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  • Review Article
  • Published:

Antigen-specific immunotherapies in rheumatic diseases

Nature Reviews Rheumatology volume 13, pages 525–537 (2017)Cite this article

Subjects

Key Points

  • The main goal of antigen-specific immunotherapies (ASIs) in autoimmune diseases is to reprogramme or remove autoreactive cells and to induce immune tolerance to self-antigens

  • Depleting autoreactive T cells, B cells and plasma cells could be a future therapeutic strategy for rheumatic diseases and could lead to temporary improvement in disease

  • Awakening antigen-specific tolerance by inducing regulatory T (Treg) cells using antigen-specific tolerogenic peptides alone or coupled to cells or nanoparticles can reprogramme autoreactive cells, resulting in long-term tolerance

  • T cells can be engineered to specifically target and delete self-reactive B cells or to redirect the specificity of Treg cells towards self-antigens

  • The use of antigen-boosted tolerogenic dendritic cells and DNA-based vaccines are promising ASIs.

Abstract

The main goal of antigen-specific immunotherapy (ASI) in autoimmune and rheumatic diseases is to reprogramme or remove autoreactive cells and/or induce immune tolerance to self-antigens. Current therapies in these diseases either treat symptoms or slow down disease progression but are not yet curative or preventative — disease-specific treatments are urgently needed. In contrast to the nonspecific treatments in current use that induce generalized immune suppression, which is associated with several adverse effects including increased risk of infections, ASIs target a restricted subset of B cells or T cells, and thus do not compromise systemic immunity and host defence. This Review provides a summary of novel approaches for identifying autoepitopes and detecting and targeting autoreactive cells that might help in the development of ASIs. Promising approaches include the use of tolerizing peptides coupled to MHC constructs and/or nanocompounds, tolerizing dendritic cells and antigen-specific vaccines. Following studies in animal models of rheumatoid arthritis and systemic lupus erythematosus, several of these strategies have now entered clinical trials. However, to use these approaches in humans, several important limitations must first be addressed, such as; selecting the proper immunodominant autoantigen; identifying the optimal timing, dosing and route of administration; finding biomarkers for monitoring the therapy; and optimizing methodology.

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Figure 1: Induction of immune tolerance.
Figure 2: Strategies for detecting or eliminating autoreactive B cells and/or autoantibodies.
Figure 3: Strategies for neutralizing or re-programming autoreactive T cells.
Figure 4: Strategies for utilizing dendritic cells to target autoreactive T cells.

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References

  1. Goodnow, C. C., Sprent, J., Fazekas de St Groth, B. & Vinuesa, C. G. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature 435, 590–597 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Burns, J., Rosenzweig, A., Zweiman, B. & Lisak, R. P. Isolation of myelin basic protein-reactive T-cell lines from normal human blood. Cell. Immunol. 81, 435–440 (1983).

    Article  CAS  PubMed  Google Scholar 

  3. Matsumoto, Y. New approach to immunotherapy against organ-specific autoimmune diseases with T cell receptor and chemokine receptor DNA vaccines. Curr. Drug Targets Immune Endocr. Metabol. Disord. 5, 73–77 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Andersson, P. O. & Wadenvik, H. Chronic idiopathic thrombocytopenic purpura (ITP): molecular mechanisms and implications for therapy. Expert Rev. Mol. Med. 6, 1–17 (2004).

    Article  PubMed  Google Scholar 

  5. Schultze, J. L., Grabbe, S. & von Bergwelt-Baildon, M. S. DCs and CD40-activated B cells: current and future avenues to cellular cancer immunotherapy. Trends Immunol. 25, 659–664 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Aletaha, D. et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann. Rheum. Dis. 69, 1580–1588 (2010).

    Article  PubMed  Google Scholar 

  7. Soos, L. et al. Clinical evaluation of anti-mutated citrullinated vimentin by ELISA in rheumatoid arthritis. J. Rheumatol. 34, 1658–1663 (2007).

