Top

Published in:

Open Access 01-02-2016 | Scleroderma (J Varga, Section Editor)

Cellular Therapies in Systemic Sclerosis: Recent Progress

Authors: Femke C. C. van Rhijn-Brouwer, Hendrik Gremmels, Joost O. Fledderus, Timothy R. D. Radstake, Marianne C. Verhaar, Jacob M. van Laar

Published in: Current Rheumatology Reports | Issue 2/2016

Abstract

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with a high mortality and morbidity. While progress has been made in terms of identifying high-risk patients and implementing new treatment strategies, therapeutic options remain limited. In the past few decades, various cellular therapies have emerged, which have been studied in SSc and other conditions. Here, we provide a comprehensive review of currently available cellular therapies and critically assess their merit as disease-modifying treatment for SSc. Currently, hematopoietic stem cell transplantation is the only cellular therapy that has demonstrated clinical effects on the immune system, neoangiogenesis, and fibrosis. Robust mechanistic studies as well as clinical trials are essential to move the field forward.

Nikpour M, Baron M. Mortality in systemic sclerosis: lessons learned from population-based and observational cohort studies. Curr Opin Rheumatol. 2014;26(2):131–7. doi:10.1097/BOR.0000000000000027.CrossRefPubMed

Tyndall AJ, Bannert B, Vonk M, Airò P, Cozzi F, Carreira PE, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 2010;69(10):1809–15. doi:10.1136/ard.2009.114264.CrossRefPubMed

LeRoy EC, Medsger TA. Criteria for the classification of early systemic sclerosis. J Rheumatol. 2001;28(7):1573–6.PubMed

Rubio-Rivas M, Royo C, Simeón CP, Corbella X, Fonollosa V. Mortality and survival in systemic sclerosis: systematic review and meta-analysis. Semin Arthritis Rheum. 2014;44(2):208–19. doi:10.1016/j.semarthrit.2014.05.010.CrossRefPubMed

5.•

Young A, Khanna D. Systemic sclerosis: a systematic review on therapeutic management from 2011 to 2014. Curr Opin Rheumatol. 2015;27(3):241–8. doi:10.1097/BOR.0000000000000172. Comprehensive evaluation of therapeutic options in SSc.CrossRefPubMed

Postlethwaite AE, Harris LJ, Raza SH, Kodura S, Akhigbe T. Pharmacotherapy of systemic sclerosis. Expert Opin Pharmacother. 2010;11(5):789–806. doi:10.1517/14656561003592177.CrossRefPubMedPubMedCentral

Phumethum V, Jamal S, Johnson SR. Biologic therapy for systemic sclerosis: a systematic review. J Rheumatol. 2011;38(2):289–96. doi:10.3899/jrheum.100361.CrossRefPubMed

Katsumoto TR, Whitfield ML, Connolly MK. The pathogenesis of systemic sclerosis. Annu Rev Pathol. 2011;6:509–37. doi:10.1146/annurev-pathol-011110-130312.CrossRefPubMed

Castelino FV, Varga J. Emerging cellular and molecular targets in fibrosis: implications for scleroderma pathogenesis and targeted therapy. Curr Opin Rheumatol. 2014;26(6):607–14. doi:10.1097/BOR.0000000000000110.CrossRefPubMed

10.

Guiducci S, Distler O, Distler JHW, Matucci-Cerinic M. Mechanisms of vascular damage in SSc—implications for vascular treatment strategies. Rheumatology (Oxford). 2008;47 Suppl 5:v18–20. doi:10.1093/rheumatology/ken267.CrossRef

11.

Prakken JR. Niehans cellular therapy as discussed in the lay press & in our journal. Ned Tijdschr Geneeskd. 1958;102(47):2313–4.PubMed

12.

Unproven methods of cancer management. Fresh cell therapy. CA Cancer J Clin. 1991;41(2):126–8. doi:10.3322/canjclin.41.2.126.

13.

Moira E, Bardon L. Siccacell treatment in mongolism. Lancet. 1964;284(7353):234–5. doi:10.1016/S0140-6736(64)90185-0.CrossRef

14.

Cipriani P, Carubbi F, Liakouli V, Marrelli A, Perricone C, Perricone R, et al. Stem cells in autoimmune diseases: implications for pathogenesis and future trends in therapy. Autoimmun Rev. 2013;12(7):709–16. doi:10.1016/j.autrev.2012.10.004.CrossRefPubMed

15.

