Tolerance regeneration by T regulatory cells in autologous haematopoietic stem cell transplantation for autoimmune diseases

Abstract

Autologous haematopoietic stem cell transplantation shows increasing promise as a therapeutic option for patients with treatment-refractory autoimmune disease, particularly systemic sclerosis and multiple sclerosis. However, this intensive chemotherapy-based procedure is not always possible due to potential treatment toxicities and comorbidities. The biological mechanisms of how this procedure induces long-term remission in autoimmune disease are increasingly understood. The focus of this review is on recent research findings on the role of CD4+ T regulatory cells (Tregs) in resetting the immune system leading to the eradication of the autoimmune disease after transplantation. Discovery of the precise mechanisms of this process will allow development of novel Treg-based therapies and thus avoid the need for intensive chemotherapy-based treatment for these autoimmune diseases in the future.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Alexander T, Arnold R, Hiepe F, Radbruch A. Resetting the immune system with immunoablation and autologous haematopoietic stem cell transplantation in autoimmune diseases. Clin Exp Rheumatol. 2016;34:53–7.

  2. 2.

    Consortium TAaNZMSG. Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat Genet. 2009;41:824–8. http://www.nature.com/ng/journal/v41/n7/suppinfo/ng.396_S1.html.

  3. 3.

    Tschochner M, Leary S, Cooper D, Strautins K, Chopra A, Clark H, et al. Identifying patient-specific epstein-barr nuclear antigen-1 genetic variation and potential autoreactive targets relevant to multiple sclerosis pathogenesis. PLoS ONE. 2016;11:e0147567. https://doi.org/10.1371/journal.pone.0147567.

  4. 4.

    Pattanaik D, Brown M, Postlethwaite BC, Postlethwaite AE. Pathogenesis of systemic sclerosis. Front Immunol. 2015;6:272–272. https://doi.org/10.3389/fimmu.2015.00272.

  5. 5.

    Farge D, Labopin M, Tyndall A, Fassas A, Mancardi GL, Van Laar J, et al. Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on 12 years’ experience from the European Group for Blood and Marrow Transplantation Working Party on autoimmune diseases. Haematologica. 2010;95:284–92. https://doi.org/10.3324/haematol.2009.013458.

  6. 6.

    van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014;311:2490–8. https://doi.org/10.1001/jama.2014.6368.

  7. 7.

    Muraro PA, Martin R, Mancardi GL, Nicholas R, Sormani MP, Saccardi R. Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis. Nat Rev Neurol. 2017;13:391.

  8. 8.

    Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC, et al. Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: a randomized clinical trial effect of nonmyeloablative HSCT vs disease-modifying therapy on relapsing-remitting MS disease progression effect of nonmyeloablative HSCT vs disease-modifying therapy on relapsing-remitting MS disease progression. JAMA. 2019;321:165–74. https://doi.org/10.1001/jama.2018.18743.

  9. 9.

    Snowden JA, Badoglio M, Labopin M, Giebel S, McGrath E, Marjanovic Z, et al. Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases. Blood Adv. 2017;1:2742–55. https://doi.org/10.1182/bloodadvances.2017010041.

  10. 10.

    Atkins HL, Bowman M, Allan D, Anstee G, Arnold DL, Bar-Or A, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016;388:576–85.

  11. 11.

    Grant CR, Liberal R, Mieli-Vergani G, Vergani D, Longhi MS. Regulatory T-cells in autoimmune diseases: challenges, controversies and—yet—unanswered questions. Autoimmun Rev. 2015;14:105–16. https://doi.org/10.1016/j.autrev.2014.10.012.

  12. 12.

    Sakaguchi S, Wing K, Miyara M. Regulatory T cells—a brief history and perspective. Eur J Immunol. 2007;37:S116–23. https://doi.org/10.1002/eji.200737593.

  13. 13.

    Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–87. https://doi.org/10.1016/j.cell.2008.05.009.

  14. 14.

    Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30:636–45. https://doi.org/10.1016/j.immuni.2009.04.010.

  15. 15.

    Koreth J, Ritz J. Tregs, HSCT, and acute GVHD: up close and personal. Blood. 2013;122:1690–1691. https://doi.org/10.1182/blood-2013-07-514125.

  16. 16.

    Goodyear OC, Dennis M, Jilani NY, Loke J, Siddique S, Ryan G, et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood. 2012;119:3361–9. https://doi.org/10.1182/blood-2011-09-377044.

  17. 17.

    Craddock C, Jilani N, Siddique S, Yap C, Khan J, Nagra S, et al. Tolerability and clinical activity of post-transplantation azacitidine in patients allografted for acute myeloid leukemia treated on the RICAZA trial. Biol Blood Marrow Transplant. 2016;22:385–90. https://doi.org/10.1016/j.bbmt.2015.09.004.

  18. 18.

    Malmegrim KC, de Azevedo JT, Arruda L, Abreu JR, Couri CE, de Oliveira GL et al. Immunological balance is associated with clinical outcome after autologous hematopoietic stem cell transplantation in type 1 diabetes. Front Immunol. 2017; 8. https://doi.org/10.3389/fimmu.2017.00167.

  19. 19.

    Massey JC, Sutton IJ, Ma DDF, Moore JJ. Regenerating immunotolerance in multiple sclerosis with autologous hematopoietic stem cell transplant. Front. Immunol. 2018; 9. https://doi.org/10.3389/fimmu.2018.00410.

  20. 20.

    Zhang L, Bertucci AM, Ramsey-Goldman R, Burt RK, Datta SK. Regulatory T cell (Treg) subsets return in patients with refractory lupus following stem cell transplantation, and TGF-beta-producing CD8+ Treg cells are associated with immunological remission of lupus. J Immunol. 2009;183:6346–58. https://doi.org/10.4049/jimmunol.0901773.

  21. 21.

    Arruda LC, Clave E, Moins-Teisserenc H, Douay C, Farge D, Toubert A. Resetting the immune response after autologous hematopoietic stem cell transplantation for autoimmune diseases. Curr Res Transl Med. 2016;64:107–13. https://doi.org/10.1016/j.retram.2016.03.004.

  22. 22.

    Delemarre EM, van den Broek T, Mijnheer G, Meerding J, Wehrens EJ, Olek S, et al. Autologous stem cell transplantation benefits autoimmune patients through functional renewal and TCR diversification of the regulatory T cell compartment. Blood. 2015;127:91–101. https://doi.org/10.1182/blood-2015-06-649145.

  23. 23.

    Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 2006;6:823.

  24. 24.

    Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4 + CD25high regulatory cells in human peripheral blood. J Immunol. 2001;167:1245–53. https://doi.org/10.4049/jimmunol.167.3.1245.

  25. 25.

    Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203:1701–11. https://doi.org/10.1084/jem.20060772.

  26. 26.

    Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203:1693–1700. https://doi.org/10.1084/jem.20060468.

  27. 27.

    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155:1151–64.

  28. 28.

    Bacchetta R, Passerini L, Gambineri E, Dai M, Allan SE, Perroni L, et al. Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Investig. 2006;116:1713–22. https://doi.org/10.1172/JCI25112.

  29. 29.

    Le Bras S, Geha RS. IPEX and the role of Foxp3 in the development and function of human Tregs. J Clin Investig. 2006;116:1473–5. https://doi.org/10.1172/JCI28880.

  30. 30.

    Dhamne C, Chung Y, Alousi AM, Cooper LJN, Tran DQ. Peripheral and thymic foxp3(+) regulatory T cells in search of origin, distinction, and function. Front Immunol. 2013;4:253–253. https://doi.org/10.3389/fimmu.2013.00253.

  31. 31.

    Ohkura N, Kitagawa Y, Sakaguchi S. Development and maintenance of regulatory T cells. Immunity; 38 : 414–23. https://doi.org/10.1016/j.immuni.2013.03.002.

  32. 32.

    Himmel ME, MacDonald KG, Garcia RV, Steiner TS, Levings MK. Helios+ and Helios-cells coexist within the natural FOXP3+ T regulatory cell subset in humans. J Immunol. 2013;190:2001–8.

  33. 33.

