Scleroderma pp 591-602 | Cite as

Cell-Based Therapies

  • Alan G. TyndallEmail author
  • Keith M. Sullivan


Cell therapy describes the process of introducing new cells into a tissue in order to treat a disease. Cell therapies often focus on the treatment of hereditary diseases, with or without the addition of gene therapy. There are many potential forms of cell therapy: the transplantation of stem cells that are autologous (from the patient) or allogeneic (from another donor), the transplantation of mature, functional cells, the application of modified human cells that are used to produce a needed substance, the xenotransplantation of non-human cells that are used to produce a needed substance (e.g., treating diabetic patients by introducing insulin-producing pig cells directly into their muscle) and the transplantation of trans-differentiated cells derived from the patient’s own differentiated cells (e.g., the use of insulin producing beta cells trans-differentiated from isolated hepatocytes as a treatment for diabetes).


Allogeneic HSCT autologous hematopoietic stem cell transplantation (HSCT) autoreactive graft-versus-host disease immunoablation multipotent mesenchymal stromal cells stem cells 


  1. 1.
    Yamanaka S, Blau HM. Nuclear reprogramming to a pluripotent state by three approaches. Nature. 2010;465(7299):704–12.PubMedCrossRefGoogle Scholar
  2. 2.
    Ikehara S, Good RA, Nakamura T, et al. Rationale for bone marrow transplantation in the treatment of autoimmune diseases. Proc Natl Acad Sci USA. 1985;82:2483–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Van Bekkum DW, Bohre EP, Houben PF, Knaan-Shanzer S. Regressionof adjuvant-induced arthritis in rats following bone marrow transplantation. Proc Natl Acad Sci USA. 1989;86:10090–4.PubMedCrossRefGoogle Scholar
  4. 4.
    Tamm M, Gratwohl A, Tichelli A, Perruchoud AP, Tyndall A. Autologous haemopoietic stem cell transplantation in a patient with severe pulmonary hypertension complicating connective tissue disease. Ann Rheum Dis. 1996;55(10):779–80.PubMedCrossRefGoogle Scholar
  5. 5.
    Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117(3):557–67.PubMedCrossRefGoogle Scholar
  6. 6.
    Burness ML, Sipkins DA. The stem cell niche in health and malignancy. Semin Cancer Biol. 2010;20(2):107–15.PubMedCrossRefGoogle Scholar
  7. 7.
    Deregibus MC, Tetta C, Camussi G. The dynamic stem cell microenvironment is orchestrated by microvesicle-mediated transfer of genetic information. Histol Histopathol. 2010;25(3):397–404.PubMedGoogle Scholar
  8. 8.
    Brodsky RA, Petri M, Jones RJ. Hematopoietic stem cell transplantation for systemic lupus erythematosus. Rheum Dis Clin North Am. 2000;26(2):377–87.PubMedCrossRefGoogle Scholar
  9. 9.
    Tyndall A, Gratwohl A. Blood and marrow stem cell transplants in autoimmune disease. A consensus report written on behalf of the European League Against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation (EBMT). Br J Rheumatol. 1997;36(3):390–2.PubMedCrossRefGoogle Scholar
  10. 10.
    McSweeney PA, Nash RA, Storb R, Furst DE, Gauthier J, Sullivan KM. Autologous stem cell transplantation for autoimmune diseases: issues in protocol development. J Rheumatol Suppl. 1997;48:79–84.PubMedGoogle Scholar
  11. 11.
    Nelson JL, Torrez R, Louie FM, Choe OS, Storb R, Sullivan KM. Pre-existing autoimmune disease in patients with long-term survival after allogeneic bone marrow transplantation. J Rheumatol. 1997;24(Suppl 48):23–9.Google Scholar
  12. 12.
    van Bekkum DW. Conditioning regimens for the treatment of experimental arthritis with autologous bone marrow transplantation. Bone Marrow Transplant. 2000;25:357–64.PubMedCrossRefGoogle Scholar
  13. 13.
    Gratwohl A, Passweg J, Bocelli-Tyndal C, Fassas A, van Laar JM, Farge D, Andolina M, et al. Autologous hematopoietic stem cell transplantation for autoimmune diseases. Bone Marrow Transplant. 2005;35(9):869–79.PubMedCrossRefGoogle Scholar
  14. 14.
    McKendry RJ, Huebsch L, Leclair B. Progression of rheumatoid arthritis following bone marrow transplantation. A case report with a 13-year follow-up. Arthritis Rheum. 1996;39(7):1246–53.PubMedCrossRefGoogle Scholar
  15. 15.
    Lowenthal RM, Cohen ML, Atkinson K, Biggs JC. Apparent cure of rheumatoid arthritis by bone marrow transplantation. J Rheumatol. 1993;20(1):137–40.PubMedGoogle Scholar
  16. 16.
    Binks M, Passweg JR, Furst D, McSweeney P, Sullivan K, Besenthal C, et al. 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.PubMedCrossRefGoogle Scholar