Raval Z, Losordo DW. Cell therapy of peripheral arterial disease: from experimental findings to clinical trials. Circ Res. 2013;112(9):1288–302. doi:10.1161/CIRCRESAHA.113.300565.CrossRefPubMed

16.

Kim SU, de Vellis J. Stem cell-based cell therapy in neurological diseases: a review. J Neurosci Res. 2009;87(10):2183–200. doi:10.1002/jnr.22054.CrossRefPubMed

17.

Stroncek DF, Berger C, Cheever MA, Childs RW, Dudley ME, Flynn P, et al. New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer. J Transl Med. 2012;10:48. doi:10.1186/1479-5876-10-48.CrossRefPubMedPubMedCentral

18.

Petrof G, Abdul-Wahab A, McGrath JA. Cell therapy in dermatology. Cold Spring Harb Perspect Med. 2014;4(6). doi:10.1101/cshperspect.a015156.

19.

Tyndall A. Stem cells: HSCT for systemic sclerosis—swallows and summers. Nat Rev Rheumatol. 2011;7(11):624–6. doi:10.1038/nrrheum.2011.136.CrossRefPubMed

20.

Tsukamoto H, Nagafuji K, Horiuchi T, Mitoma H, Niiro H, Arinobu Y, et al. Analysis of immune reconstitution after autologous CD34+ stem/progenitor cell transplantation for systemic sclerosis: predominant reconstitution of Th1 CD4+ T cells. Rheumatology (Oxford). 2011;50(5):944–52. doi:10.1093/rheumatology/keq414.CrossRef

21.

Verrecchia F, Laboureau J, Verola O, Roos N, Porcher R, Bruneval P, et al. Skin involvement in scleroderma—where histological and clinical scores meet. Rheumatology (Oxford). 2007;46(5):833–41. doi:10.1093/rheumatology/kel451.CrossRef

22.

Launay D, Marjanovic Z, de Bazelaire C, Florea L, Zohar S, Keshtmand H, et al. Autologous hematopoietic stem cell transplant in systemic sclerosis: quantitative high resolution computed tomography of the chest scoring. J Rheumatol. 2009;36(7):1460–3. doi:10.3899/jrheum.081212.CrossRefPubMed

23.

Fleming JN, Nash RA, McLeod DO, Fiorentino DF, Shulman HM, Connolly MK, et al. Capillary regeneration in scleroderma: stem cell therapy reverses phenotype? PLoS One. 2008;3(1):e1452-e. doi:10.1371/journal.pone.0001452.CrossRef

24.

Miniati I, Guiducci S, Conforti ML, Rogai V, Fiori G, Cinelli M, et al. Autologous stem cell transplantation improves microcirculation in systemic sclerosis. Ann Rheum Dis. 2009;68(1):94–8. doi:10.1136/ard.2007.082495.CrossRefPubMed

25.

Losordo DW, Kibbe MR, Mendelsohn F, Marston W, Driver VR, Sharafuddin M, et al. A randomized, controlled pilot study of autologous CD34+ cell therapy for critical limb ischemia. Circ Cardiovasc Interv. 2012;5(6):821–30. doi:10.1161/CIRCINTERVENTIONS.112.968321.CrossRefPubMedPubMedCentral

26.

Binks M. Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann Rheum Dis. 2001;60(6):577–84. doi:10.1136/ard.60.6.577.CrossRefPubMedPubMedCentral

27.

Farge D, Passweg J, van Laar JM, Marjanovic Z, Besenthal C, Finke J, et al. Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR Registry. Ann Rheum Dis. 2004;63(8):974–81. doi:10.1136/ard.2003.011205.CrossRefPubMedPubMedCentral

28.

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(1):98–104. doi:10.1136/ard.2007.071464.CrossRefPubMed

29.

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(9790):498–506. doi:10.1016/S0140-6736(11)60982-3.CrossRefPubMed

30.••

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. JAMA. 2014;311(24):2490–2498. doi:10.1001/jama.2014.6368. Landmark clinical trial that confirmed the therapeutic efficacy of HSCT for progressive SSc.

31.

Craciunescu OI, Steffey BA, Kelsey CR, Larrier NA, Paarz-Largay CJ, Prosnitz RG, et al. Renal shielding and dosimetry for patients with severe systemic sclerosis receiving immunoablation with total body irradiation in the scleroderma: cyclophosphamide or transplantation trial. Int J Radiat Oncol Biol Phys. 2011;79(4):1248–55. doi:10.1016/j.ijrobp.2010.05.036.CrossRefPubMed

32.

