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Antigen-specific therapeutic approaches for autoimmunity

Nature Biotechnology volume 37, pages 238–251 (2019)Cite this article

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Abstract

The main function of the immune system in health is to protect the host from infection by microbes and parasites. Because immune responses to nonself bear the risk of unleashing accidental immunity against self, evolution has endowed the immune system with central and peripheral mechanisms of tolerance, including regulatory T and B cells. Although the past two decades have witnessed the successful clinical translation of a whole host of novel therapies for the treatment of chronic inflammation, the development of antigen-based approaches capable of selectively blunting autoimmune inflammation without impairing normal immunity has remained elusive. Earlier autoantigen-specific approaches employing peptides or whole antigens have evolved into strategies that seek to preferentially deliver these molecules to autoreactive T cells either indirectly, via antigen-presenting cells, or directly, via major histocompatibility complex molecules, in ways intended to promote clonal deletion and/or immunoregulation. The disease specificity, mechanistic underpinnings, developability and translational potential of many of these strategies remain unclear.

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Fig. 1: Transfer of unmodified or antigen-specific Treg cells, peptides, autoantigens or autoantigen-encoding DNA, or autoantigen-loaded vehicles.
Fig. 2: Immunological consequences of therapy as a function of antigenic specificity and site of antigen uptake.
Fig. 3: pMHC-based nanomedicines.

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References

  1. Tsai, S., Serra, P., Clemente-Casares, X., Slattery, R. M. & Santamaria, P. Dendritic cell-dependent in vivo generation of autoregulatory T cells by antidiabetogenic MHC class II. J. Immunol. 191, 70–82 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Yamanouchi, J. et al. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat. Genet. 39, 329–337 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Maine, C. J. et al. PTPN22 alters the development of regulatory T cells in the thymus. J. Immunol. 188, 5267–5275 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Solvason, N. et al. Improved efficacy of a tolerizing DNA vaccine for reversal of hyperglycemia through enhancement of gene expression and localization to intracellular sites. J. Immunol. 181, 8298–8307 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Wolfe, T. et al. Endogenous expression levels of autoantigens influence success or failure of DNA immunizations to prevent type 1 diabetes: addition of IL-4 increases safety. Eur. J. Immunol. 32, 113–121 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Garren, H. et al. Combination of gene delivery and DNA vaccination to protect from and reverse Th1 autoimmune disease via deviation to the Th2 pathway. Immunity 15, 15–22 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Roep, B. O. et al. Plasmid-encoded proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8+ T cells in type 1 diabetes. Sci. Transl. Med. 5, 191ra82 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bar-Or, A. et al. Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial. Arch. Neurol. 64, 1407–1415 (2007).

    Article  PubMed  Google Scholar 

  9. Garren, H. et al. Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis. Ann. Neurol. 63, 611–620 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Thomson, A. W. & Knolle, P. A. Antigen-presenting cell function in the tolerogenic liver environment. Nat. Rev. Immunol. 10, 753–766 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Akbarpour, M. et al. Insulin B chain 9-23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3+ Tregs. Sci. Transl. Med. 7, 289ra81 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Lüth, S. et al. Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. J. Clin. Invest. 118, 3403–3410 (2008).

    PubMed  PubMed Central  Google Scholar 

  13. Pozsgay, J., Szekanecz, Z. & Sármay, G. Antigen-specific immunotherapies in rheumatic diseases. Nat. Rev. Rheumatol. 13, 525–537 (2017).

    Article  CAS  PubMed  Google Scholar 

  14. Zhang, N. & Nandakumar, K. S. Recent advances in the development of vaccines for chronic inflammatory autoimmune diseases. Vaccine 36, 3208–3220 (2018).

    Article  CAS  PubMed  Google Scholar 

  15. Pozzilli, P. et al. IMDIAB Group. No effect of oral insulin on residual beta-cell function in recent-onset type I diabetes (the IMDIAB VII). Diabetologia 43, 1000–1004 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Näntö-Salonen, K. 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 372, 1746–1755 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Harrison, L. C. et al. Pancreatic beta-cell function and immune responses to insulin after administration of intranasal insulin to humans at risk for type 1 diabetes. Diabetes Care 27, 2348–2355 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Chaillous, L. et al. Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Diabète Insuline Orale group. Lancet 356, 545–549 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Skyler, J. S. et al. Effects of oral insulin in relatives of patients with type 1 diabetes: the Diabetes Prevention Trial—Type 1. Diabetes Care 28, 1068–1076 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Diabetes Prevention Trial–Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N. Engl. J. Med. 346, 1685–1691 (2002).

