease. Front Immunol. 2022;13:1075813.

84. Longhi MS, Mieli-Vergani G, Vergani D. Regulatory T cells in autoimmune hepatitis: an updated overview. J Autoimmun. 2021;119:102619.

85. Oo YH, Ackrill S, Cole R, et al. Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis. JHEP Rep. 2019;1:286-96.

86. de Picciotto S, DeVita N, Hsiao CJ, et al. Selective activation and expansion of regulatory T cells using lipid encapsulated mRNA encoding a long-acting IL-2 mutein. Nat Commun. 2022;13:3866.

87. Strauss L, Whiteside TL, Knights A, Bergmann C, Knuth A, Zippelius A. Selective survival of naturally occurring human CD4+CD25+Foxp3+ regulatory T cells cultured with rapamycin. J Immunol. 2007;178:320-9.

88. Baron KJ, Turnquist HR. Clinical manufacturing of regulatory T cell products for adoptive cell therapy and strategies to improve therapeutic efficacy. Organogenesis. 2023;19:2164159.

89. Telford WG. Flow cytometry and cell sorting. Front Med. 2023;10:1287884.

90. Trzonkowski P, Bacchetta R, Battaglia M, et al. Hurdles in therapy with regulatory T cells. Sci Transl Med. 2015;7:304ps18.

91. Duggleby R, Danby RD, Madrigal JA, Saudemont A. Clinical grade regulatory CD4+ T cells (Tregs): moving toward cellular-based immunomodulatory therapies. Front Immunol. 2018;9:252.

92. Fraser H, Safinia N, Grageda N, et al. A rapamycin-based GMP-compatible process for the isolation and expansion of regulatory T cells for clinical trials. Mol Ther Methods Clin Dev. 2018;8:198-209.

93. Janssens I, Cools N. Regulating the regulators: is introduction of an antigen-specific approach in regulatory T cells the next step to treat autoimmunity? Cell Immunol. 2020;358:104236.

94. Amini L, Kaeda J, Fritsche E, Roemhild A, Kaiser D, Reinke P. Clinical adoptive regulatory T cell therapy: state of the art, challenges, and prospective. Front Cell Dev Biol. 2022;10:1081644.

95. Bluestone JA, Buckner JH, Fitch M, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015;7:315ra189.

96. Uenishi GI, Repic M, Yam JY, et al. GNTI-122: an autologous antigen-specific engineered Treg cell therapy for type 1 diabetes. JCI Insight. 2024;9:e171844.

97. Liston A, Gray DH. Homeostatic control of regulatory T cell diversity. Nat Rev Immunol. 2014;14:154-65.

98. Amini L, Greig J, Schmueck-Henneresse M, et al. Super-Treg: toward a new era of adoptive treg therapy enabled by genetic modifications. Front Immunol. 2020;11:611638.

99. Cabrera SM, Rigby MR, Mirmira RG. Targeting regulatory T cells in the treatment of type 1 diabetes mellitus. Curr Mol Med. 2012;12:1261-72.

100. Ballou LM, Lin RZ. Rapamycin and mTOR kinase inhibitors. J Chem Biol. 2008;1:27-36.

101. Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol. 2006;177:8338-47.

102. Monti P, Scirpoli M, Maffi P, et al. Rapamycin monotherapy in patients with type 1 diabetes modifies CD4+CD25+FOXP3+ regulatory T-cells. Diabetes. 2008;57:2341-7.

103. Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346:1692-8.

104. Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005;352:2598-608.

105. Herold KC, Bundy BN, Long SA, et al; Type 1 Diabetes TrialNet Study Group. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N Engl J Med. 2019;381:603-13.

106. Sims EK, Bundy BN, Stier K, et al; Type 1 Diabetes TrialNet Study Group. Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Sci Transl Med. 2021;13:eabc8980.

107. Evans-Molina C, Oram RA. Teplizumab approval for type 1 diabetes in the USA. Lancet Diabetes Endocrinol. 2023;11:76-7.

108. Kokori E, Olatunji G, Ogieuhi IJ, et al. Teplizumab’s immunomodulatory effects on pancreatic β-cell function in type 1 diabetes mellitus. Clin Diabetes Endocrinol. 2024;10:23.

109. Sims EK, Besser REJ, Dayan C, et al; NIDDK Type 1 Diabetes TrialNet Study Group. Screening for type 1 diabetes in the general population: a status report and perspective. Diabetes. 2022;71:610-23.