Friedenstein AJ, Chailakhyan RK. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues: cloning in vitro and retransplantation in vivo. Transplantation. 1974;17(4):331–40.CrossRefPubMed

33.

Caplan AI. Mesenchymal stem cells. J Orthop Res : Off Publ Orthopaedic Res Soc. 1991;9(5):641–50. doi:10.1002/jor.1100090504.CrossRef

34.

Bianco P, Cao X, Frenette PS, Mao JJ, Robey PG, Simmons PJ, et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med. 2013;19(1):35–42. doi:10.1038/nm.3028.CrossRefPubMedPubMedCentral

35.

Dazzi F, van Laar JM, Cope A, Tyndall A. Cell therapy for autoimmune diseases. Arthritis Res Ther. 2007;9(2):206. doi:10.1186/ar2128.CrossRefPubMedPubMedCentral

36.••

Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One. 2012;7(10):e47559. doi:10.1371/journal.pone.0047559. Excellent overview of safety outcomes of clinical trials utilizing MSC.CrossRefPubMedPubMedCentral

37.

Bronckaers A, Hilkens P, Martens W, Gervois P, Ratajczak J, Struys T, et al. Mesenchymal stem/stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis. Pharmacol Ther. 2014;143(2):181–96. doi:10.1016/j.pharmthera.2014.02.013.CrossRefPubMed

38.

Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98(5):1076–84. doi:10.1002/jcb.20886.CrossRefPubMed

39.

Griffin MD, Ritter T, Mahon BP. Immunological aspects of allogeneic mesenchymal stem cell therapies. Hum Gene Ther. 2010;21(12):1641–55. doi:10.1089/hum.2010.156.CrossRefPubMed

40.

Khosrotehrani K. Mesenchymal stem cell therapy in skin: why and what for? Exp Dermatol. 2013;22(5):307–10. doi:10.1111/exd.12141.CrossRefPubMed

41.

Smith AN, Willis E, Chan VT, Muffley LA, Isik FF, Gibran NS, et al. Mesenchymal stem cells induce dermal fibroblast responses to injury. Exp Cell Res. 2010;316(1):48–54. doi:10.1016/j.yexcr.2009.08.001.CrossRefPubMedPubMedCentral

42.

Duffy GP, Ahsan T, OBrien T, Barry F, Nerem RM. Bone marrow-derived mesenchymal stem cells promote angiogenic processes in a time- and dose-dependent manner in vitro. Tissue Eng A. 2009;15(9):2459–70. doi:10.1089/ten.TEA.2008.0341.

43.

Uccelli A, Moretta L, Pistoia V. Immunoregulatory function of mesenchymal stem cells. Eur J Immunol. 2006;36(10):2566–73. doi:10.1002/eji.200636416.CrossRefPubMed

44.

Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371(9624):1579–86. doi:10.1016/S0140-6736(08)60690-X.CrossRefPubMed

45.

Wang D, Zhang H, Liang J, Li X, Feng X, Wang H, et al. Allogeneic mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus: 4 years of experience. Cell Transplant. 2013;22(12):2267–77. doi:10.3727/096368911X582769.CrossRefPubMed

46.

Peng Y, Chen X, Liu Q, Zhang X, Huang K, Liu L, et al. Mesenchymal stromal cells infusions improve refractory chronic graft versus host disease through an increase of CD5+ regulatory B cells producing interleukin 10. Leukemia. 2015;29(3):636–46. doi:10.1038/leu.2014.225.CrossRefPubMed

47.

Herrmann R, Sturm M, Shaw K, Purtill D, Cooney J, Wright M, et al. Mesenchymal stromal cell therapy for steroid-refractory acute and chronic graft versus host disease: a phase 1 study. Int J Hematol. 2012;95(2):182–8. doi:10.1007/s12185-011-0989-2.CrossRefPubMed

48.•

Liew A, O’Brien T. Therapeutic potential for mesenchymal stem cell transplantation in critical limb ischemia. Stem Cell Res Ther. 2012;3(4):28. doi:10.1186/scrt119. Comprehensive overview of MSC transplantation in both preclinical and clinical studies.CrossRefPubMedPubMedCentral

49.