    CAS  PubMed  Google Scholar 

  8. Baeten, D. et al. Specific presence of intracellular citrullinated proteins in rheumatoid arthritis synovium: relevance to antifilaggrin autoantibodies. Arthritis Rheum. 44, 2255–2262 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Szarka, E. et al. Recognition of new citrulline-containing peptide epitopes by autoantibodies produced in vivo and in vitro by B cells of rheumatoid arthritis patients. Immunology 141, 181–191 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Burkhardt, H. et al. Humoral immune response to citrullinated collagen type II determinants in early rheumatoid arthritis. Eur. J. Immunol. 35, 1643–1652 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Cornillet, M. et al. The fibrin-derived citrullinated peptide beta60-74Cit(6)(0),(7)(2),(7)(4) bears the major ACPA epitope recognised by the rheumatoid arthritis-specific anticitrullinated fibrinogen autoantibodies and anti-CCP2 antibodies. Ann. Rheum. Dis. 73, 1246–1252 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Schwenzer, A. et al. Identification of an immunodominant peptide from citrullinated tenascin-C as a major target for autoantibodies in rheumatoid arthritis. Ann. Rheum. Dis. 75, 1876–1883 (2016).

    Article  CAS  PubMed  Google Scholar 

  13. Pruijn, G. J. Citrullination and carbamylation in the pathophysiology of rheumatoid arthritis. Front. Immunol. 6, 192 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tiffin, N., Adeyemo, A. & Okpechi, I. A diverse array of genetic factors contribute to the pathogenesis of systemic lupus erythematosus. Orphanet J. Rare Dis. 8, 2 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Sun, X. Y., Shi, J., Han, L., Su, Y. & Li, Z. G. Anti-histones antibodies in systemic lupus erythematosus: prevalence and frequency in neuropsychiatric lupus. J. Clin. Lab. Anal. 22, 271–277 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Konya, C., Paz, Z. & Tsokos, G. C. The role of T cells in systemic lupus erythematosus: an update. Curr. Opin. Rheumatol. 26, 493–501 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Noack, M. & Miossec, P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun. Rev. 13, 668–677 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Kerkman, P. F. et al. Identification and characterisation of citrullinated antigen-specific B cells in peripheral blood of patients with rheumatoid arthritis. Ann. Rheum. Dis. 75, 1170–1176 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Pozsgay, J. et al. in vitro eradication of citrullinated protein specific B-lymphocytes of rheumatoid arthritis patients by targeted bifunctional nanoparticles. Arthritis Res. Ther. 18, 15 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gaynor, B. et al. Peptide inhibition of glomerular deposition of an anti-DNA antibody. Proc. Natl Acad. Sci. USA 94, 1955–1960 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Putterman, C. & Diamond, B. Immunization with a peptide surrogate for double-stranded DNA (dsDNA) induces autoantibody production and renal immunoglobulin deposition. J. Exp. Med. 188, 29–38 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Newman, J., Rice, J. S., Wang, C., Harris, S. L. & Diamond, B. Identification of an antigen-specific B cell population. J. Immunol. Methods 272, 177–187 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Jacobi, A. M., Zhang, J., Mackay, M., Aranow, C. & Diamond, B. Phenotypic characterization of autoreactive B cells — checkpoints of B cell tolerance in patients with systemic lupus erythematosus. PLoS ONE 4, e5776 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. van Schooten, W. C., Strang, G. & Palathumpat, V. Biological properties of dendritic cells: implications to their use in the treatment of cancer. Mol. Med. Today 3, 254–260 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Mihaylova, N. et al. Selective silencing of disease-associated B-lymphocytes by chimeric molecules targeting their Fc gamma IIb receptor. Int. Immunol. 20, 165–175 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Jeltsch-David, H. & Muller, S. Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: the MRL-lpr mouse strain as a model. Autoimmun. Rev. 13, 963–973 (2014).