110. Mital S, Nguyen HV. Cost effectiveness of teplizumab for prevention of type 1 diabetes among different target patient groups. Pharmacoeconomics. 2020;38:1359-72.

111. Fanaropoulou NM, Tsatsani GC, Koufakis T, Kotsa K. Teplizumab: promises and challenges of a recently approved monoclonal antibody for the prevention of type 1 diabetes or preservation of residual beta cell function. Expert Rev Clin Immunol. 2024;20:185-96.

112. Ludvigsson J, Faresjö M, Hjorth M, et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med. 2008;359:1909-20.

113. Ludvigsson J. Autoantigen treatment in type 1 diabetes: unsolved questions on how to select autoantigen and administration route. Int J Mol Sci. 2020;21:1598.

114. 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;138:117-26.

115. Hodak E, David M. Alefacept: a review of the literature and practical guidelines for management. Dermatol Ther. 2004;17:383-92.

116. Krueger GG. Selective targeting of T cell subsets: focus on alefacept - a remittive therapy for psoriasis. Expert Opin Biol Ther. 2002;2:431-41.

117. Chamian F, Lin SL, Lee E, et al. Alefacept (anti-CD2) causes a selective reduction in circulating effector memory T cells (Tem) and relative preservation of central memory T cells (Tcm) in psoriasis. J Transl Med. 2007;5:27.

118. Rigby MR, Harris KM, Pinckney A, et al. Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. J Clin Invest. 2015;125:3285-96.

119. Yamanouchi J, Rainbow D, Serra P, et al. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat Genet. 2007;39:329-37.

120. Dendrou CA, Wicker LS. The IL-2/CD25 pathway determines susceptibility to T1D in humans and NOD mice. J Clin Immunol. 2008;28:685-96.

121. Rosenzwajg M, Salet R, Lorenzon R, et al. Low-dose IL-2 in children with recently diagnosed type 1 diabetes: a Phase I/II randomised, double-blind, placebo-controlled, dose-finding study. Diabetologia. 2020;63:1808-21.

122. Gonçalves GAR, Paiva RMA. Gene therapy: advances, challenges and perspectives. Einstein. 2017;15:369-75.

123. Chellappan DK, Sivam NS, Teoh KX, et al. Gene therapy and type 1 diabetes mellitus. Biomed Pharmacother. 2018;108:1188-200.

124. Srinivasan M, Thangaraj SR, Arzoun H. Gene therapy - can it cure type 1 diabetes? Cureus. 2021;13:e20516.

125. Lin Y, Sun Z. Antiaging gene Klotho attenuates pancreatic β-cell apoptosis in type 1 diabetes. Diabetes. 2015;64:4298-311.

126. Xu A, Zhu W, Li T, et al. Interleukin-10 gene transfer into insulin-producing β cells protects against diabetes in non-obese diabetic mice. Mol Med Rep. 2015;12:3881-9.

127. Tuomela K, Levings MK. Genetic engineering of regulatory T cells for treatment of autoimmune disorders including type 1 diabetes. Diabetologia. 2024;67:611-22.

128. Li D, Zhao B, Luo Y, et al. Transplantation of Aire-overexpressing bone marrow-derived dendritic cells delays the onset of type 1 diabetes. Int Immunopharmacol. 2017;49:13-20.

129. Johnson MC, Wang B, Tisch R. Genetic vaccination for re-establishing T-cell tolerance in type 1 diabetes. Hum Vaccin. 2011;7:27-36.

130. Shigihara T, Shimada A, Oikawa Y, et al. CXCL10 DNA vaccination prevents spontaneous diabetes through enhanced beta cell proliferation in NOD mice. J Immunol. 2005;175:8401-8.

131. Xia F, Cao H, Du J, Liu X, Liu Y, Xiang M. Reg3g overexpression promotes β cell regeneration and induces immune tolerance in nonobese-diabetic mouse model. J Leukoc Biol. 2016;99:1131-40.

