Peripheral blood regulatory t cells in patients with diffuse systemic sclerosis (ssc) before and after autologous hematopoietic sct: a pilot study

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ABSTRACT The present pilot study aims to evaluate the frequency and the function of regulatory T (Treg) cells in patients with diffuse cutaneous SSc (dcSSc) before and after autologous


hematopoietic SCT (aHSCT). Peripheral blood lymphocytes from seven dcSSc patients were analyzed before and 24 months after aHSCT and were compared with those from seven healthy donors


(controls). Immunophenotyping of CD4+CD25highFoxP3+ natural Treg (nTreg), CD4+CD25+TGF-β+ and CD4+CD25+IL-10+ adaptive Treg (aTreg) cell subsets was performed using four-color flow


cytometry. Treg-suppressive capability was measured after coculture with autologous T effector cells by evaluation of T-cell proliferation using 3H-thymidine incorporation. Peripheral


CD4+CD25highFoxP3+ (2±0.5 vs 4.2±1.1, _P_<0.01), CD4+CD25+TGF-β+ (6.9±1.8 vs 14.6±5.0, _P_<0.05) and CD4+CD25+IL-10+ (10.7±0.5 vs 16.1±3.2, _P_<0.01) Tregs as well as


CD4+CD25highCD127low Tregs suppressive capacity (_P_<0.05) were decreased in dcSSc patients vs controls. After aHSCT (_n_=7), the percentages of CD4+CD25highFoxP3+ (4.1±1.8) and


CD4+CD25+IL-10+ (15.7±2.2) Treg cells and the suppressive activity of CD4+CD25highCD127low were restored to the levels in controls. The decreased frequency and the functional defect of


peripheral Treg cells from patients with dcSSc are reversed following aHSCT to reach those observed in controls. This pilot study brings evidence of an effective restoration of nTreg and


aTreg subsets, and recovery of nTreg suppressive function following aHSCT. Access through your institution Buy or subscribe This is a preview of subscription content, access via your


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* Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS HIGH PROPORTION OF TERMINALLY DIFFERENTIATED REGULATORY T CELLS


AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION Article 04 March 2021 CD70 EXPRESSION DETERMINES THE THERAPEUTIC EFFICACY OF EXPANDED HUMAN REGULATORY T CELLS Article Open access 14


July 2020 A DONOR PD-1+CD8+ TSCM-LIKE REGULATORY SUBSET MOBILIZED BY G-CSF ALLEVIATES RECIPIENT ACUTE GRAFT-VERSUS-HOST-DISEASE Article Open access 02 April 2025 REFERENCES * Gabrielli A,


Avvedimento EV, Krieg T . Scleroderma. _N Engl J Med_ 2009; 360: 1989–2003. Article  CAS  PubMed  Google Scholar  * Baraut J, Michel L, Verrecchia F, Farge D . Relationship between cytokine


profiles and clinical outcomes in patients with systemic sclerosis. _Autoimmun Rev_ 2010; 10: 65–73. Article  CAS  PubMed  Google Scholar  * Chizzolini C . T cells, B cells, and polarized


immune response in the pathogenesis of fibrosis and systemic sclerosis. _Curr Opin Rheumatol_ 2008; 20: 707–712. Article  CAS  PubMed  Google Scholar  * Yurovsky VV, Wigley FM, Wise RA,


White B . Skewing of the CD8+ T-cell repertoire in the lungs of patients with systemic sclerosis. _Hum Immunol_ 1996; 48: 84–97. Article  CAS  PubMed  Google Scholar  * Dieckmann D, Plottner


H, Berchtold S, Berger T, Schuler G . _Ex vivo_ isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. _J Exp Med_ 2001; 193: 1303–1310.


Article  CAS  PubMed  PubMed Central  Google Scholar  * Fontenot JD, Gavin MA, Rudensky AY . Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. _Nat Immunol_ 2003;


4: 330–336. Article  CAS  PubMed  Google Scholar  * Bluestone JA, Abbas AK . Natural versus adaptive regulatory T cells. _Nat Rev Immunol_ 2003; 3: 253–257. Article  CAS  PubMed  Google


Scholar  * Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M _et al_. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling


autoimmunity, tumor immunity, and transplantation tolerance. _Immunol Rev_ 2001; 182: 18–32. Article  CAS  PubMed  Google Scholar  * Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J,


Sakaguchi N _et al_. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. _J Exp Med_ 2000; 192:


303–310. Article  CAS  PubMed  PubMed Central  Google Scholar  * Wood KJ, Sakaguchi S . Regulatory T cells in transplantation tolerance. _Nat Rev Immunol_ 2003; 3: 199–210. Article  CAS 


PubMed  Google Scholar  * Curotto de Lafaille MA, Lafaille JJ . CD4(+) regulatory T cells in autoimmunity and allergy. _Curr Opin Immunol_ 2002; 14: 771–778. Article  CAS  PubMed  Google


Scholar  * Banica L, Besliu A, Pistol G, Stavaru C, Ionescu R, Forsea A-M _et al_. Quantification and molecular characterization of regulatory T cells in connective tissue diseases.