  17. 17.
    Chien J, Sullivan KM. Carbon monoxide diffusion capacity: how low can you go for hematopoietic cell transplantation eligibility? Biol Blood Marrow Transplant. 2009;15:447–53.PubMedCrossRefGoogle Scholar
  18. 18.
    Storek J, Zhao Z, Lin E, Berger T, McSweeney P, Nash R, Akatsuka Y, Metcalf M, Lu H, Kalina T, Reindl M, Storb R, Hansen J, Sullivan KM, Kraft G, Furst D, Maloney DG. Recovery from and consequences of severe iatrogenic lymphopenia (induced to treat autoimmune diseases). Clin Immunol. 2004;113:285–98.PubMedCrossRefGoogle Scholar
  19. 19.
    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(2):185–8.CrossRefGoogle Scholar
  20. 20.
    Tyndall A, Black C, Finke J, Winkler J, Mertlesmann R, Peter HH, et al. Treatment of systemic sclerosis with autologous haemopoietic stem cell transplantation. Lancet. 1997;349(9047):254.PubMedCrossRefGoogle Scholar
  21. 21.
    McSweeney PA, Nash RA, Sullivan KM, Storek J, Crofford LJ, Dansey R, et al. High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes. Blood. 2002;100(5):1602–10.PubMedGoogle Scholar
  22. 22.
    Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen CS, Godwin JD, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the U.S. multicenter pilot study. Blood. 2007;110:1388–96.PubMedCrossRefGoogle Scholar
  23. 23.
    Vonk MC, Marjanovic Z, van den Hoogen FH, Zohar S, Schattenberg AV, 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.PubMedCrossRefGoogle Scholar
  24. 24.
    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.CrossRefGoogle Scholar
  25. 25.
    Nash RA, McSweeney PA, Nelson JL, Wener M, Georges GE, Langston AA, et al. Allogeneic marrow transplantation in patients with severe systemic sclerosis: resolution of dermal fibrosis. Arthritis Rheum. 2006;54(6):1982–6.PubMedCrossRefGoogle Scholar
  26. 26.
    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.PubMedCrossRefGoogle Scholar
  27. 27.
    Aschwanden M, Kesten F, Stern M, Thalhammer C, Walker UA, Tyndall A, et al. Vascular involvement in patients with giant cell arteritis determined by duplex sonography of 2x11 arterial regions. Ann Rheum Dis. 2010;69(7):1356–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Wang J, Nash RA, Chu B, Yarnykh VL, Schwartz SM, Sullivan KM, et al. Improvements in digital vasculature observed using micro magnetic resonance angiography after high-dose immunosuppression for severe systemic sclerosis. Bone Marrow Transplant. 2009;44(6):387–9.PubMedCrossRefGoogle Scholar
  29. 29.
    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(5):805–16.PubMedCrossRefGoogle Scholar
  30. 30.
    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(1):214–23.PubMedCrossRefGoogle Scholar
  31. 31.
    Williams KM, Hakim FT, Gress RE. T cell immune reconstitution following lymphodepletion. Semin Immunol. 2007;19(5):318–30.PubMedCrossRefGoogle Scholar
  32. 32.
    Couzin-Frankel J. Immunology. Replacing an immune system gone haywire. Science. 2010;327:772–4.PubMedCrossRefGoogle Scholar
  33. 33.
    Sullivan KM, Muraro P, Tyndall A. Hematopoietic cell transplantation for autoimmune disease: updates from Europe and the United States. Biol Blood Marrow Transplant. 2010;16:S48–56.PubMedCrossRefGoogle Scholar
  34. 34.
    van Laar JM, Farge D, Tyndall A. Autologous Stem cell Transplantation International Scleroderma (ASTIS) trial: hope on the horizon for patients with severe systemic sclerosis. Ann Rheum Dis. 2005;64(10):1515.PubMedCrossRefGoogle Scholar
  35. 35.
    Hosing C, Nash R, McSweeney P, Mineishi S, Seibold J, Griffith L, Shulman H, Goldmuntz E, Mayes M, Parikh C, Crofford L, Keyes-Elstein L, Furst D, Steen V, Sullivan KM. Acute kidney injury in patients with systemic sclerosis participating in hematopoietic cell transplantation trials in the United States. Biol Blood Marrow Transplant. 2011;17(5):674–81.PubMedCrossRefGoogle Scholar
  36. 36.
    Craciunescu O, Steffey A, Kelsey C, Larrier N, Paarz-Largay C, Prosnitz RG, Chao N, Chute J, Gasparetto C, Horwitz M, Long G, Rizzieri D, Sullivan KM. 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.PubMedCrossRefGoogle Scholar
  37. 37.
    Tyndall A. Why do we need noncommercial, investigator-initiated clinical trials? Nat Clin Pract Rheumatol. 2008;4(7):354–5.PubMedGoogle Scholar
  38. 38.