    Article  PubMed  Google Scholar 

  28. Horton, H. M. et al. Antibody-mediated coengagement of FcgammaRIIb and B cell receptor complex suppresses humoral immunity in systemic lupus erythematosus. J. Immunol. 186, 4223–4233 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Szili, D. et al. Suppression of innate and adaptive B cell activation pathways by antibody coengagement of FcgammaRIIb and CD19. MAbs 6, 991–999 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  30. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02725515 (2017).

  31. Cohen, M. D. & Keystone, E. Rituximab for rheumatoid arthritis. Rheumatol. Ther. 2, 99–111 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hoffman, W., Lakkis, F. G. & Chalasani, G. B. Cells, antibodies, and more. Clin. J. Am. Soc. Nephrol. 11, 137–154 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Manz, R., Assenmacher, M., Pfluger, E., Miltenyi, S. & Radbruch, A. Analysis and sorting of live cells according to secreted molecules, relocated to a cell-surface affinity matrix. Proc. Natl Acad. Sci. USA 92, 1921–1925 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Taddeo, A. et al. Selection and depletion of plasma cells based on the specificity of the secreted antibody. Eur. J. Immunol. 45, 317–319 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Hiepe, F. & Radbruch, A. Plasma cells as an innovative target in autoimmune disease with renal manifestations. Nat. Rev. Nephrol. 12, 232–240 (2016).

    Article  CAS  PubMed  Google Scholar 

  36. Caraux, A. et al. Circulating human B and plasma cells. Age-associated changes in counts and detailed characterization of circulating normal CD138- and CD138+ plasma cells. Haematologica 95, 1016–1020 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Suurmond, J. & Diamond, B. Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity. J. Clin. Invest. 125, 2194–2202 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Iking-Konert, C. et al. First clinical trials of a new heteropolymer technology agent in normal healthy volunteers and patients with systemic lupus erythematosus: safety and proof of principle of the antigen-heteropolymer ETI-104. Ann. Rheum. Dis. 63, 1104–1112 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cornacoff, J. B. et al. Primate erythrocyte-immune complex-clearing mechanism. J. Clin. Invest. 71, 236–247 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. [No authors listed]. Abetimus: abetimus sodium, LJP 394. BioDrugs 17, 212–215 (2003).

  41. Horowitz, D. M. & Furie, R. A. Abetimus sodium: a medication for the prevention of lupus nephritis flares. Expert Opin. Pharmacother. 10, 1501–1507 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Cardiel, M. H. et al. Abetimus sodium for renal flare in systemic lupus erythematosus: results of a randomized, controlled phase III trial. Arthritis Rheum. 58, 2470–2480 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Enouz, S., Carrie, L., Merkler, D., Bevan, M. J. & Zehn, D. Autoreactive T cells bypass negative selection and respond to self-antigen stimulation during infection. J. Exp. Med. 209, 1769–1779 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kyewski, B. & Derbinski, J. Self-representation in the thymus: an extended view. Nat. Rev. Immunol. 4, 688–698 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Sewell, A. K. Why must T cells be cross-reactive? Nat. Rev. Immunol. 12, 669–677 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Eisenbarth, G. S. & Kotzin, B. L. Enumerating autoreactive T cells in peripheral blood: a big step in diabetes prediction. J. Clin. Invest. 111, 179–181 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Trudeau, J. D. et al. Prediction of spontaneous autoimmune diabetes in NOD mice by quantification of autoreactive T cells in peripheral blood. J. Clin. Invest. 111, 217–223 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tisch, R. & McDevitt, H. Insulin-dependent diabetes mellitus. Cell 85, 291–297 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. 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 

  50. Vincent, B. G. et al. Toxin-coupled MHC class I tetramers can specifically ablate autoreactive CD8+ T cells and delay diabetes in nonobese diabetic mice. J. Immunol. 184, 4196–4204 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Bischof, F. et al. Analysis of autoreactive CD4 T cells in experimental autoimmune encephalomyelitis after primary and secondary challenge using MHC class II tetramers. J. Immunol. 172, 2878–2884 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Kobezda, T., Ghassemi-Nejad, S., Mikecz, K., Glant, T. T. & Szekanecz, Z. Of mice and men: how animal models advance our understanding of T-cell function in RA. Nat. Rev. Rheumatol. 10, 160–170 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gertel, S., Serre, G., Shoenfeld, Y. & Amital, H. Immune tolerance induction with multiepitope peptide derived from citrullinated autoantigens attenuates arthritis manifestations in adjuvant arthritis rats. J. Immunol. 194, 5674–5680 (2015).

