FOXP3 Gene Expression in Multiple Sclerosis Patients Pre- and Post Mesenchymal Stem Cell Therapy


Multiple Sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disorder of  the  central  nervous  system (CNS), which mainly affects  young adults. Activated T lymphocytes promote the neuro-inflammatory cascade of MS by secreting pro-inflammatory cytokines and play a significant role in its pathogenesis. T  lymphocytes may trigger the inflammation, which in turn leads to axonal loss and neurodegeneration observed in the course of MS.
Currently, there is no cure for MS, however, one of the most promising neuroprotective research tools consists of the use of bone marrow derived mesenchymal stem cells (MSC). This method promotes immune system regulation and possibly induces neurological repair and re-myelination of the damaged axons. Recent studies have shown that MSC exert an immune regulatory function  and induce T regulatory-cell proliferation, therefore,  it may serve as a potentially useful treatment for immune-mediated diseases such as MS.
In this pilot study a group of MS patients underwent MSC therapy and we assayed the expression of an X-linked transcription factor, FoxP3, as a specific marker of T Regulatory cells in peripheral blood, prior to and after the treatment. Using q RT-PCR for measurement of expression of FoxP3 by peripheral blood mononuclear cells, we found that in all subjects, except for one, the expression of FoxP3 at 6 months after intrathecal injection of MSC was significantly higher than the levels prior to treatment.
Such significant enhanced expression of FoxP3 associated with clinical stability. Findings from  this  pilot  study further  support  the  potential  of  bone  marrow  derived MSC for treatment of MS patients.