    Sullivan KM, Seibold J, Mineishi S, Mayes MD, Hosing C, Nash RA, Wener M, et al. Denials of treatment coverage by health insurance carriers restrict patient recruitment on a randomized clinical trial: experience of 95 patients with systemic sclerosis enrolled in the SCOT (scleroderma: cyclophosphamice or transplantation) trial. Biol Blood Marrow Transplant. 2010;16:S164 (abstract).CrossRefGoogle Scholar
  39. 39.
    Daikeler T, Hugle T, Farge D, Andolina M, Gualandi F, Baldomero H, et al. Allogeneic hematopoietic SCT for patients with autoimmune diseases. Bone Marrow Transplant. 2009;44(1):27–33.PubMedCrossRefGoogle Scholar
  40. 40.
    Shiratsuchi M, Motomura S, Abe Y, Shiokawa S, Nishimura J. Long-term follow-up after nonmyeloablative allogeneic hematopoietic stem cell transplantation for systemic sclerosis. Clin Rheumatol. 2008;27(9):1207–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Tyndall A, Dazzi F. Chronic GVHD as an autoimmune disease. Best Pract Res Clin Haematol. 2008;21(2):281–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Griffith LM, Pavletic Z, Tyndall A, Bredeson CN, Bowen J, Childs R, Gratwohl A, Van Laar J, Mayes M, Martin R, McSweeney P, Muraro P, Opensbaw H, Saccardi R, Sandmaier B, Forman S, Nash R. Feasibility of allogeneic hematopoietic stem cell transplantation for autoimmune disease: position statement from a National Institute of Allergy and Infectious Diseases and National Cancer Institute-Sponsored International Workshop, Bethesda, MD, 12 and 18 March, 2005. Biol Blood Marrow Transplant. 2005;11:862–70.PubMedCrossRefGoogle Scholar
  43. 43.
    Tyndall A, Uccelli A. Multipotent mesenchymal stromal cells for autoimmune diseases: teaching new dogs old tricks. Bone Marrow Transplant. 2009;43(11):821–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Mei SH, Haitsma JJ, Dos Santos CC, Deng Y, Lai PF, Slutsky AS, Liles WC, Stewart DJ. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med. 2010;182:1047–57.PubMedCrossRefGoogle Scholar
  45. 45.
    Bocelli-Tyndall C, Bracci L, Spagnoli G, Braccini A, Bouchenaki M, Ceredig R, et al. Bone marrow mesenchymal stromal cells (BM-MSCs) from healthy donors and auto-immune disease patients reduce the proliferation of autologous- and allogeneic-stimulated lymphocytes in vitro. Rheumatology (Oxford). 2007;46(3):403–8.CrossRefGoogle Scholar
  46. 46.
    Larghero J, Farge D, Braccini A, Lecourt S, Scherberich A, Fois E, et al. Phenotypical and functional characteristics of in vitro expanded bone marrow mesenchymal stem cells from systemic sclerosis patients. Ann Rheum Dis. 2008;67(4):443–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Cipriani P, Guiducci S, Miniati I, Cinelli M, Urbani S, Marrelli A, et al. Impairment of endothelial cell differentiation from bone marrow-derived mesenchymal stem cells: new insight into the pathogenesis of systemic sclerosis. Arthritis Rheum. 2007;56(6):1994–2004.PubMedCrossRefGoogle Scholar
  48. 48.
    Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood. 2003;102(10):3837–44.PubMedCrossRefGoogle Scholar
  49. 49.
    Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S, et al. Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis. 2010;69(8):1423–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Sun L, Wang D, Liang J, Zhang H, Feng X, Wang H, et al. Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus. Arthritis Rheum. 2010;62:2467–75.PubMedCrossRefGoogle Scholar
  51. 51.
    Christopeit M, Schendel M, Foll J, Muller 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.PubMedCrossRefGoogle Scholar
  52. 52.
    Zhou H, Guo M, Bian C, Sun Z, Yang Z, Seng Y, Ai HS, Zhao RC. Efficacy of bone marrow-derived mesenchymal stem cells in the treatment of sclerodermatous chronic graft-versus-host disease: clinical report. Biol Blood Marrow Transplant. 2010;16:403–12.PubMedCrossRefGoogle Scholar
  53. 53.
    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.PubMedCrossRefGoogle Scholar
  54. 54.
    Kim SW, Han H, Chae GT, Lee SH, Bo S, Yoon JH, et al. Successful stem cell therapy using umbilical cord blood-derived multipotent stem cells for Buerger’s disease and ischemic limb disease animal model. Stem Cells. 2006;24(6):1620–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Tyndall A, Houssiau FA. Mesenchymal stem cells in the treatment of autoimmune diseases. Ann Rheum Dis. 2010;69(8):1413–14.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of RheumatologyFelix Plater Spital BaselBaselSwitzerland
  2. 2.Department of Medicine, Division of Cellular TherapyDuke University Medical CenterDurhamUSA

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