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Recent Advances in Cell Therapeutics for Systemic Autoimmune Diseases

곽승기|박영재
대한면역학회 (The Korean Association of Immunologists)|2022.02|Immune Network|제22권 제1호|pp. 1-17|DOI 10.4110/in.2022.22.e10

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키워드

Autoimmune diseaseMesenchymal stromal cellsCell therapyRegulatory T cellsMyeloid-derived suppressor cells

초록

Systemic autoimmune diseases arise from loss of self-tolerance and immune homeostasis between effector and regulator functions. There are many therapeutic modalities for autoimmune diseases ranging from conventional disease-modifying anti-rheumatic drugs and immunosuppressants exerting nonspecific immune suppression to targeted agents including biologic agents and small molecule inhibitors aiming at specific cytokines and intracellular signal pathways. However, such current therapeutic strategies can rarely induce recovery of immune tolerance in autoimmune disease patients. To overcome limitations of conventional treatment modalities, novel approaches using specific cell populations with immune-regulatory properties have been attempted to attenuate autoimmunity. Recently progressed biotechnologies enable sufficient in vitro expansion and proper manipulation of such ‘tolerogenic’ cell populations to be considered for clinical application. We introduce 3 representative cell types with immunosuppressive features, including mesenchymal stromal cells, Tregs, and myeloid-derived suppressor cells. Their cellular definitions, characteristics, mechanisms of immune regulation, and recent data about preclinical and clinical studies in systemic autoimmune diseases are reviewed here. Challenges and limitations of each cell therapy are also addressed.

Abstract

Systemic autoimmune diseases arise from loss of self-tolerance and immune homeostasis between effector and regulator functions. There are many therapeutic modalities for autoimmune diseases ranging from conventional disease-modifying anti-rheumatic drugs and immunosuppressants exerting nonspecific immune suppression to targeted agents including biologic agents and small molecule inhibitors aiming at specific cytokines and intracellular signal pathways. However, such current therapeutic strategies can rarely induce recovery of immune tolerance in autoimmune disease patients. To overcome limitations of conventional treatment modalities, novel approaches using specific cell populations with immune-regulatory properties have been attempted to attenuate autoimmunity. Recently progressed biotechnologies enable sufficient in vitro expansion and proper manipulation of such ‘tolerogenic’ cell populations to be considered for clinical application. We introduce 3 representative cell types with immunosuppressive features, including mesenchymal stromal cells, Tregs, and myeloid-derived suppressor cells. Their cellular definitions, characteristics, mechanisms of immune regulation, and recent data about preclinical and clinical studies in systemic autoimmune diseases are reviewed here. Challenges and limitations of each cell therapy are also addressed.

참고문헌 (96)

  1. Marrack P, "Autoimmune disease : why and where it occurs", Nat Med, 7, pp.899~905 (2001)
  2. Cronstein BN, "Methotrexate and its mechanisms of action in inflammatory arthritis", Nat Rev Rheumatol, 16, pp.145~154 (2020)
  3. Hardy RS, "Therapeutic glucocorticoids : mechanisms of actions in rheumatic diseases", Nat Rev Rheumatol, 16, pp.133~144 (2020)
  4. Nikiphorou E, "Biologics registers in RA : methodological aspects, current role and future applications", Nat Rev Rheumatol, 13, pp.503~510 (2017)
  5. Rendas-Baum R, "Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients with an inadequate response to tumor necrosis factor-α inhibitors", Arthritis Res Ther, 13, pp.R25~ (2011)
  6. Kuijper TM, "Flare rate in patients with rheumatoid arthritis in low disease activity or remission when tapering or stopping synthetic or biologic DMARD : a systematic review", J Rheumatol, 42, pp.2012~2022 (2015)
  7. Murphy G, "New therapies for systemic lupus erythematosus-past imperfect, future tense", Nat Rev Rheumatol, 15, pp.403~412 (2019)
  8. Mosanya CH, "Tolerising cellular therapies : what is their promise for autoimmune disease", Ann Rheum Dis, 78, pp.297~310 (2019)
  9. Dominici M, "Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement", Cytotherapy, 8, pp.315~317 (2006)
  10. Wang Y, "Plasticity of mesenchymal stem cells in immunomodulation : pathological and therapeutic implications", Nat Immunol, 15, pp.1009~1016 (2014)
  11. Friedenstein AJ, "Fibroblast precursors in normal and irradiated mouse hematopoietic organs", Exp Hematol, 4, pp.267~274 (1976)
  12. El-Jawhari JJ, "Multipotent mesenchymal stromal cells in rheumatoid arthritis and systemic lupus erythematosus; from a leading role in pathogenesis to potential therapeutic saviors", Front Immunol, 12, pp.643170~ (2021)
  13. Kyurkchiev D, "Secretion of immunoregulatory cytokines by mesenchymal stem cells", World J Stem Cells, 6, pp.552~570 (2014)
  14. Jiang D, "Suppression of neutrophil-mediated tissue damage-a novel skill of mesenchymal stem cells", Stem Cells, 34, pp.2393~2406 (2016)
  15. Ren G, "Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1in mesenchymal stem cells are critical for immunosuppression", J Immunol, 184, pp.2321~2328 (2010)
  16. Ryan ST, "Extracellular vesicles from mesenchymal stromal cells for the treatment of inflammation-related conditions", Int J Mol Sci, 22, pp.3023~ (2021)
  17. Maccario R, "Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory", suppressive phenotype, 2005, pp.90, 516~525
  18. Corcione A, "Human mesenchymal stem cells modulate B-cell functions", Blood, 107, pp.367~372 (2006)
  19. Le Blanc K, "HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells", Exp Hematol, 31, pp.890~896 (2003)
  20. Majumdar MK, "Characterization and functionality of cell surface molecules on human mesenchymal stem cells", J Biomed Sci, 10, pp.228~241 (2003)
  21. Haynesworth SE, "Characterization of cells with osteogenic potential from human marrow", Bone, 13, pp.81~88 (1992)
  22. In ’t Anker PS, "Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta", Stem Cells, 22, pp.1338~1345 (2004)
  23. Zuk PA, "Multilineage cells from human adipose tissue : implications for cell-based therapies", Tissue Eng, 7, pp.211~228 (2001)
  24. Kim HJ, "Nasal turbinate mesenchymal stromal cells preserve characteristics of their neural crest origin and exert distinct paracrine activity", J Clin Med, 10, pp.1792~ (2021)
  25. Ménard C, "Immunoregulatory properties of clinical grade mesenchymal stromal cells : evidence, uncertainties, and clinical application", Stem Cell Res Ther, 4, pp.64~ (2013)
  26. Djouad F, "Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collageninduced arthritis", Arthritis Rheum, 52, pp.1595~1603 (2005)
  27. Augello A, "Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis", Arthritis Rheum, 56, pp.1175~1186 (2007)
  28. González MA, "Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells", Arthritis Rheum, 60, pp.1006~1019 (2009)
  29. Park EH, "Intravenous infusion of umbilical cord bloodderived mesenchymal stem cells in rheumatoid arthritis : a phase Ia clinical trial", Stem Cells Transl Med, 7, pp.636~642 (2018)
  30. Wang L, "Human umbilical cord mesenchymal stem cell therapy for patients with active rheumatoid arthritis : safety and efficacy", Stem Cells Dev, 22, pp.3192~3202 (2013)
  31. Álvaro-Gracia JM, "Intravenous administration of expanded allogeneic adiposederived mesenchymal stem cells in refractory rheumatoid arthritis(Cx611) : results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib", IIa clinical trial, 2017, pp.76, 196~202
  32. Ghoryani M, "The sufficient immunoregulatory effect of autologous bone marrow-derived mesenchymal stem cell transplantation on regulatory T cells in patients with refractory rheumatoid arthritis", J Immunol Res, 2020, pp.3562753~ (2020)
  33. Zhou K, "Transplantation of human bone marrow mesenchymal stem cell ameliorates the autoimmune pathogenesis in MRL", lpr mice, 2008, pp.5, 417~424
  34. Choi EW, "Reversal of serologic, immunologic, and histologic dysfunction in mice with systemic lupus erythematosus by long-term serial adipose tissue-derived mesenchymal stem cell transplantation", Arthritis Rheum, 64, pp.243~253 (2012)
  35. Gu Z, "Transplantation of umbilical cord mesenchymal stem cells alleviates lupus nephritis in MRL", lpr mice, 2010, pp.19, 1502~1514
  36. Sun L, "Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans", Stem Cells, 27, pp.1421~1432 (2009)
  37. Liang J, "Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus : a pilot clinical study", Ann Rheum Dis, 69, pp.1423~1429 (2010)
  38. Sun L, "Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus", Arthritis Rheum, 62, pp.2467~2475 (2010)
  39. Li X, "Mesenchymal SCT ameliorates refractory cytopenia in patients with systemic lupus erythematosus", Bone Marrow Transplant, 48, pp.544~550 (2013)
  40. Wang D, "Allogeneic mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus : 4 years of experience", Cell Transplant, 22, pp.2267~2277 (2013)
  41. Gu F, "Allogeneic mesenchymal stem cell transplantation for lupus nephritis patients refractory to conventional therapy", Clin Rheumatol, 33, pp.1611~1619 (2014)
  42. Carrion F, "Autologous mesenchymal stem cell treatment increased T regulatory cells with no effect on disease activity in two systemic lupus erythematosus patients", Lupus, 19, pp.317~322 (2010)
  43. Liang J, "Safety analysis in patients with autoimmune disease receiving allogeneic mesenchymal stem cells infusion : a long-term retrospective study", Stem Cell Res Ther, 9, pp.312~ (2018)
  44. Farge D, "Mesenchymal stromal cells for systemic sclerosis treatment", Autoimmun Rev, 20, pp.102755~ (2021)
  45. Guiducci S, "Autologous mesenchymal stem cells foster revascularization of ischemic limbs in systemic sclerosis : a case report", Ann Intern Med, 153, pp.650~654 (2010)
  46. Ishigatsubo Y, "Therapeutic angiogenesis in patients with systemic sclerosis by autologous transplantation of bone-marrow-derived cells", Mod Rheumatol, 20, pp.263~272 (2010)
  47. Christopeit M, "Marked improvement of severe progressive systemic sclerosis after transplantation of mesenchymal stem cells from an allogeneic haploidentical-related donor mediated by ligation of CD137L", Leukemia, 22, pp.1062~1064 (2008)
  48. Keyszer G, "Treatment of severe progressive systemic sclerosis with transplantation of mesenchymal stromal cells from allogeneic related donors : report of five cases", Arthritis Rheum, 63, pp.2540~2542 (2011)
  49. Chihaby N, "Treatment of Sjögren’s syndrome with mesenchymal stem cells : a systematic review", Int J Mol Sci, 22, pp.10474~ (2021)
  50. Xu J, "Allogeneic mesenchymal stem cell treatment alleviates experimental and clinical Sjögren syndrome", Blood, 120, pp.3142~3151 (2012)
  51. Lukomska B, "Challenges and controversies in human mesenchymal stem cell therapy", Stem Cells Int, 2019, pp.9628536~ (2019)
  52. Liu M, "Adipose-derived mesenchymal stem cells from the elderly exhibit decreased migration and differentiation abilities with senescent properties", Cell Transplant, 26, pp.1505~1519 (2017)
  53. Joswig AJ, "Repeated intraarticular injection of allogeneic mesenchymal stem cells causes an adverse response compared to autologous cells in the equine model", Stem Cell Res Ther, 8, pp.42~ (2017)
  54. Vignali DA, "How regulatory T cells work", Nat Rev Immunol, 8, pp.523~532 (2008)
  55. Dominguez-Villar M, "Regulatory T cells in autoimmune disease", Nat Immunol, 19, pp.665~673 (2018)
  56. Sharabi A, "Regulatory T cells in the treatment of disease", Nat Rev Drug Discov, 17, pp.823~844 (2018)
  57. Jordan MS, "Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide", Nat Immunol, 2, pp.301~306 (2001)
  58. Sojka DK, "Mechanisms of regulatory T-cell suppression-a diverse arsenal for a moving target", Immunology, 124, pp.13~22 (2008)
  59. Sakaguchi S, "Regulatory T cells : how do they suppress immune responses", Int Immunol, 21, pp.1105~1111 (2009)
  60. Selck C, "Antigen-specific regulatory T cell therapy in autoimmune diseases and transplantation", Front Immunol, 12, pp.661875~ (2021)
  61. Marek-Trzonkowska N, "Administration of CD4+CD25highCD127-regulatory T cells preserves β-cell function in type 1 diabetes in children", Diabetes Care, 35, pp.1817~1820 (2012)
  62. Chwojnicki K, "Administration of CD4+CD25highCD127-FoxP3+ regulatory T cells for relapsing-remitting multiple sclerosis : a phase 1 study", BioDrugs, 35, pp.47~60 (2021)
  63. Sánchez-Fueyo A, "Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation", Am J Transplant, 20, pp.1125~1136 (2020)
  64. Thornton AM, "Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific", J Immunol, 164, pp.183~190 (2000)
  65. Tang Q, "In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes", J Exp Med, 199, pp.1455~1465 (2004)
  66. Stephens LA, "Curing CNS autoimmune disease with myelin-reactive Foxp3+Treg", Eur J Immunol, 39, pp.1108~1117 (2009)
  67. Desreumaux P, "Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease", Gastroenterology, 143, pp.1207~1217 (2012)
  68. Sadeqi Nezhad M, "Chimeric antigen receptor based therapy as a potential approach in autoimmune diseases : how close are we to the treatment", Front Immunol, 11, pp.603237~ (2020)
  69. Wright GP, "Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis", Proc Natl Acad Sci U S A, 106, pp.19078~19083 (2009)
  70. Fujio K, "Gene therapy of arthritis with TCR isolated from the inflamed paw", J Immunol, 177, pp.8140~8147 (2006)
  71. Mougiakakos D, "CD19-targeted CAR T cells in refractory systemic lupus erythematosus", N Engl J Med, 385, pp.567~569 (2021)
  72. Rana J, "Regulatory T cell therapy : current and future design perspectives", Cell Immunol, 356, pp.104193~ (2020)
  73. Veglia F, "Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity", Nat Rev Immunol, 21, pp.485~498 (2021)
  74. Zhang J, "Myeloid-derived suppressor cells as cellular immunotherapy in transplantation and autoimmune diseases", Cell Immunol, 362, pp.104300~ (2021)
  75. Bronte V, "Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards", Nat Commun, 7, pp.12150~ (2016)
  76. Zhao F, "S100A9 a new marker for monocytic human myeloid-derived suppressor cells", Immunology, 136, pp.176~183 (2012)
  77. Condamine T, "Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients", Sci Immunol, 1, pp.aaf8943~ (2016)
  78. Youn JI, "Subsets of myeloid-derived suppressor cells in tumorbearing mice", J Immunol, 181, pp.5791~5802 (2008)
  79. Kusmartsev S, "Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species", J Immunol, 172, pp.989~999 (2004)
  80. Raber PL, "Subpopulations of myeloid-derived suppressor cells impair T cell responses through independent nitric oxide-related pathways", Int J Cancer, 134, pp.2853~2864 (2014)
  81. Bingisser RM, "Macrophage-derived nitric oxide regulates T cell activation via reversible disruption of the Jak3", STAT5 signaling pathway, 1998, pp.160, 5729~5734
  82. Emily L. Yarosz, "The Role of Reactive Oxygen Species in Regulating T Cell-mediated Immunity and Disease", Immune Network, 18(1), pp.1~15 (2018), 대한면역학회[DOI]
  83. Rodriguez PC, "Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses", Cancer Res, 64, pp.5839~5849 (2004)
  84. Srivastava MK, "Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine", Cancer Res, 70, pp.68~77 (2010)
  85. Hanson EM, "Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4+ and CD8+ T cells", J Immunol, 183, pp.937~944 (2009)
  86. Yang Y, "Myeloid-derived suppressor cells in tumors : from mechanisms to antigen specificity and microenvironmental regulation", Front Immunol, 11, pp.1371~ (2020)
  87. Juneja VR, "PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity", J Exp Med, 214, pp.895~904 (2017)
  88. Groth C, "Immunosuppression mediated by myeloid-derived suppressor cells(MDSCs)during tumour progression", Br J Cancer, 120, pp.16~25 (2019)
  89. Leipe J, "Role of Th17 cells in human autoimmune arthritis", Arthritis Rheum, 62, pp.2876~2885 (2010)
  90. Zhang H, "Myeloid-derived suppressor cells are proinflammatory and regulate collagen-induced arthritis through manipulating Th17 cell differentiation", Clin Immunol, 157, pp.175~186 (2015)
  91. Park MJ, "Interleukin-10 produced by myeloid-derived suppressor cells is critical for the induction of Tregs and attenuation of rheumatoid inflammation in mice", Sci Rep, 8, pp.3753~ (2018)
  92. Wu H, "Arginase-1-dependent promotion of TH17 differentiation and disease progression by MDSCs in systemic lupus erythematosus", Sci Transl Med, 8, pp.331~ (2016)
  93. Park YS, "Mouse models of primary Sjogren’s syndrome", Curr Pharm Des, 21, pp.2350~2364 (2015)
  94. Qi J, "Myeloid-derived suppressor cells exacerbate Sjögren’s syndrome by inhibiting Th2 immune responses", Mol Immunol, 101, pp.251~258 (2018)
  95. Park MJ, "Myeloid-derived suppressor cells induce the expansion of regulatory B cells and ameliorate autoimmunity in the sanroque mouse model of systemic lupus erythematosus", Arthritis Rheumatol, 68, pp.2717~2727 (2016)
  96. Park MJ, "Programmed death-ligand 1expression potentiates the immune modulatory function of myeloid-derived suppressor cells in systemic lupus erythematosus", Front Immunol, 12, pp.606024~ (2021)

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