  1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000;343(13):938-52.
  2. Rocio S, Lopez D, Weiner HL. Novel therapeutic strategies for multiplesclerosis-a multifaceted adversary. Nat Rev Drug Discov 2008; 7(11):909-25.
  3. Nikbin B, Mohyeddin Bonab M, Khosravi F, Talebian F.Role of B cells inpathogenesis of multiple sclerosis. IntRev Neurobiol 2007; 79:13-42.
  4. Karussis D, Grigoriadis S, Polyzoidou E, Grigoriadis N, Slavin S, Abramsky O. Neuroprotection in multiple sclerosis. Clin Neurol Neurosurg 2006; 108(3):250–4.
  5. Steinman L. Multiple sclerosis: a two-stage disease. Nat Immunol 2001; 2(9):762-4.
  6. Slavin S, Kurkalli BG, Karussis D. The potential use of adult stem cells for the treatment of multiple sclerosis and other neurodegenerative disorders. Clin Neurol Neurosurg 2008; 110(9):943-6.
  7. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4):315-7.
  8. Kassis I, Grigoriadis N, Gowda-Kurkalli B, Mizrachi-Kol R, Ben-Hur T, Slavin S, et al. Neuroprotection and immunomodulation with mesenchymal stem cells in chronic experimental autoimmune encephalomyelitis. Arch Neurol 2008; 65(6):753-61.
  9. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK,Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science1999;284(5411):143-7.
  10. Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival invivo. ExpHematol 2002; 30(1):42-8.
  11. Le Blanc K, Rasmusson I, Sundberg B, Götherström C, Hassan M, Uzunel M, et al. Treatment of severe graft- versus-hostdisease with third party haploidentical mesenchymal stem cells. Lancet 2004; 363(9419):1439-41.
  12. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development andfunction of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4(4):330-6.
  13. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory Tcells in immunological self- tolerance to self and non-self. Nat Immunol 2005;6(4):345-52.
  14. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineagespecification by the fork-head transcription factor FoxP3. Immunity 2005; 22(3):329-41.
  15. Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin inCD4+CD25+ T regulatory cells. Nat Immunol 2003; 4(4):337-42.
  16. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development bythe transcription factor Foxp3. Science 2003; 299(5609):1057–61.
  17. Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factorFoxP3. Nat Immunol 2005; 6(4):331-7.
  18. Chang X, Zheng P, Liu Y. FoxP3: A genetic link betweenimmunodeficiency and autoimmune diseases. Autoimmun Rev 2006; 5(6):399-402.
  19. Huan J, Culbertson N, Spencer L, Bartholomew R, Burrows GG, Chou YK, et al. DecreasedFOXP3 levels in multiple sclerosis patients. J Neurosci Res 2005;81(1):45-52.
  20. Hori S, Sakaguchi S: Foxp3: a critical regulator of the development and function of regulatory T cells. Microbes Infect 2004; 6(8):745-51.
  21. Baecher-Allan C, Hafler DA. Suppressor T cells in human diseases. J Exp Med 2004; 200(3):273-6.
  22. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA.Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiplesclerosis. J Exp Med 2004; 199(7):971-9.
  23. Kriegel MA, Lohmann T, Gabler C, Blank N, Kalden JR, Lorenz HM. Defective suppressor function of human CD4+CD25+regulatory T cells in autoimmune polyglandular syndrome type II. J Exp Med 2004;199(9):1285–91.
  24. Offner H, VandenbarkAA. Congruent effects of estrogen and T-cell receptorpeptide therapy on regulatory T cells in EAE and MS. Int Rev Immunol 2005; 24(5-6):447–77.
  25. Venken K, Hellings N, Hensen K, Rummens JL, Medaer R, D'hooghe MB, et al. Secondaryprogressive in contrast to relapsing-remitting multiple sclerosis patients showa normal CD4+CD25+ regulatory T-cell function and FOXP3 expression. J Neurosci Res 2006; 83(8):1432–46.
  26. Jane Hoyt Buckner: Mechanisms of impaired regulation by CD4+CD25+FOXP3+ regulatory T cells in human autoimmune diseases. Nat Rev Immunol. 2010;10(12):849–859. doi:10.1038/nri2889.
  27. Schneider A, Long SA, Kita M, Buckner JH: Persistence of FOXP3 expressionis impaired in RR-MS Treg. J Immunology 2009; 182:99.3.
  28. Shi M, Liu ZW, Wang FS: Immunomodulatory properties and therapeutic application of mesenchymal stem cells. Clin Exp Immunol. 2011;164(1):1-8.
  29. Zappia E, Casazza S, Pedemonte E, Federica BenvenutoF, Ivan Bonanni I,Gerdoni E, Giunti D, Ceravolo A,Cazzanti F, Frassoni F, Mancardi G, Uccelli A:Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005;106:5.
  30. Bernardo ME, Avanzino MA, Perotti C, et al:Optimization of in vitro expansion of human multipotent mesenchymal stromal cells for cell-therapy approaches: further insights in the search for a fetal calf serum substitute. JCell Physiol 2007;211:121-30.
  31. Maccario R, Podesta M, Moretta A, et al: Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favorsthe differentiation of CD4+T-cell subsets expressing a regulatory/suppressivephenotype. Haematologica 2005;90:516-25.
  32. Prevosto C, Zancolli M, Canevali P, et al: Generation of CD4+ or CD8+regulatory T cells upon mesenchymal stem cell-lymphocyte interaction. Haematologica 2007;92:881-8.
  33. Batten P, Sarathchandra P, Antoniw JW, et al: Human mesenchymal stem cells induce T cell anergy and dowregulate T cell allo-responses via TH2 pathway: relevance to tissue engineering human heart valves. Tissue Eng 2006; 18:2263-73.
  34. Mauro Di Ianni, Beatrice Del Papaa, Maria De Ioanni, Lorenzo Moretti, Elisabetta Bonifacioa, Debora Cecchini,2008. Mesenchymal cells recruit and regulate Tregulatory cells. Experimental Hematology 2008; 36:309-18.
  35. Shimon Slavin, Basan G.S. Kurkalli, Dimitrios, Karussis: The potential use of adult stem cells for the treatment of multiple sclerosis and other neurodegenerative disorders.clinical neurology and neurosurgery, 2008; 110:943-6.

IssueVol 10, No 3 (2011) QRcode
Mesenchymal Stem Cells (MSC) Multiple Sclerosis (MS) Transcription Factor (FOXP3) T Regulatory Cells (Treg)

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Mohajeri M, Farazmand A, Mohyeddin Bonab M, Nikbin B, Minagar A. FOXP3 Gene Expression in Multiple Sclerosis Patients Pre- and Post Mesenchymal Stem Cell Therapy. Iran J Allergy Asthma Immunol. 1;10(3):155-161.