Guiducci S, Porta F, Saccardi R, Guidi S, Ibba-Manneschi L, Manetti M, et al. Autologous mesenchymal stem cells foster revascularization of ischemic limbs in systemic sclerosis: a case report. Ann Intern Med. 2010;153(10):650–4. doi:10.7326/0003-4819-153-10-201011160-00007.CrossRefPubMed

50.

Watt SM, Gullo F, van der Garde M, Markeson D, Camicia R, Khoo CP, et al. The angiogenic properties of mesenchymal stem/stromal cells and their therapeutic potential. Br Med Bull. 2013;108(1):25–53. doi:10.1093/bmb/ldt031.CrossRefPubMedPubMedCentral

51.

Christopeit M, Schendel M, Föll J, Müller LP, Keysser G, Behre G. 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. 2008;22(5):1062–4. doi:10.1038/sj.leu.2404996.CrossRefPubMed

52.

Keyszer G, Christopeit M, Fick S, Schendel M, Taute BM, Behre G, et al. Treatment of severe progressive systemic sclerosis with transplantation of mesenchymal stromal cells from allogeneic related donors: report of five cases. Arthritis Rheum. 2011;63(8):2540–2. doi:10.1002/art.30431.CrossRefPubMed

53.

Schrepfer S, Deuse T, Reichenspurner H, Fischbein MP, Robbins RC, Pelletier MP. Stem cell transplantation: the lung barrier. Transplant Proc. 2007;39(2):573–6. doi:10.1016/j.transproceed.2006.12.019.CrossRefPubMed

54.

Gholamrezanezhad A, Mirpour S, Bagheri M, Mohamadnejad M, Alimoghaddam K, Abdolahzadeh L, et al. In vivo tracking of 111In-oxine labeled mesenchymal stem cells following infusion in patients with advanced cirrhosis. Nucl Med Biol. 2011;38(7):961–7. doi:10.1016/j.nucmedbio.2011.03.008.CrossRefPubMed

55.

Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275(5302):964–7.CrossRefPubMed

56.

Sprengers RW, Moll FL, Verhaar MC. Stem cell therapy in PAD. Eur J Vasc Endovasc Surg : Off J Eur Soc Vasc Surg. 2010;39 Suppl 1:S38–43. doi:10.1016/j.ejvs.2009.12.001.CrossRef

57.

Nevskaya T, Ananieva L, Bykovskaia S, Eremin I, Karandashov E, Khrennikov J, et al. Autologous progenitor cell implantation as a novel therapeutic intervention for ischaemic digits in systemic sclerosis. Rheumatology (Oxford). 2009;48(1):61–4. doi:10.1093/rheumatology/ken407.CrossRef

58.

Takagi G, Miyamoto M, Tara S, Kirinoki-Ichikawa S, Kubota Y, Hada T, et al. Therapeutic vascular angiogenesis for intractable macroangiopathy-related digital ulcer in patients with systemic sclerosis: a pilot study. Rheumatology (U K). 2014;53(5):854–9. doi:10.1093/rheumatology/ket432.CrossRef

59.

Ishigatsubo Y, Ihata A, Kobayashi H, Hama M, Kirino Y, Ueda A, et al. Therapeutic angiogenesis in patients with systemic sclerosis by autologous transplantation of bone-marrow-derived cells. Mod Rheumatol. 2010;20(3):263–72. doi:10.1007/s10165-010-0274-x.

60.

Kamata Y, Takahashi Y, Iwamoto M, Matsui K, Murakami Y, Muroi K, et al. Local implantation of autologous mononuclear cells from bone marrow and peripheral blood for treatment of ischaemic digits in patients with connective tissue diseases. Rheumatology (Oxford). 2007;46(5):882–4. doi:10.1093/rheumatology/kel436.CrossRef

61.•

Del Papa N, Di Luca G, Sambataro D, Zaccara E, Maglione W, Gabrielli A, et al. Regional implantation of autologous adipose tissue-derived cells induces a prompt healing of long-lasting indolent digital ulcers in patients with systemic sclerosis. Cell Transplant. 2014. doi:10.3727/096368914X685636. Report detailing implantation of unexpanded ADC in fifteen patients.PubMed

62.

Granel B, Daumas A, Jouve E, Harlé J-R, Nguyen P-S, Chabannon C, et al. Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial. Ann Rheum Dis. 2014. doi:10.1136/annrheumdis-2014-205681.PubMedPubMedCentral

63.

