Research Article
No access
Published Online: 13 August 2013

Human Umbilical Cord Mesenchymal Stem Cell Therapy for Patients with Active Rheumatoid Arthritis: Safety and Efficacy

Publication: Stem Cells and Development
Volume 22, Issue Number 24

Abstract

This study was designed to assess the safety and efficacy of human umbilical cord mesenchymal stem cells (UC-MSCs) in the treatment of rheumatoid arthritis (RA). In this ongoing cohort, 172 patients with active RA who had inadequate responses to traditional medication were enrolled. Patients were divided into two groups for different treatment: disease-modifying anti-rheumatic drugs (DMARDs) plus medium without UC-MSCs, or DMARDs plus UC-MSCs group (4×107 cells per time) via intravenous injection. Adverse events and the clinical information were recorded. Tests for serological markers to assess safety and disease activity were conducted. Serum levels of inflammatory chemokines/cytokines were measured, and lymphocyte subsets in peripheral blood were analyzed. No serious adverse effects were observed during or after infusion. The serum levels of tumor necrosis factor-alpha and interleukin-6 decreased after the first UC-MSCs treatment (P<0.05). The percentage of CD4+CD25+Foxp3+ regulatory T cells of peripheral blood was increased (P<0.05). The treatment induced a significant remission of disease according to the American College of Rheumatology improvement criteria, the 28-joint disease activity score, and the Health Assessment Questionnaire. The therapeutic effects maintained for 3–6 months without continuous administration, correlating with the increased percentage of regulatory T cells of peripheral blood. Repeated infusion after this period can enhance the therapeutic efficacy. In comparison, there were no such benefits observed in control group of DMARDS plus medium without UC-MSCs. Thus, our data indicate that treatment with DMARDs plus UC-MSCs may provide safe, significant, and persistent clinical benefits for patients with active RA.

Get full access to this article

View all available purchase options and get full access to this article.