  21. Bonifacio, E. 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. J. Am. Med. Assoc. 313, 1541–1549 (2015).

    Article  CAS  Google Scholar 

  22. Ludvigsson, J. et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N. Engl. J. Med. 359, 1909–1920 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Ludvigsson, J. et al. GAD-treatment of children and adolescents with recent-onset type 1 diabetes preserves residual insulin secretion after 30 months. Diabetes Metab. Res. Rev. 30, 405–414 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Wherrett, D. K. et al. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet 378, 319–327 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Weiner, H. L. et al. Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science 259, 1321–1324 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Evavold, B. D. & Allen, P. M. Separation of IL-4 production from Th cell proliferation by an altered T cell receptor ligand. Science 252, 1308–1310 (1991).

    Article  CAS  PubMed  Google Scholar 

  27. Wraith, D. C., Smilek, D. E., Mitchell, D. J., Steinman, L. & McDevitt, H. O. Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy. Cell 59, 247–255 (1989).

    Article  CAS  PubMed  Google Scholar 

  28. Han, B. et al. Prevention of diabetes by manipulation of anti-IGRP autoimmunity: high efficiency of a low-affinity peptide. Nat. Med. 11, 645–652 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Han, B. et al. Developmental control of CD8 T cell-avidity maturation in autoimmune diabetes. J. Clin. Invest. 115, 1879–1887 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Anderton, S. M. & Wraith, D. C. Hierarchy in the ability of T cell epitopes to induce peripheral tolerance to antigens from myelin. Eur. J. Immunol. 28, 1251–1261 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Amrani, A. et al. Progression of autoimmune diabetes driven by avidity maturation of a T-cell population. Nature 406, 739–742 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Tsai, S. et al. Reversal of autoimmunity by boosting memory-like autoregulatory T cells. Immunity 32, 568–580 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Chen, T. C., Waldmann, H. & Fairchild, P. J. Induction of dominant transplantation tolerance by an altered peptide ligand of the male antigen Dby. J. Clin. Invest. 113, 1754–1762 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Burkhart, C., Liu, G. Y., Anderton, S. M., Metzler, B. & Wraith, D. C. Peptide-induced T cell regulation of experimental autoimmune encephalomyelitis: a role for IL-10. Int. Immunol. 11, 1625–1634 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Gabrysová, L. et al. Negative feedback control of the autoimmune response through antigen-induced differentiation of IL-10-secreting Th1 cells. J. Exp. Med. 206, 1755–1767 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Burton, B. R. et al. Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy. Nat. Commun. 5, 4741 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Carlier, V. A., VanderElst, L., Janssens, W., Jacquemin, M. G. & Saint-Remy, J. M. Increased synapse formation obtained by T cell epitopes containing a CxxC motif in flanking residues convert CD4+ T cells into cytolytic effectors. PLoS One 7, e45366 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Malek Abrahimians, E., Vander Elst, L., Carlier, V. A. & Saint-Remy, J. M. Thioreductase-containing epitopes inhibit the development of type 1 diabetes in the NOD mouse model. Front. Immunol. 7, 67 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Anderton, S. M. et al. Fine specificity of the myelin-reactive T cell repertoire: implications for TCR antagonism in autoimmunity. J. Immunol. 161, 3357–3364 (1998).