Scuderi N, Ceccarelli S, Onesti MG, Fioramonti P, Guidi C, Romano F, et al. Human adipose-derived stromal cells for cell-based therapies in the treatment of systemic sclerosis. Cell Transplant. 2013;22(5):779–95. doi:10.3727/096368912X639017.CrossRefPubMed

64.

Lu D, Chen B, Liang Z, Deng W, Jiang Y, Li S, et al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res Clin Pract. 2011;92(1):26–36. doi:10.1016/j.diabres.2010.12.010.CrossRefPubMed

65.

Iwase T, Nagaya N, Fujii T, Itoh T, Murakami S, Matsumoto T, et al. Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hindlimb ischemia. Cardiovasc Res. 2005;66(3):543–51. doi:10.1016/j.cardiores.2005.02.006.CrossRefPubMed

66.

Chung CYJ, Ysebaert D, Berneman ZN, Cools N. Dendritic cells: cellular mediators for immunological tolerance. Clin Dev Immunol. 2013;2013:972865. doi:10.1155/2013/972865.CrossRefPubMedPubMedCentral

67.

Van Brussel I, Lee WP, Rombouts M, Nuyts AH, Heylen M, De Winter BY, et al. Tolerogenic dendritic cell vaccines to treat autoimmune diseases: can the unattainable dream turn into reality? Autoimmun Rev. 2014;13(2):138–50. doi:10.1016/j.autrev.2013.09.008.CrossRefPubMed

68.

Gross CC, Wiendl H. Dendritic cell vaccination in autoimmune disease. Curr Opin Rheumatol. 2013;25(2):268–74. doi:10.1097/BOR.0b013e32835cb9f2.CrossRefPubMed

69.

van Bon L, Popa C, Huijbens R, Vonk M, York M, Simms R, et al. Distinct evolution of TLR-mediated dendritic cell cytokine secretion in patients with limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2010;69(8):1539–47. doi:10.1136/ard.2009.128207.CrossRefPubMed

70.

Lu TT. Dendritic cells: novel players in fibrosis and scleroderma. Curr Rheumatol Rep. 2012;14(1):30–8. doi:10.1007/s11926-011-0215-5.CrossRefPubMed

71.•

van Bon L, Affandi AJ, Broen J, Christmann RB, Marijnissen RJ, Stawski L, et al. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med. 2014;370(5):433–43. doi:10.1056/NEJMoa1114576. Evidence for a role of DC in the pathogenesis of SSc.CrossRefPubMedPubMedCentral

72.

Sozzani S, Rusnati M, Riboldi E, Mitola S, Presta M. Dendritic cell-endothelial cell cross-talk in angiogenesis. Trends Immunol. 2007;28(9):385–92. doi:10.1016/j.it.2007.07.006.CrossRefPubMed

73.

Pizzurro GA, Barrio MM. Dendritic cell-based vaccine efficacy: aiming for hot spots. Front Immunol. 2015;6:91. doi:10.3389/fimmu.2015.00091.CrossRefPubMedPubMedCentral

74.

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. 2011;34(9):2026–32. doi:10.2337/dc11-0472.CrossRefPubMedPubMedCentral

75.

Benham H, Nel HJ, Law SC, Mehdi AM, Street S, Ramnoruth N, et al. Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. Sci Transl Med. 2015;7(290):290ra87–ra87. doi:10.1126/scitranslmed.aaa9301.CrossRefPubMed

76.

Bantsimba-Malanda C, Marchal-Sommé J, Goven D, Freynet O, Michel L, Crestani B, et al. A role for dendritic cells in bleomycin-induced pulmonary fibrosis in mice? Am J Respir Crit Care Med. 2010;182(3):385–95. doi:10.1164/rccm.200907-1164OC.CrossRefPubMed

77.

Mackern-Oberti JP, Llanos C, Vega F, Salazar-Onfray F, Riedel CA, Bueno SM, et al. Role of dendritic cells in the initiation, progress and modulation of systemic autoimmune diseases. Autoimmun Rev. 2015;14(2):127–39. doi:10.1016/j.autrev.2014.10.010.CrossRefPubMed

78.

Bluestone JA. Opinion: regulatory T-cell therapy: is it ready for the clinic? Nat Rev Immunol. 2005;5(4):343–9. doi:10.1038/nri1574.CrossRefPubMed

79.

Miyara M, Ito Y, Sakaguchi S. TREG-cell therapies for autoimmune rheumatic diseases. Nat Rev Rheumatol. 2014;10(9):543–51. doi:10.1038/nrrheum.2014.105.CrossRefPubMed

80.

Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011;117(3):1061–70. doi:10.1182/blood-2010-07-293795.CrossRefPubMedPubMedCentral

81.

O’Reilly S, Hügle T, van Laar JM. T cells in systemic sclerosis: a reappraisal. Rheumatology (Oxford). 2012;51(9):1540–9. doi:10.1093/rheumatology/kes090.CrossRef

82.

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(8):1475–81. doi:10.1136/ard.2009.116525.CrossRefPubMed

83.

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(6):e5981. doi:10.1371/journal.pone.0005981.

84.

MacDonald KG, Dawson NAJ, Huang Q, Dunne JV, Levings MK, Broady R. Regulatory T cells produce profibrotic cytokines in the skin of patients with systemic sclerosis. J Allergy Clin Immunol. 2015;135(4):946–955.e9. doi:10.1016/j.jaci.2014.12.1932.

85.

Boveda-Ruiz D, D’Alessandro-Gabazza CN, Toda M, Takagi T, Naito M, Matsushima Y, et al. Differential role of regulatory T cells in early and late stages of pulmonary fibrosis. Immunobiology. 2013;218(2):245–54. doi:10.1016/j.imbio.2012.05.020.CrossRefPubMed

86.

Roh YS, Park S, Lim CW, Kim B. Depletion of Foxp3+ regulatory T cells promotes profibrogenic milieu of cholestasis-induced liver injury. Dig Dis Sci. 2015;60(7):2009–18. doi:10.1007/s10620-014-3438-2.CrossRefPubMed

87.

D’Alessio FR, Zhong Q, Jenkins J, Moldobaeva A, Wagner EM. Lung angiogenesis requires CD4(+) forkhead homeobox protein-3(+) regulatory T cells. Am J Respir Cell Mol Biol. 2015;52(5):603–10. doi:10.1165/rcmb.2014-0278OC.CrossRefPubMed

88.

Trzonkowski P, Bieniaszewska M, Juścińska J, Dobyszuk A, Krzystyniak A, Marek N, et al. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. Clin Immunol (Orlando, Fla). 2009;133(1):22–6. doi:10.1016/j.clim.2009.06.001.CrossRef

89.

Desreumaux P, Foussat A, Allez M, Beaugerie L, Hébuterne X, Bouhnik Y et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease. Gastroenterology. 2012;143(5):1207–17.e1-2. doi:10.1053/j.gastro.2012.07.116.

90.

Chung L, Denton CP, Distler O, Furst DE, Khanna D, Merkel PA et al. Clinical trial design in scleroderma: where are we and where do we go next?. Clin Exp Rheumatol. 2012;30(2 Suppl 71):S97–102.

91.••

Hare JM, Sanina C. Bone marrow mononuclear cell therapy and granulocyte colony-stimulating factor for acute myocardial infarction: is it time to reconsider? J Am Coll Cardiol. 2015;65(22):2383–7. doi:10.1016/j.jacc.2015.03.571. Important lessons in trial design for cell therapy can be drawn from this paper.CrossRefPubMed

92.

Teraa M, Sprengers RW, Schutgens REG, Slaper-Cortenbach ICM, van der Graaf Y, Algra A et al. Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: the randomized, double-blind, placebo-controlled JUVENTAS Trial. Circulation. 2015(Cv). doi:10.1161/CIRCULATIONAHA.114.012913.

Title: Cellular Therapies in Systemic Sclerosis: Recent Progress
Authors: Femke C. C. van Rhijn-Brouwer
Hendrik Gremmels
Joost O. Fledderus
Timothy R. D. Radstake
Marianne C. Verhaar
Jacob M. van Laar
Publication date: 01-02-2016
Publisher: Springer US
Published in: Current Rheumatology Reports / Issue 2/2016
Print ISSN: 1523-3774
Electronic ISSN: 1534-6307
DOI: https://doi.org/10.1007/s11926-015-0555-7

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2016

Organ Damage and Quality of Life in Antiphospholipid Syndrome

Current Research in Outcome Measures for Pediatric Rheumatic and Autoinflammatory Diseases

Current Approaches to the Treatment of Systemic-Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH)

Non-stroke Central Neurologic Manifestations in Antiphospholipid Syndrome

Causality of Chlamydiae in Arthritis and Spondyloarthritis: a Plea for Increased Translational Research

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage