ENTtoday

Cellular Therapy of Autoimmune Disease

by Dr. Tyndall •

Autologous bone marrow derived MSCs have been shown to be potently antiproliferative to stimulated T cells from normal subjects and autoimmune (e.g., RA, SSc, Sjögren’s, SLE) patients; in SSc patients, these MSCs were normal in respect to proliferation, clonogenicity, and differentiation to bone and fat.14,15

Currently, few peer-reviewed publications concerning the results of using of MSCs in human autoimmune disease are available. There are several ongoing phase I/II clinical trials in autoimmune disease including MS, with discussions underway concerning other trials for other autoimmune disease such as type 1 diabetes mellitus, SSc, vasculitis, and SLE.

Important is the setting of clear therapeutic targets and harmonization of cell products, especially MSC source and type (autologous or allogeneic), cell expansion conditions, and trial protocols. In addition, long-term safety data collection across disciplines is required, and an international interdisciplinary registry of MSC-treated patients has been launched.

Summary

Cellular therapy using hematopoietic stem cells to support the ablated normal blood cells has enabled crossing a threshold of immunoablation, and early results suggest that a “resetting” of the immune system in patients with autoimmune disease beyond just immunosuppression is possible. Only phase III randomized trials will establish the true value of this approach. In contrast to the goals of treatment with HSC, MSCs are being used as “homing and healing” cells in various severe inflammatory settings including autoimmune disease, with phase I/II studies beginning. Importantly, no patient conditioning is required. Certainly, for diseases such as SSc where existing immunosuppressive has not been highly effective, stem-cell therapy may offer a fundamentally new approach to correct immune abnormalities and initiate repair. Although much work on stem cells needs to be performed in both the clinical and laboratory, there is strong optimism that a potential new era of therapy is now at hand.

Dr. Tyndall is professor and head of the department of rheumatology at the University of Basel, Felix Platter Hospital, in Basel, Switzerland.

References

  1. 1. 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; 55:779–780.
  2. 2. van Laar JM, Tyndall A. Adult stem cells in the treatment of autoimmune diseases. Rheumatology (Oxford). 2006; 45:1187–1193.
  3. 3. Muraro PA, Douek DC, Packer A, 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.
  4. 4. Jayne D, Passweg J, Marmont A, et al. Autologous stem cell transplantation for systemic lupus erythematosus. Lupus. 2004; 13:168–176.
  5. 5. Burt RK, Traynor A, Statkute L, et al. Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus. JAMA. 2006; 295:527–535.
  6. 6. Verrecchia F, Laboureau J, Verola O, et al. Skin involvement in scleroderma—where histological and clinical scores meet. Rheumatology (Oxford). 2007; 46:833–841.
  7. 7. Nash RA, McSweeney PA, Crofford LJ, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: Long-term follow-up of the US multicenter pilot study. Blood. 2007; 110:1388–1396.
  8. 8. Fleming JN, Nash RA, McLeod DO, et al. Capillary regeneration in scleroderma: stem cell therapy reverses phenotype? PLoS ONE. 2008;3(1):e1452.
  9. 9. Aschwanden M, Daikeler T, Jaeger KA, et al. Rapid improvement of nailfold capillaroscopy after intense immunosuppression for systemic sclerosis and mixed connective tissue disease. Ann Rheum Dis. 2008; 67:1057–1059.
  10. 10. Griffith LM, Pavletic SZ, Tyndall A, et al. Target populations in allogeneic hematopoietic cell transplantation for autoimmune diseases—a workshop accompanying: Cellular therapy for treatment of autoimmune diseases, basic science and clinical studies, including new developments in hematopoietic and mesenchymal stem cell therapy. Biol Blood Marrow Transplant. 2006; 12:688–690.
  11. 11. Javazon EH, Beggs KJ, Flake AW. Mesenchymal stem cells: paradoxes of passaging. Exp Hematol. 2004; 32:414–425.
  12. 12. Dazzi F, van Laar JM, Cope A, Tyndall A. Cell therapy for autoimmune diseases. Arthritis Res Ther. 2007;9:206.
  13. 13. Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: A phase II study. Lancet. 2008; 371:1579–1586.
  14. 14. Bocelli-Tyndall C, Bracci L, Spagnoli G, 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; 46:403–408.
  15. 15. Larghero J, Farge D, Braccini A, et al. Phenotypical and functional characteristics of in vitro expanded bone marrow mesenchymal stem cells from patients with systemic sclerosis. Ann Rheum Dis. 2008; 67:443–449.