_Autoimmunity_ 2009; 42: 41–49. Article  CAS  PubMed  Google Scholar  * Brusko TM, Putnam AL, Bluestone JA . Human regulatory T cells: role in autoimmune disease and therapeutic


opportunities. _Immunol Rev_ 2008; 223: 371–390. Article  CAS  PubMed  Google Scholar  * Bonelli M, Savitskaya A, von Dalwigk K, Steiner CW, Aletaha D, Smolen JS _et al_. Quantitative and


qualitative deficiencies of regulatory T cells in patients with systemic lupus erythematosus (SLE). _Int Immunol_ 2008; 20: 861–868. Article  CAS  PubMed  Google Scholar  * Cao D, Malmström


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: 215–223. Article  CAS  PubMed  Google Scholar  * 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: 971–979. Article  CAS  PubMed  PubMed Central  Google Scholar  * Kriegel MA, Lohmann T, Gabler C, Blank N,


Kalden JR, Lorenz H-M . Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II. _J Exp Med_ 2004; 199: 1285–1291. Article  CAS 


PubMed  PubMed Central  Google Scholar  * Balandina A, Lécart S, Dartevelle P, Saoudi A, Berrih-Aknin S . Functional defect of regulatory CD4(+)CD25+ T cells in the thymus of patients with


autoimmune myasthenia gravis. _Blood_ 2005; 105: 735–741. Article  CAS  PubMed  Google Scholar  * Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TIM . Defective suppressor function


in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. _Diabetes_ 2005; 54: 92–99. Article  CAS  PubMed  Google Scholar  * 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: 1056–1063. Article  CAS  PubMed  Google


Scholar  * Papp G, Horvath IF, Barath S, Gyimesi E, Sipka S, Szodoray P _et al_. Altered T-cell and regulatory cell repertoire in patients with diffuse cutaneous systemic sclerosis. _Scand J


Rheumatol_ 2011; 40: 205–210. Article  CAS  PubMed  Google Scholar  * Fenoglio D, Battaglia F, Parodi A, Stringara S, Negrini S, Panico N _et al_. Alteration of Th17 and Treg cell


subpopulations co-exist in patients affected with systemic sclerosis. _Clin Immunol_ 2011; 139: 249–257. Article  CAS  PubMed  Google Scholar  * Radstake TRDJ, 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 TGFbeta expression. _PLoS


One_ 2009; 4: e5981. Article  PubMed  PubMed Central  Google Scholar  * Giovannetti A, Rosato E, Renzi C, Maselli A, Gambardella L, Giammarioli AM _et al_. Analyses of T cell phenotype and


function reveal an altered T cell homeostasis in systemic sclerosis. Correlations with disease severity and phenotypes. _Clin Immunol_ 2010; 137: 122–133. Article  CAS  PubMed  Google


Scholar  * Slobodin G, Ahmad MS, Rosner I, Peri R, Rozenbaum M, Kessel A _et al_. Regulatory T cells (CD4(+)CD25(bright)FoxP3(+)) expansion in systemic sclerosis correlates with disease


activity and severity. _Cell Immunol_ 2010; 261: 77–80. Article  CAS  PubMed  Google Scholar  * Klein S, Kretz CC, Ruland V, Stumpf C, Haust M, Hartschuh W _et al_. Reduction of regulatory T


cells in skin lesions but not in peripheral blood of patients with systemic scleroderma. _Ann Rheum Dis_ 2011; 70: 1475–1481. Article  CAS  PubMed  Google Scholar  * Burt RK, Shah SJ, Dill


K, Grant T, Gheorghiade M, Schroeder J _et al_. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis


(ASSIST): an open-label, randomised phase 2 trial. _Lancet_ 2011; 378: 498–506. Article  CAS  PubMed  Google Scholar  * Vonk MC, Marjanovic Z, van den Hoogen FHJ, Zohar S, Schattenberg


AVMB, Fibbe WE _et al_. Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis. _Ann Rheum Dis_ 2008; 67: 98–104. Article  CAS 


PubMed  Google Scholar  * Farge D, Henegar C, Carmagnat M, Daneshpouy M, Marjanovic Z, Rabian C _et al_. Analysis of immune reconstitution after autologous bone marrow transplantation in


systemic sclerosis. _Arthritis Rheum_ 2005; 52: 1555–1563. Article  CAS  PubMed  Google Scholar  * Bohgaki T, Atsumi T, Bohgaki M, Furusaki A, Kondo M, Sato-Matsumura KC _et al_.