132. Skyler JS. Hope vs hype: where are we in type 1 diabetes? Diabetologia. 2018;61:509-16.

133. Michels AW, Eisenbarth GS. Immune intervention in type 1 diabetes. Semin Immunol. 2011;23:214-9.

134. Schweiger D. Recent advances in immune-based therapies for type 1 diabetes. Horm Res Paediatr. 2023;96:631-45.

135. Manirarora JN, Wei CH. Combination therapy using IL-2/IL-2 monoclonal antibody complexes, rapamycin, and islet autoantigen peptides increases regulatory T cell frequency and protects against spontaneous and induced type 1 diabetes in nonobese diabetic mice. J Immunol. 2015;195:5203-14.

136. Kabakchieva P, Assyov Y, Gerasoudis S, et al. Islet transplantation-immunological challenges and current perspectives. World J Transplant. 2023;13:107-21.

137. Wang Q, Huang YX, Liu L, et al. Pancreatic islet transplantation: current advances and challenges. Front Immunol. 2024;15:1391504.

138. Long SA, Rieck M, Sanda S, et al; Diabetes TrialNet and the Immune Tolerance Network. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs β-cell function. Diabetes. 2012;61:2340-8.

139. Tanemura M, Saga A, Kawamoto K, et al. Rapamycin induces autophagy in islets: relevance in islet transplantation. Transplant Proc. 2009;41:334-8.

140. Caridade M, Graca L, Ribeiro RM. Mechanisms underlying CD4+ Treg immune regulation in the adult: from experiments to models. Front Immunol. 2013;4:378.

141. Raffin C, Vo LT, Bluestone JA. Treg cell-based therapies: challenges and perspectives. Nat Rev Immunol. 2020;20:158-72.

142. MacDonald KN, Piret JM, Levings MK. Methods to manufacture regulatory T cells for cell therapy. Clin Exp Immunol. 2019;197:52-63.

143. Gootjes C, Zwaginga JJ, Roep BO, Nikolic T. Defining human regulatory T cells beyond FOXP3: the need to combine phenotype with function. Cells. 2024;13:941.

144. Chae WJ, Bothwell ALM. Therapeutic potential of gene-modified regulatory T cells: from bench to bedside. Front Immunol. 2018;9:303.

145. Bayati F, Mohammadi M, Valadi M, Jamshidi S, Foma AM, Sharif-Paghaleh E. The therapeutic potential of regulatory T cells: challenges and opportunities. Front Immunol. 2020;11:585819.

146. Massoud AH, Charbonnier LM, Lopez D, Pellegrini M, Phipatanakul W, Chatila TA. An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells. Nat Med. 2016;22:1013-22.

147. Hennessy C, Deptula M, Hester J, Issa F. Barriers to Treg therapy in Europe: from production to regulation. Front Med. 2023;10:1090721.

148. Chen X, Zhong S, Zhan Y, Zhang X. CRISPR-Cas9 applications in T cells and adoptive T cell therapies. Cell Mol Biol Lett. 2024;29:52.

149. Haque M, Song J, Fino K, et al. Stem cell-derived tissue-associated regulatory T cells ameliorate the development of autoimmunity. Sci Rep. 2016;6:20588.

150. Luo Y, Xu C, Wang B, et al. Single-cell transcriptomic analysis reveals disparate effector differentiation pathways in human Treg compartment. Nat Commun. 2021;12:3913.

151. McGovern JL, Wright GP, Stauss HJ. Engineering specificity and function of therapeutic regulatory T cells. Front Immunol. 2017;8:1517.

152. Reddy NR, Maachi H, Xiao Y, et al. Engineering synthetic suppressor T cells that execute locally targeted immunoprotective programs. Science. 2024;386:eadl4793.

153. Mashayekhi K, Khazaie K, Faubion WA Jr, Kim GB. Biomaterial-enhanced treg cell immunotherapy: a promising approach for transplant medicine and autoimmune disease treatment. Bioact Mater. 2024;37:269-98.

154. Zieliński M, Żalińska M, Iwaszkiewicz-Grześ D, et al. Combined therapy with CD4+ CD25highCD127- T regulatory cells and anti-CD20 antibody in recent-onset type 1 diabetes is superior to monotherapy: randomized phase I/II trial. Diabetes Obes Metab. 2022;24:1534-43.

155. Infante M, Alejandro R, Fabbri A, Ricordi C. The heterogeneity of type 1 diabetes: from immunopathology to immune intervention. Translational autoimmunity. Elsevier; 2022. pp. 83-104.

Metabolism and Target Organ Damage
ISSN 2769-6375 (Online)
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