    Ito T, Hanabuchi S, Wang Y-H, Park WR, Arima K, Bover L, et al. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity. 2008;28:870–80. https://doi.org/10.1016/j.immuni.2008.03.018.

  34. 34.

    Haas J, Fritzsching B, Trübswetter P, Korporal M, Milkova L, Fritz B, et al. Prevalence of newly generated naive regulatory T cells (Treg) is critical for treg suppressive function and determines Treg dysfunction in multiple sclerosis. J Immunol. 2007;179:1322–30. https://doi.org/10.4049/jimmunol.179.2.1322.

  35. 35.

    Larbi A, Fulop T. From “truly naïve” to “exhausted senescent” T cells: when markers predict functionality. Cytom Part A. 2014;85:25–35.

  36. 36.

    Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–63.

  37. 37.

    Vukmanovic-Stejic M, Zhang Y, Cook JE, Fletcher JM, McQuaid A, Masters JE, et al. Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo. J Clin Investig. 2006;116:2423–33. https://doi.org/10.1172/JCI28941.

  38. 38.

    Bono MR, Fernandez D, Flores-Santibanez F, Rosemblatt M, Sauma D. CD73 and CD39 ectonucleotidases in T cell differentiation: beyond immunosuppression. FEBS Lett. 2015;589:3454–60. https://doi.org/10.1016/j.febslet.2015.07.027.

  39. 39.

    Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood. 2007;110:1225–32. https://doi.org/10.1182/blood-2006-12-064527.

  40. 40.

    Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O’Farrelly C, et al. CD39+Foxp3+ regulatory T cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol. 2009;183:7602–10. https://doi.org/10.4049/jimmunol.0901881.

  41. 41.

    Fuschiotti P. Current perspectives on the role of CD8+ T cells in systemic sclerosis. Immunol Lett. 2018;195:55–60. https://doi.org/10.1016/j.imlet.2017.10.002.

  42. 42.

    Negrini S, Fenoglio D, Parodi A, Kalli F, Battaglia F, Nasi G et al. Phenotypic alterations involved in CD8+ treg impairment in systemic sclerosis. Front Immunol. 2017; 8. https://doi.org/10.3389/fimmu.2017.00018.

  43. 43.

    Friedman DJ, Kunzli BM, AR YI, Sevigny J, Berberat PO, Enjyoji K, et al. CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease. Proc Natl Acad Sci. 2009;106:16788–93. https://doi.org/10.1073/pnas.0902869106.

  44. 44.

    Rissiek A, Baumann I, Cuapio A, Mautner A, Kolster M, Arck PC, et al. The expression of CD39 on regulatory T cells is genetically driven and further upregulated at sites of inflammation. J Autoimmun. 2015;58:12–20. https://doi.org/10.1016/j.jaut.2014.12.007.

  45. 45.

    Huehn J, Hamann A. Homing to suppress: address codes for Treg migration. Trends Immunol. 2005;26:632–6. https://doi.org/10.1016/j.it.2005.10.001.

  46. 46.

    Huehn J, Siegmund K, Lehmann JC, Siewert C, Haubold U, Feuerer M, et al. Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. J Exp Med. 2004;199:303–13. https://doi.org/10.1084/jem.20031562.

  47. 47.

    Cao D, Malmstrom V, Baecher-Allan C, Hafler D, Klareskog L, Trollmo C. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol. 2003;33:215–23. https://doi.org/10.1002/immu.200390024.

  48. 48.

    van Amelsfort JM, Jacobs KM, Bijlsma JW, Lafeber FP, Taams LS. CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheumatol. 2004;50:2775–85. https://doi.org/10.1002/art.20499.

  49. 49.

    Baranzini SE, Oksenberg JR. The genetics of multiple sclerosis: from 0 to 200 in 50 years. Trends Genet. 2017;33:960–70. https://doi.org/10.1016/j.tig.2017.09.004.

  50. 50.

    Astier AL, Hafler DA. Abnormal Tr1 differentiation in multiple sclerosis. J Neuroimmunol. 2007;191:70–8. https://doi.org/10.1016/j.jneuroim.2007.09.018.

  51. 51.

    Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199:971–9. https://doi.org/10.1084/jem.20031579.

  52. 52.

    Huan J, Culbertson N, Spencer L, Bartholomew R, Burrows GG, Chou YK, et al. Decreased FOXP3 levels in multiple sclerosis patients. J Neurosci Res. 2005;81:45–52. https://doi.org/10.1002/jnr.20522.

  53. 53.

    Venken K, Hellings N, Thewissen M, Somers V, Hensen K, Rummens J-L, et al. Compromised CD4(+) CD25(high) regulatory T-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level. Immunology. 2008;123:79–89. https://doi.org/10.1111/j.1365-2567.2007.02690.x.

  54. 54.

    Arruda LC, de Azevedo JT, de Oliveira GL, Scortegagna GT, Rodrigues ES, Palma PV, et al. Immunological correlates of favorable long-term clinical outcome in multiple sclerosis patients after autologous hematopoietic stem cell transplantation. Clin Immunol. 2016;169:47–57. https://doi.org/10.1016/j.clim.2016.06.005.

  55. 55.

    Dalla Libera D, Di Mitri D, Bergami A, Centonze D, Gasperini C, Grasso MG, et al. T regulatory cells are markers of disease activity in multiple sclerosis patients. PLoS ONE. 2011;6:e21386 https://doi.org/10.1371/journal.pone.0021386.

  56. 56.

    Peelen E, Damoiseaux J, Smolders J, Knippenberg S, Menheere P, Tervaert JW, et al. Th17 expansion in MS patients is counterbalanced by an expanded CD39+ regulatory T cell population during remission but not during relapse. J Neuroimmunol. 2011;240-241:97–103. https://doi.org/10.1016/j.jneuroim.2011.09.013.

  57. 57.

    Muls NG, Dang HA, Sindic CJ, van Pesch V. Regulation of Treg-associated CD39 in multiple sclerosis and effects of corticotherapy during relapse. Mult Scler J. 2015;21:1533–45. https://doi.org/10.1177/1352458514567215.

  58. 58.

    Antiga E, Quaglino P, Bellandi S, Volpi W, Del Bianco E, Comessatti A, et al. Regulatory T cells in the skin lesions and blood of patients with systemic sclerosis and morphoea. Br J Dermatol. 2010;162:1056–63.

  59. 59.

    Radstake TR, Van Bon L, Broen J, Wenink M, Santegoets K, Deng Y, et al. Increased frequency and compromised function of T regulatory cells in systemic sclerosis (SSc) is related to a diminished CD69 and TGFβ expression. PloS ONE. 2009;4:e5981.

  60. 60.

    Mathian A, Parizot C, Dorgham K, Trad S, Arnaud L, Larsen M, et al. Activated and resting regulatory T cell exhaustion concurs with high levels of interleukin-22 expression in systemic sclerosis lesions. Ann Rheum Dis. 2012;71:1227–34.

  61. 61.

    Muraro PA, Douek DC, Packer A, Chung K, Guenaga FJ, Cassiani-Ingoni R, et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J Exp Med. 2005;201:805–16.

  62. 62.

    Muraro PA, Robins H, Malhotra S, Howell M, Phippard D, Desmarais C, et al. T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Investig. 2014;124:1168–72.

  63. 63.

    Arruda LC, Malmegrim KC, Lima-Júnior JR, Clave E, Dias JB, Moraes DA, et al. Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients. Blood Adv. 2018;2:126–41.

  64. 64.

    Rebeiro P, Moore J. The role of autologous haemopoietic stem cell transplantation in the treatment of autoimmune disorders. Intern Med J. 2016;46:17–28. https://doi.org/10.1111/imj.12944.

  65. 65.

    Alexander T, Thiel A, Rosen O, Massenkeil G, Sattler A, Kohler S, et al. Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood. 2009;113:214–23.

  66. 66.

    Abrahamsson SV, Angelini DF, Dubinsky AN, Morel E, Oh U, Jones JL, et al. Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis. Brain. 2013;136:2888–903.

  67. 67.

    Baraut J, Grigore EI, Jean-Louis F, Khelifa SH, Durand C, Verrecchia F, et al. Peripheral blood regulatory T cells in patients with diffuse systemic sclerosis (SSc) before and after autologous hematopoietic SCT: a pilot study. Bone Marrow Transpl. 2014;49:349–54. https://doi.org/10.1038/bmt.2013.202.