    Article  CAS  PubMed  Google Scholar 

  54. Wehrens, E. J., Prakken, B. J. & van Wijk, F. T cells out of control — impaired immune regulation in the inflamed joint. Nat. Rev. Rheumatol. 9, 34–42 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Miyara, M., Ito, Y. & Sakaguchi, S. TREG-cell therapies for autoimmune rheumatic diseases. Nat. Rev. Rheumatol. 10, 543–551 (2014).

    Article  CAS  PubMed  Google Scholar 

  56. Saadoun, D. et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N. Engl. J. Med. 365, 2067–2077 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. 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.e1–2 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Ahmed, M. S. & Bae, Y. S. Dendritic cell-based immunotherapy for rheumatoid arthritis: from bench to bedside. Immune Netw. 16, 44–51 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  59. 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 

  60. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT02772679 (2017).

  61. Marcos, M. A. et al. Coelomic and bone marrow-derived B cells. Developmental constraints versus antigen-specific selection. Ann. NY Acad. Sci. 651, 433–442 (1992).

    Article  CAS  PubMed  Google Scholar 

  62. Krall, W. J. & Braun, J. in vivo retroviral marking of antigen-specific B lymphocytes. Semin. Immunol. 4, 19–28 (1992).

    CAS  PubMed  Google Scholar 

  63. Venigalla, R. K. et al. Reduced CD4+,CD25- T cell sensitivity to the suppressive function of CD4+,CD25high, CD127-/low regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum. 58, 2120–2130 (2008).

    Article  PubMed  Google Scholar 

  64. Briner, T. J., Kuo, M. C., Keating, K. M., Rogers, B. L. & Greenstein, J. L. Peripheral T-cell tolerance induced in naive and primed mice by subcutaneous injection of peptides from the major cat allergen Fel d I. Proc. Natl Acad. Sci. USA 90, 7608–7612 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kaliyaperumal, A., Michaels, M. A. & Datta, S. K. Antigen-specific therapy of murine lupus nephritis using nucleosomal peptides: tolerance spreading impairs pathogenic function of autoimmune T and B cells. J. Immunol. 162, 5775–5783 (1999).

    CAS  PubMed  Google Scholar 

  66. Kang, H. K., Michaels, M. A., Berner, B. R. & Datta, S. K. Very low-dose tolerance with nucleosomal peptides controls lupus and induces potent regulatory T cell subsets. J. Immunol. 174, 3247–3255 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Zhang, L. et al. Major pathogenic steps in human lupus can be effectively suppressed by nucleosomal histone peptide epitope-induced regulatory immunity. Clin. Immunol. 149, 365–378 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Wooley, P. H. The usefulness and the limitations of animal models in identifying targets for therapy in arthritis. Best Pract. Res. Clin. Rheumatol. 18, 47–58 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Leavenworth, J. W., Tang, X., Kim, H. J., Wang, X. & Cantor, H. Amelioration of arthritis through mobilization of peptide-specific CD8+ regulatory T cells. J. Clin. Invest. 123, 1382–1389 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sthoeger, Z., Zinger, H., Sharabi, A., Asher, I. & Mozes, E. The tolerogenic peptide, hCDR1, down-regulates the expression of interferon-alpha in murine and human systemic lupus erythematosus. PLoS ONE 8, e60394 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sharabi, A., Zinger, H., Zborowsky, M., Sthoeger, Z. M. & Mozes, E. A peptide based on the complementarity-determining region 1 of an autoantibody ameliorates lupus by up-regulating CD4+CD25+ cells and TGF-beta. Proc. Natl Acad. Sci. USA 103, 8810–8815 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Vanderlugt, C. L. & Miller, S. D. Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat. Rev. Immunol. 2, 85–95 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Gertel, S., Shoenfeld, Y. & Amital, H. Tolerogenic citrullinated peptide for arthritis. Oncotarget 6, 19344–19345 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Turley, D. M. & Miller, S. D. Peripheral tolerance induction using ethylenecarbodiimide-fixed APCs uses both direct and indirect mechanisms of antigen presentation for prevention of experimental autoimmune encephalomyelitis. J. Immunol. 178, 2212–2220 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Sauter, B. et al. Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J. Exp. Med. 191, 423–434 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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 