Immunological reconstitution after autologous hematopoietic stem cell transplantation in patients with systemic sclerosis: relationship between clinical benefits and intensity of


immunosuppression. _J Rheumatol_ 2009; 36: 1240–1248. Article  CAS  PubMed  Google Scholar  * LeRoy EC, Medsger Jr TA . Criteria for the classification of early systemic sclerosis. _J


Rheumatol_ 2001; 28: 1573–1576. CAS  PubMed  Google Scholar  * Kuhn A, Beissert S, Krammer PH . CD4(+)CD25 (+) regulatory T cells in human lupus erythematosus. _Arch Dermatol Res_ 2009; 301:


71–81. Article  PubMed  Google Scholar  * 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: 1701–1711. Article  CAS  PubMed  PubMed Central  Google Scholar  * 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: 6346–6358. Article  CAS  PubMed  Google Scholar  * 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: 805–816. Article  CAS  PubMed  PubMed Central  Google Scholar  * 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: 1696–1702. Article  CAS  PubMed  Google Scholar  * 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: 214–223. Article  CAS  PubMed  Google Scholar  * Radbruch A, Thiel A . Cell therapy for autoimmune


diseases: does it have a future? _Ann Rheum Dis_ 2004; 63: ii96–ii101. Article  CAS  PubMed  PubMed Central  Google Scholar  * Venigalla RKC, Tretter T, Krienke S, Max R, Eckstein V, Blank N


_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_ 2008; 58: 2120–2130. Article  PubMed  Google Scholar  * van Amelsfort JMR, van Roon JAG, Noordegraaf M, Jacobs KMG, Bijlsma JWJ, Lafeber FPJG _et al_. Proinflammatory mediator-induced


reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis. _Arthritis Rheum_ 2007; 56: 732–742. Article  CAS  PubMed  Google Scholar  * O’Sullivan BJ, Thomas HE,


Pai S, Santamaria P, Iwakura Y, Steptoe RJ _et al_. IL-1 beta breaks tolerance through expansion of CD25+ effector T cells. _J Immunol_ 2006; 176: 7278–7287. Article  PubMed  Google Scholar


  * Farge D, Gluckman E . Autologous HSCT in systemic sclerosis: a step forward. _Lancet_ 2011; 378: 460–462. Article  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We


acknowledge the Association des Sclérodermiques de France (ASF) and the Groupe Francophone de Recherche sur la Sclérodermie (GFRS). This work was supported by grants from the Groupe Français


de Recherche sur la Sclérodermie (GFRS). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * INSERM U976 and Université Paris Diderot Sorbonne Paris Cité, Hôpital Saint-Louis, Paris, France J


Baraut, E I Grigore, F Jean-Louis, D Farge & L Michel * Service de Médecine Interne, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris, France S H Khelifa & D Farge *


Service de Médecine Interne, Hôpital Hôtel Dieu, Nantes, France C Durand * INSERM U957 and Université Nantes Atlantique, Nantes, France F Verrecchia Authors * J Baraut View author


publications You can also search for this author inPubMed Google Scholar * E I Grigore View author publications You can also search for this author inPubMed Google Scholar * F Jean-Louis


View author publications You can also search for this author inPubMed Google Scholar * S H Khelifa View author publications You can also search for this author inPubMed Google Scholar * C


Durand View author publications You can also search for this author inPubMed Google Scholar * F Verrecchia View author publications You can also search for this author inPubMed Google


Scholar * D Farge View author publications You can also search for this author inPubMed Google Scholar * L Michel View author publications You can also search for this author inPubMed Google


Scholar CORRESPONDING AUTHOR Correspondence to L Michel. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. RIGHTS AND PERMISSIONS Reprints and permissions


ABOUT THIS ARTICLE CITE THIS ARTICLE Baraut, J., Grigore, E., Jean-Louis, 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 Transplant_ 49, 349–354 (2014). https://doi.org/10.1038/bmt.2013.202 Download citation * Received: 13 August 2012 * Revised: 26


September 2013 * Accepted: 10 October 2013 * Published: 23 December 2013 * Issue Date: March 2014 * DOI: https://doi.org/10.1038/bmt.2013.202 SHARE THIS ARTICLE Anyone you share the


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Nature SharedIt content-sharing initiative KEYWORDS * systemic sclerosis * regulatory T cells * hematopoietic stem cell transplantation * T-cell proliferation