  68. 68.

    Clerici M, Cassinotti A, Onida F, Trabattoni D, Annaloro C, Della Volpe A, et al. Immunomodulatory effects of unselected haematopoietic stem cells autotransplantation in refractory Crohn’s disease. Digestive Liver Dis. 2011;43:946–52. https://doi.org/10.1016/j.dld.2011.07.021.

  69. 69.

    Pockley AG, Lindsay JO, Foulds GA, Rutella S, Gribben JG, Alexander T et al. Immune reconstitution after autologous hematopoietic stem cell transplantation in crohn’s disease: current status and future directions. a review on behalf of the EBMT autoimmune diseases working party and the autologous stem cell transplantation in refractory CD—low intensity therapy evaluation study investigators. Front Immunol. 2018; 9. https://doi.org/10.3389/fimmu.2018.00646.

  70. 70.

    de Kleer I, Vastert B, Klein M, Teklenburg G, Arkesteijn G, Yung GP, et al. Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4+CD25+ immune regulatory network. Blood. 2006;107:1696–702. https://doi.org/10.1182/blood-2005-07-2800.

  71. 71.

    Moore JJ, Massey JC, Ford CD, Khoo ML, Zaunders JJ, Hendrawan K, et al. Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis. J Neurol Neurosurg Psychiatry. 2019;90:514–21.

  72. 72.

    Luznik L, Fuchs EJ. High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res. 2010;47:65–77. https://doi.org/10.1007/s12026-009-8139-0.

  73. 73.

    Kanakry CG, Ganguly S, Zahurak M, Bolaños-Meade J, Thoburn C, Perkins B, et al. Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci Transl Med. 2013;5:211ra157–211ra157.

  74. 74.

    Lopez M, Clarkson MR, Albin M, Sayegh MH, Najafian N. A novel mechanism of action for anti-thymocyte globulin: induction of CD4+ CD25+ Foxp3+ regulatory T cells. J Am Soc Nephrol. 2006;17:2844–53.

  75. 75.

    Arruda LCM, Lima-Júnior JR, Clave E, Moraes DA, Douay C, Fournier I, et al. Homeostatic proliferation leads to telomere attrition and increased PD-1 expression after autologous hematopoietic SCT for systemic sclerosis. Bone Marrow Transplant. 2018;53:1319–27. https://doi.org/10.1038/s41409-018-0162-0.

  76. 76.

    Asano T, Meguri Y, Yoshioka T, Kishi Y, Iwamoto M, Nakamura M, et al. PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy. Blood. 2017;129:2186–97. e-pub ahead of print 2017/02/06; https://doi.org/10.1182/blood-2016-09-741629.

  77. 77.

    Amarnath S, Mangus CW, Wang JCM, Wei F, He A, Kapoor V. et al. The PDL1-PD1 axis converts human Th1 cells into regulatory Tcells. Sci Transl Med. 2011;3:111ra120–111ra120. https://doi.org/10.1126/scitranslmed.3003130.

  78. 78.

    Karnell FG, Lin D, Motley S, Duhen T, Lim N, Campbell DJ, et al. Reconstitution of immune cell populations in multiple sclerosis patients after autologous stem cell transplantation. Clin Exp Immunol. 2017;189:268–78. https://doi.org/10.1111/cei.12985.

  79. 79.

    Arruda L, Lorenzi J, Sousa A, Zanette D, Palma P, Panepucci R, et al. Autologous hematopoietic SCT normalizes miR-16,-155 and-142-3p expression in multiple sclerosis patients. Bone marrow Transplant. 2015;50:380–9.

  80. 80.

    Basdeo SA, Moran B, Cluxton D, Canavan M, McCormick J, Connolly M, et al. Polyfunctional, pathogenic CD161+ Th17 lineage cells are resistant to regulatory T cell-mediated suppression in the context of autoimmunity. J Immunol. 2015;195:528–40. https://doi.org/10.4049/jimmunol.1402990.

  81. 81.

    Radstake TRDJ, van Bon L, Broen J, Hussiani A, Hesselstrand R, Wuttge DM, et al. The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFβ and IFNγ distinguishes SSc phenotypes. Plos ONE. 2009;4:e5903 https://doi.org/10.1371/journal.pone.0005903.

  82. 82.

    Murata M, Fujimoto M, Matsushita T, Hamaguchi Y, Hasegawa M, Takehara K, et al. Clinical association of serum interleukin-17 levels in systemic sclerosis: Is systemic sclerosis a Th17 disease? J Dermatological Sci. 2008;50:240–2. https://doi.org/10.1016/j.jdermsci.2008.01.001.

  83. 83.

    Kurasawa K, Hirose K, Sano H, Endo H, Shinkai H, Nawata Y, et al. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheumatism. 2000;43:2455–63. 10.1002/1529-0131(200011)43:11<2455::AID-ANR12>3.0.CO;2-K

  84. 84.

    Fenoglio D, Bernuzzi F, Battaglia F, Parodi A, Kalli F, Negrini S, et al. Th17 and regulatory T lymphocytes in primary biliary cirrhosis and systemic sclerosis as models of autoimmune fibrotic diseases. Autoimmun Rev. 2012;12:300–4. https://doi.org/10.1016/j.autrev.2012.05.004.

  85. 85.

    Bengsch B, Ohtani T, Khan O, Setty M, Manne S, O’Brien S, et al. Epigenomic-guided mass cytometry profiling reveals disease-specific features of exhausted CD8 T cells. Immunity. 2018;48:1029–45.e1025. https://doi.org/10.1016/j.immuni.2018.04.026.

  86. 86.

    Ochoa-Reparaz J, Kasper LH. The influence of gut-derived CD39 regulatory T cells in CNS demyelinating disease. Transl Res. 2017;179:126–38. https://doi.org/10.1016/j.trsl.2016.07.016.

  87. 87.

    Wang C, Kang SG, Lee J, Sun Z, Kim CH. The roles of CCR6 in migration of Th17 cells and regulation of effector T-cell balance in the gut. Mucosal Immunol. 2009;2:173–83. https://doi.org/10.1038/mi.2008.84.

  88. 88.

    Yamazaki T, Yang XO, Chung Y, Fukunaga A, Nurieva R, Pappu B, et al. CCR6 regulates the migration of inflammatory and regulatory T cells. J Immunol. 2008;181:8391–401. https://doi.org/10.4049/jimmunol.181.12.8391.

  89. 89.

    Koreth J, Matsuoka K-i, Kim HT, McDonough SM, Bindra B, Alyea EP, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. New Engl J Med. 2011;365:2055–66. https://doi.org/10.1056/NEJMoa1108188.

  90. 90.

    K-i Matsuoka, Koreth J, Kim HT, Bascug G, McDonough S, Kawano Y, et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med. 2013;5:179ra143–179ra143. https://doi.org/10.1126/scitranslmed.3005265.

  91. 91.

    Theil A, Tuve S, Oelschlagel U, Maiwald A, Dohler D, Ossmann D, et al. Adoptive transfer of allogeneic regulatory T cells into patients with chronic graft-versus-host disease. Cytotherapy. 2015;17:473–86. https://doi.org/10.1016/j.jcyt.2014.11.005.

Download references

Acknowledgements

KH is supported by a scholarship from the National Health and Medical Research Council. JM, DDFM and MV are supported by the St Vincent’s Foundation Clinic Grant, Reset Australia, SVH Haematology Research Fund, Maple-Brown Family Foundation, John Kirkpatrick Family Foundation, Medich Family Foundation and NSW Health Australia.

Author information

Correspondence to John J. Moore.

Ethics declarations

Conflict of interest

DDFM receives a research grant from Phebra Pty Ltd outside of submitted work. The remaining authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hendrawan, K., Visweswaran, M., Ma, D.D.F. et al. Tolerance regeneration by T regulatory cells in autologous haematopoietic stem cell transplantation for autoimmune diseases. Bone Marrow Transplant (2019). https://doi.org/10.1038/s41409-019-0710-2

Download citation