    CAS  PubMed  Google Scholar 

  40. Mohan, J. F., Petzold, S. J. & Unanue, E. R. Register shifting of an insulin peptide-MHC complex allows diabetogenic T cells to escape thymic deletion. J. Exp. Med. 208, 2375–2383 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Paas-Rozner, M., Sela, M. & Mozes, E. A dual altered peptide ligand down-regulates myasthenogenic T cell responses by up-regulating CD25- and CTLA-4-expressing CD4+ T cells. Proc. Natl Acad. Sci. USA 100, 6676–6681 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Daniel, C. & von Boehmer, H. Extrathymic generation of regulatory T cells—chances and challenges for prevention of autoimmune disease. Adv. Immunol. 112, 177–213 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Bergman, M. L. et al. Tolerogenic insulin peptide therapy precipitates type 1 diabetes. J. Exp. Med. 214, 2153–2156 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kretschmer, K. et al. Inducing and expanding regulatory T cell populations by foreign antigen. Nat. Immunol. 6, 1219–1227 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Walter, M., Philotheou, A., Bonnici, F., Ziegler, A. G. & 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 32, 2036–2040 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Alhadj Ali, M. et al. Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes. Sci. Transl. Med. 9, eaaf7779 (2017).

    Article  CAS  PubMed  Google Scholar 

  47. Warren, K. G., Catz, I., Ferenczi, L. Z. & Krantz, M. J. Intravenous synthetic peptide MBP8298 delayed disease progression in an HLA class II-defined cohort of patients with progressive multiple sclerosis: results of a 24-month double-blind placebo-controlled clinical trial and 5 years of follow-up treatment. Eur. J. Neurol. 13, 887–895 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Freedman, M. S. et al. A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS. Neurology 77, 1551–1560 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Chataway, J. et al. Effects of ATX-MS-1467 immunotherapy over 16 weeks in relapsing multiple sclerosis. Neurology 90, e955–e962 (2018).

    Article  CAS  PubMed  Google Scholar 

  50. Walczak, A., Siger, M., Ciach, A., Szczepanik, M. & Selmaj, K. Transdermal application of myelin peptides in multiple sclerosis treatment. JAMA Neurol. 70, 1105–1109 (2013).

    Article  PubMed  Google Scholar 

  51. Juryńczyk, M. et al. Immune regulation of multiple sclerosis by transdermally applied myelin peptides. Ann. Neurol. 68, 593–601 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Koffeman, E. C. et al. Epitope-specific immunotherapy of rheumatoid arthritis: clinical responsiveness occurs with immune deviation and relies on the expression of a cluster of molecules associated with T cell tolerance in a double-blind, placebo-controlled, pilot phase II trial. Arthritis Rheum. 60, 3207–3216 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Tye-Din, J. A. et al. Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease. Sci. Transl. Med. 2, 41ra51 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Goel, G. et al. Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies. Lancet. Gastroenterol. Hepatol. 2, 479–493 (2017).

    Google Scholar 

  55. Daveson, A. J. M. et al. Epitope-specific immunotherapy targeting CD4-positive T cells in celiac disease: safety, pharmacokinetics, and effects on intestinal histology and plasma cytokines with escalating dose regimens of Nexvax2 in a randomized, double-blind, placebo-controlled phase 1 study. EBioMedicine 26, 78–90 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Bodd, M. et al. Direct cloning and tetramer staining to measure the frequency of intestinal gluten-reactive T cells in celiac disease. Eur. J. Immunol. 43, 2605–2612 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Bielekova, B. 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. 6, 1167–1175 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Kappos, L. et al. 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. 6, 1176–1182 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Liu, E. et al. Anti-peptide autoantibodies and fatal anaphylaxis in NOD mice in response to insulin self-peptides B:9-23 and B:13-23. J. Clin. Invest. 110, 1021–1027 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Spack, E. G. et al. Induction of tolerance in experimental autoimmune myasthenia gravis with solubilized MHC class II:acetylcholine receptor peptide complexes. J. Autoimmun. 8, 787–807 (1995).

    Article  CAS  PubMed  Google Scholar 

  61. Sharma, S. D. et al. Antigen-specific therapy of experimental allergic encephalomyelitis by soluble class II major histocompatibility complex-peptide complexes. Proc. Natl Acad. Sci. USA 88, 11465–11469 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Vandenbark, A. A. et al. Recombinant TCR ligand induces tolerance to myelin oligodendrocyte glycoprotein 35-55 peptide and reverses clinical and histological signs of chronic experimental autoimmune encephalomyelitis in HLA-DR2 transgenic mice. J. Immunol. 171, 127–133 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Goodkin, D. E. et al. A phase I trial of solubilized DR2:MBP84-102 (AG284) in multiple sclerosis. Neurology 54, 1414–1420 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Yadav, V. et al. Recombinant T-cell receptor ligand (RTL) for treatment of multiple sclerosis: a double-blind, placebo-controlled, phase 1, dose-escalation study. Autoimmune Dis. 2012, 954739 (2012).

    PubMed  PubMed Central  Google Scholar 

  65. Casares, S. et al. Down-regulation of diabetogenic CD4+ T cells by a soluble dimeric peptide-MHC class II chimera. Nat. Immunol. 3, 383–391 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Preda-Pais, A., Stan, A. C., Casares, S., Bona, C. & Brumeanu, T. D. Efficacy of clonal deletion vs. anergy of self-reactive CD4 T-cells for the prevention and reversal of autoimmune diabetes. J. Autoimmun. 25, 21–32 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Lin, M. et al. Reversal of type 1 diabetes by a new MHC II-peptide chimera: “single-epitope-mediated suppression” to stabilize a polyclonal autoimmune T-cell process. Eur. J. Immunol. 40, 2277–2288 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Li, L., Yi, Z., Wang, B. & Tisch, R. Suppression of ongoing T cell-mediated autoimmunity by peptide-MHC class II dimer vaccination. J. Immunol. 183, 4809–4816 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Getts, D. R., McCarthy, D. P. & Miller, S. D. Exploiting apoptosis for therapeutic tolerance induction. J. Immunol. 191, 5341–5346 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Miller, S. D., Wetzig, R. P. & Claman, H. N. The induction of cell-mediated immunity and tolerance with protein antigens coupled to syngeneic lymphoid cells. J. Exp. Med. 149, 758–773 (1979).

    Article  CAS  PubMed  Google Scholar 

  71. Lorentz, K. M., Kontos, S., Diaceri, G., Henry, H. & Hubbell, J. A. Engineered binding to erythrocytes induces immunological tolerance to E. coli asparaginase. Sci. Adv. 1, e1500112 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Prasad, S., Kohm, A. P., McMahon, J. S., Luo, X. & Miller, S. D. Pathogenesis of NOD diabetes is initiated by reactivity to the insulin B chain 9-23 epitope and involves functional epitope spreading. J. Autoimmun. 39, 347–353 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Getts, D. R. et al. Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells. J. Immunol. 187, 2405–2417 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Lutterotti, A. et al. Antigen-specific tolerance by autologous myelin peptide-coupled cells: a phase 1 trial in multiple sclerosis. Sci. Transl. Med. 5, 188ra75 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hunter, Z. et al. A biodegradable nanoparticle platform for the induction of antigen-specific immune tolerance for treatment of autoimmune disease. ACS Nano 8, 2148–2160 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Getts, D. R. et al. Microparticles bearing encephalitogenic peptides induce T-cell tolerance and ameliorate experimental autoimmune encephalomyelitis. Nat. Biotechnol. 30, 1217–1224 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Clemente-Casares, X. et al. Expanding antigen-specific regulatory networks to treat autoimmunity. Nature 530, 434–440 (2016).

    Article  CAS  PubMed  Google Scholar 

  78. Macauley, M. S. et al. Antigenic liposomes displaying CD22 ligands induce antigen-specific B cell apoptosis. J. Clin. Invest. 123, 3074–3083 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Pujol-Autonell, I. et al. Use of autoantigen-loaded phosphatidylserine-liposomes to arrest autoimmunity in type 1 diabetes. PLoS One 10, e0127057 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Capini, C. et al. Antigen-specific suppression of inflammatory arthritis using liposomes. J. Immunol. 182, 3556–3565 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Maldonado, R. A. et al. Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance. Proc. Natl Acad. Sci. USA 112, E156–E165 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. LaMothe, R. A. et al. Tolerogenic nanoparticles induce antigen-specific regulatory T cells and provide therapeutic efficacy and transferrable tolerance against experimental autoimmune encephalomyelitis. Front. Immunol. 9, 281 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Yeste, A. et al. Tolerogenic nanoparticles inhibit T cell-mediated autoimmunity through SOCS2. Sci. Signal. 9, ra61 (2016).

    Article  CAS  PubMed  Google Scholar 

  84. Carambia, A. et al. Nanoparticle-based autoantigen delivery to Treg-inducing liver sinusoidal endothelial cells enables control of autoimmunity in mice. J. Hepatol. 62, 1349–1356 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Grimm, A. J., Kontos, S., Diaceri, G., Quaglia-Thermes, X. & Hubbell, J. A. Memory of tolerance and induction of regulatory T cells by erythrocyte-targeted antigens. Sci. Rep. 5, 15907 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kontos, S., Kourtis, I. C., Dane, K. Y. & Hubbell, J. A. Engineering antigens for in situ erythrocyte binding induces T-cell deletion. Proc. Natl Acad. Sci. USA 110, E60–E68 (2013).

    Article  PubMed  Google Scholar 

  87. Pishesha, N. et al. Engineered erythrocytes covalently linked to antigenic peptides can protect against autoimmune disease. Proc. Natl Acad. Sci. USA 114, 3157–3162 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cook, D. P., Gysemans, C. & Mathieu, C. Lactococcus lactis as a versatile vehicle for tolerogenic immunotherapy. Front. Immunol. 8, 1961 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Robert, S. et al. Oral delivery of glutamic acid decarboxylase (GAD)-65 and IL10 by Lactococcus lactis reverses diabetes in recent-onset NOD mice. Diabetes 63, 2876–2887 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Takiishi, T. et al. Reversal of diabetes in NOD mice by clinical-grade proinsulin and IL-10-secreting Lactococcus lactis in combination with low-dose anti-CD3 depends on the induction of Foxp3-positive T cells. Diabetes 66, 448–459 (2017).

    Article  CAS  PubMed  Google Scholar 

  91. Takiishi, T. et al. Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice. J. Clin. Invest. 122, 1717–1725 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Anderson, B., Park, B. J., Verdaguer, J., Amrani, A. & Santamaria, P. Prevalent CD8+ T cell response against one peptide/MHC complex in autoimmune diabetes. Proc. Natl Acad. Sci. USA 96, 9311–9316 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lieberman, S. M. et al. Identification of the beta cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc. Natl Acad. Sci. USA 100, 8384–8388 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Desreumaux, P. et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease. Gastroenterology 143, 1207–1217.e2 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. Marek-Trzonkowska, N. et al. Factors affecting long-term efficacy of T regulatory cell-based therapy in type 1 diabetes. J. Transl. Med. 14, 332 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Bluestone, J. A. et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci. Transl. Med. 7, 315ra189 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mekala, D. J. & Geiger, T. L. Immunotherapy of autoimmune encephalomyelitis with redirected CD4+CD25+ T lymphocytes. Blood 105, 2090–2092 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Moisini, I., Nguyen, P., Fugger, L. & Geiger, T. L. Redirecting therapeutic T cells against myelin-specific T lymphocytes using a humanized myelin basic protein-HLA-DR2-zeta chimeric receptor. J. Immunol. 180, 3601–3611 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Qian, Z. et al. Engineered regulatory T cells coexpressing MHC class II:peptide complexes are efficient inhibitors of autoimmune T cell function and prevent the development of autoimmune arthritis. J. Immunol. 190, 5382–5391 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Fransson, M. et al. CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery. J. Neuroinflammation 9, 112 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ellebrecht, C. T. et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353, 179–184 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. June, C. H., Riddell, S. R. & Schumacher, T. N. Adoptive cellular therapy: a race to the finish line. Sci. Transl. Med. 7, 280ps7 (2015).

    Article  CAS  PubMed  Google Scholar 

  104. Raϊch-Regué, D. et al. Stable antigen-specific T-cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients. Eur. J. Immunol. 42, 771–782 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Harry, R. A., Anderson, A. E., Isaacs, J. D. & Hilkens, C. M. Generation and characterisation of therapeutic tolerogenic dendritic cells for rheumatoid arthritis. Ann. Rheum. Dis. 69, 2042–2050 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Giannoukakis, N., Phillips, B., Finegold, D., Harnaha, J. & Trucco, M. Phase I (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients. Diabetes Care 34, 2026–2032 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Lan, P., Tonomura, N., Shimizu, A., Wang, S. & Yang, Y. G. Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation. Blood 108, 487–492 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Billerbeck, E. et al. Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor-, granulocyte-macrophage colony-stimulating factor-, and interleukin-3-expressing NOD-SCID IL2Rγ(null) humanized mice. Blood 117, 3076–3086 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Tan, S. et al. Type 1 diabetes induction in humanized mice. Proc. Natl Acad. Sci. USA 114, 10954–10959 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Akdis, C. A. & Akdis, M. Mechanisms of immune tolerance to allergens: role of IL-10 and Tregs. J. Clin. Invest. 124, 4678–4680 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Gabryšová, L. et al. c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells. Nat. Immunol. 19, 497–507 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Zheng, W. & Flavell, R. A. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89, 587–596 (1997).

    Article  CAS  PubMed  Google Scholar 

  113. Motomura, Y. et al. The transcription factor E4BP4 regulates the production of IL-10 and IL-13 in CD4+ T cells. Nat. Immunol. 12, 450–459 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Wang, Z. Y. et al. Regulation of IL-10 gene expression in Th2 cells by Jun proteins. J. Immunol. 174, 2098–2105 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Pot, C. et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J. Immunol. 183, 797–801 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Kwok, W. W. et al. Direct ex vivo analysis of allergen-specific CD4+ T cells. J. Allergy Clin. Immunol. 125, 1407–1409.e1401 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Pugliese, A. Autoreactive T cells in type 1 diabetes. J. Clin. Invest. 127, 2881–2891 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Elong Ngono, A. et al. Frequency of circulating autoreactive T cells committed to myelin determinants in relapsing-remitting multiple sclerosis patients. Clin. Immunol. 144, 117–126 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Singha, S. et al. Peptide-MHC-based nanomedicines for autoimmunity function as T-cell receptor microclustering devices. Nat. Nanotechnol. 12, 701–710 (2017).

    Article  CAS  PubMed  Google Scholar 

  120. Gabrysová, L. & Wraith, D. C. Antigenic strength controls the generation of antigen-specific IL-10-secreting T regulatory cells. Eur. J. Immunol. 40, 1386–1395 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Couper, K. N., Blount, D. G. & Riley, E. M. IL-10: the master regulator of immunity to infection. J. Immunol. 180, 5771–5777 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. White, A. M. & Wraith, D. C. Tr1-like T cells — an enigmatic regulatory T cell lineage. Front. Immunol. 7, 355 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Jauregui-Amezaga, A. et al. Intraperitoneal administration of autologous tolerogenic dendritic cells for refractory Crohn’s disease: a phase I study. J. Crohns Colitis 9, 1071–1078 (2015).

    Article  PubMed  Google Scholar 

  124. Benham, H. et al. Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. Sci. Transl. Med. 7, 290ra87 (2015).

    Article  CAS  PubMed  Google Scholar 

  125. Bell, G. M. et al. Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis. Ann. Rheum. Dis. 76, 227–234 (2017).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the members of our laboratories for their contributions and insights. The authors’ work summarized here was funded by the Canadian Institutes of Health Research (CIHR), Diabetes Canada, the Crohn’s and Colitis Foundation of Canada, the Multiple Sclerosis Society of Canada (MSSC), ISCIII and FEDER (PIE14/00027, PI15/0797), NEURON-ERANET (European Research Projects on Neuroinflammation; NEURON7-FP-715-018), the Ministerio de Economia y Competitividad of Spain (MINECO) and Generalitat de Catalunya (SGR and CERCA Programmes). P. Serra was an investigator of the Ramon y Cajal Re-integration Program and is supported by a JDRF Career Development Award. P. Santamaria was a Scientist of the Alberta-Innovates – Health Solutions (AI–HS) and a scholar of the Instituto de Investigaciones Sanitarias Carlos III. The JMDRC was supported by the Diabetes Association (Foothills) and currently by Diabetes Canada.

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  1. Institut D’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain

    Pau Serra & Pere Santamaria

  2. Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Pere Santamaria

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P. Santamaria is scientific founder of Parvus Therapeutics Inc. and has a financial interest in the company.

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Serra, P., Santamaria, P. Antigen-specific therapeutic approaches for autoimmunity. Nat Biotechnol 37, 238–251 (2019). https://doi.org/10.1038/s41587-019-0015-4

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