  77. Kundig, T. M. et al. On T cell memory: arguments for antigen dependence. Immunol. Rev. 150, 63–90 (1996).

    Article  CAS  PubMed  Google Scholar 

  78. Sayegh, M. H. & Turka, L. A. T cell costimulatory pathways: promising novel targets for immunosuppression and tolerance induction. J. Am. Soc. Nephrol. 6, 1143–1150 (1995).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    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. 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 

  83. 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 

  84. McCarthy, D. P. et al. An antigen-encapsulating nanoparticle platform for TH1/17 immune tolerance therapy. Nanomedicine 13, 191–200 (2017).

    Article  CAS  PubMed  Google Scholar 

  85. Anderson, R. P. & Jabri, B. Vaccine against autoimmune disease: antigen-specific immunotherapy. Curr. Opin. Immunol. 25, 410–417 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Marion, T. N. & Postlethwaite, A. E. Chance, genetics, and the heterogeneity of disease and pathogenesis in systemic lupus erythematosus. Semin. Immunopathol. 36, 495–517 (2014).

    Article  CAS  PubMed  Google Scholar 

  87. 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 

  88. 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 

  89. Ho, P. P. et al. Tolerizing DNA vaccines for autoimmune arthritis. Autoimmunity 39, 675–682 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Gottlieb, P., Utz, P. J., Robinson, W. & Steinman, L. Clinical optimization of antigen specific modulation of type 1 diabetes with the plasmid DNA platform. Clin. Immunol. 149, 297–306 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. James, E. A. et al. Citrulline-specific Th1 cells are increased in rheumatoid arthritis and their frequency is influenced by disease duration and therapy. Arthritis Rheumatol. 66, 1712–1722 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Couzin-Frankel, J. Breakthrough of the year 2013. Cancer immunotherapy. Science 342, 1432–1433 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  94. 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 

  95. Hilkens, C. M. & Isaacs, J. D. Tolerogenic dendritic cell therapy for rheumatoid arthritis: where are we now? Clin. Exp. Immunol. 172, 148–157 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Raker, V. K., Domogalla, M. P. & Steinbrink, K. Tolerogenic dendritic cells for regulatory T cell induction in man. Front. Immunol. 6, 569 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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 

  98. Bin Joo, Y. et al. Phase 1 study of immunotherapy using autoantigen-loaded dendritic cells in patients with anti-citrullinated peptide antigen positive rheumatoid arthritis [abstract 946]. Arthritis Rheumatol. 66, S420–S421 (2014).

    Google Scholar 

  99. 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 

  100. Bach, J. F., Koutouzov, S. & van Endert, P. M. Are there unique autoantigens triggering autoimmune diseases? Immunol. Rev. 164, 139–155 (1998).

    Article  CAS  PubMed  Google Scholar 

  101. Lorenz, H. M., Herrmann, M. & Kalden, J. R. The pathogenesis of autoimmune diseases. Scand. J. Clin. Lab. Invest. Suppl. 235, 16–26 (2001).

    CAS  PubMed  Google Scholar 

  102. Miyara, M. et al. Human FoxP3+ regulatory T cells in systemic autoimmune diseases. Autoimmun. Rev. 10, 744–755 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. Sakaguchi, S., Miyara, M., Costantino, C. M. & Hafler, D. A. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol. 10, 490–500 (2010).

    Article  CAS  PubMed  Google Scholar 

  104. Odegard, J. M., Nepom, G. T. & Wambre, E. Biomarkers for antigen immunotherapy in allergy and type 1 diabetes. Clin. Immunol. 161, 44–50 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Sinha, S. et al. A promising therapeutic approach for multiple sclerosis: recombinant T-cell receptor ligands modulate experimental autoimmune encephalomyelitis by reducing interleukin-17 production and inhibiting migration of encephalitogenic cells into the CNS. J. Neurosci. 27, 12531–12539 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Offner, H., Sinha, S., Burrows, G. G., Ferro, A. J. & Vandenbark, A. A. RTL therapy for multiple sclerosis: a phase I clinical study. J. Neuroimmunol. 231, 7–14 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. 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 

  108. Ho, P. P., Fontoura, P., Ruiz, P. J., Steinman, L. & Garren, H. An immunomodulatory GpG oligonucleotide for the treatment of autoimmunity via the innate and adaptive immune systems. J. Immunol. 171, 4920–4926 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Ho, P. P. et al. A suppressive oligodeoxynucleotide enhances the efficacy of myelin cocktail/IL-4-tolerizing DNA vaccination and treats autoimmune disease. J. Immunol. 175, 6226–6234 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Bresson, D. et al. Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs . J. Clin. Invest. 116, 1371–1381 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Sarikonda, G. 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 8, e54712 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The work of the authors was supported by the Hungarian National Science Fund (NKFI OTKA NK 104846) (G.S.) and by the European Union and the State of Hungary co-financed by the European Social Fund in the framework of TAMOP-4.2.4.A/2-11/1-2012-0001 'National Excellence Program' (Z.S.).

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Authors and Affiliations

  1. Department of Immunology, Eötvös Loránd University (ELTE), Pázmány Péter Sétány 1/C, Budapest, 1117, Hungary

    Judit Pozsgay & Gabriella Sármay

  2. Division of Rheumatology, Department of Medicine, University of Debrecen Faculty of Medicine, Nagyerdei Körút 98, Debrecen, 4032, Hungary

    Zoltán Szekanecz

Authors
  1. Judit Pozsgay
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  2. Zoltán Szekanecz
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  3. Gabriella Sármay
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Contributions

All authors wrote the manuscript. Z.S. and J.P. researched the data for the article. Z.S. and G.S. undertook review and/or editing of the manuscript before submission and provided substantial contributions to discussions of its content.

Corresponding author

Correspondence to Zoltán Szekanecz.

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The authors declare no competing financial interests.

PowerPoint slides

Glossary

Tetramer

An oligomer comprised of four monomers; in the case of MHC–peptide tetramers, four copies of biotinylated MHC–peptide molecules are bound to streptavidin.

Nanoparticles

Microscopic particles sized 1–100 nm.

Mimetope

A protein or peptide that resembles the conformation or structure of an antigen, resulting in cross-reactivity.

Heteropolymer

A compound formed from multiple subunits that are not all the same.

Autoepitope

A part of the self-protein that is recognized by autoantibodies or autoreactive B cells or T cells.

Anergy

Lymphocyte unresponsiveness.

Epitope spreading

Diversification of epitope specificity, whereby during an autoimmune response additional new epitopes of the same antigen are recognized.

Shared epitope

A common sequence of amino acids at residues 70–74 of HLA-DRB1, found in alleles associated with rheumatoid arthritis.

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Pozsgay, J., Szekanecz, Z. & Sármay, G. Antigen-specific immunotherapies in rheumatic diseases. Nat Rev Rheumatol 13, 525–537 (2017). https://doi.org/10.1038/nrrheum.2017.107

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  • DOI: https://doi.org/10.1038/nrrheum.2017.107

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