References

1.
McInnes IB and Schett G. (2011). The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219.
2.
Sakaguchi S, Yamaguchi T, Nomura T and Ono M. (2008). Regulatory T cells and immune tolerance. Cell 133:775–787.
3.
van Amelsfort JM, Jacobs KM, Bijlsma JW, Lafeber FP and Taams LS. (2004). CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum 50:2775–2785.
4.
Feldmann M. (2002). Development of anti-TNF therapy for rheumatoid arthritis. Nat Rev Immunol 2:364–371.
5.
Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, Weaver AL, Keystone EC, Furst DE, et al. (1999). Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 130:478–486.
6.
Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL, Ettlinger RE, Cohen S, Koopman WJ, etal. (1997). Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 337:141–147.
7.
Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW, Kremer J, Bear MB, Rich WJ and McCabe D. (2002). Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 46:614–624.
8.
Bresnihan B and Cunnane G. (2003). Infection complications associated with the use of biologic agents. Rheum Dis Clin North Am 29:185–202.
9.
Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I and Fisk NM. (2001). Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 98:2396–2402.
10.
Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP and Hedrick MH. (2001). Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7:211–228.
11.
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S and Marshak DR. (1999). Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147.
12.
Uccelli A, Moretta L and Pistoia V. (2008). Mesenchymal stem cells in health and disease. Nat Rev Immunol 8:726–736.
13.
Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M and Ringden O. (2004). Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363:1439–1441.
14.
Sun L, Akiyama K, Zhang H, Yamaza T, Hou Y, Zhao S, Xu T, Le A and Shi S. (2009). Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans. Stem Cells 27:1421–1432.
15.
Mohanty ST, Kottam L, Gambardella A, Nicklin MJ, Coulton L, Hughes D, Wilson AG, Croucher PI and Bellantuono I. (2010). Alterations in the self-renewal and differentiation ability of bone marrow mesenchymal stem cells in a mouse model of rheumatoid arthritis. Arthritis Res Ther 12:R149
16.
Gonzalez MA, Gonzalez-Rey E, Rico L, Buscher D and Delgado M. (2009). Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells. Arthritis Rheum 60:1006–1019.
17.
Augello A, Tasso R, Negrini SM, Cancedda R and Pennesi G. (2007). Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum 56:1175–1186.
18.
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, etal. (1988). The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324.
19.
Lu LL, Liu YJ, Yang SG, Zhao QJ, Wang X, Gong W, Han ZB, Xu ZS, Lu YX, etal. (2006). Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica 91:1017–1026.
20.
Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS and Keating A. (2005). Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 7:393–395.
21.
Glasser L, Fiederlein RL and Huestis DW. (1985). Liquid preservation of human neutrophils stored in synthetic media at 22 degrees C: controlled observations on storage variables. Blood 66:267–272.
22.
van Gestel AM, Haagsma CJ and van Riel PL. (1998). Validation of rheumatoid arthritis improvement criteria that include simplified joint counts. Arthritis Rheum 41:1845–1850.
23.
Pincus T, Swearingen C and Wolfe F. (1999). Toward a multidimensional Health Assessment Questionnaire (MDHAQ): assessment of advanced activities of daily living and psychological status in the patient-friendly health assessment questionnaire format. Arthritis Rheum 42:2220–2230.
24.
Scott DL, Smolen JS, Kalden JR, van de Putte LB, Larsen A, Kvien TK, Schattenkirchner M, Nash P, Oed C and Loew-Friedrich I. (2001). Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine. Ann Rheum Dis 60:913–923.
25.
Saklatvala J. (1986). Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature 322:547–549.
26.
Buchan G, Barrett K, Fujita T, Taniguchi T, Maini R and Feldmann M. (1988). Detection of activated T cell products in the rheumatoid joint using cDNA probes to interleukin-2 (IL-2) IL-2 receptor and IFN-gamma. Clin Exp Immunol 71:295–301.
27.
Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G, Tang B, Sato K, Shimizu M, Maini R, Feldmann M, etal. (1988). Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol 18:1797–1801.
28.
Brennan FM and McInnes IB. (2008). Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 118:3537–3545.
29.
Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M and Lipsky P. (1999). Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 354:1932–1939.
30.
Giles JT, Bartlett SJ, Gelber AC, Nanda S, Fontaine K, Ruffing V and Bathon JM. (2006). Tumor necrosis factor inhibitor therapy and risk of serious postoperative orthopedic infection in rheumatoid arthritis. Arthritis Rheum 55:333–337.
31.
Liu Y, Mu R, Wang S, Long L, Liu X, Li R, Sun J, Guo J, Zhang X, etal. (2010). Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis. Arthritis Res Ther 12:R210
32.
Kastrinaki MC, Sidiropoulos P, Roche S, Ringe J, Lehmann S, Kritikos H, Vlahava VM, Delorme B, Eliopoulos GD, etal. (2008). Functional, molecular and proteomic characterisation of bone marrow mesenchymal stem cells in rheumatoid arthritis. Ann Rheum Dis 67:741–749.
33.
Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, etal. (2008). Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371:1579–1586.
34.
Badiavas EV, Abedi M, Butmarc J, Falanga V and Quesenberry P. (2003). Participation of bone marrow derived cells in cutaneous wound healing. J Cell Physiol 196:245–250.
35.
Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D and Shimizu H. (2008). Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol 180:2581–2587.
36.
Ji KH, Xiong J, Fan LX, Hu KM and Liu HQ. (2009). Rat marrow-derived multipotent adult progenitor cells differentiate into skin epidermal cells in vivo. J Dermatol 36:403–409.
37.
Yeum CE, Park EY, Lee SB, Chun HJ and Chae GT. (2013). Quantification of MSCs involved in wound healing: use of SIS to transfer MSCs to wound site and quantification of MSCs involved in skin wound healing. J Tissue Eng Regen Med 7:279–291.
38.
de Kleer I, Vastert B, Klein M, Teklenburg G, Arkesteijn G, Yung GP, Albani S, Kuis W, Wulffraat N and Prakken B. (2006). Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4+CD25+ immune regulatory network. Blood 107:1696–1702.
39.
Rai S, Marak RS, Jain S and Dhole TN. (2012). Posterior fossa midline cryptococcoma in a patient with idiopathic CD4 lymphocytopenia. Indian J Med Microbiol 30:367–370.
40.
Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G, Go K and Phinney DG. (2007). Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A 104:11002–11007.
41.
Wang Q, Li X, Luo J, Zhang L, Ma L, Lv Z and Xue L. (2012). The allogeneic umbilical cord mesenchymal stem cells regulate the function of T helper 17 cells from patients with rheumatoid arthritis in an in vitro co-culture system. BMC Musculoskelet Disord 13:249
42.
Maumus M, Jorgensen C and Noel D. (2013). Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: role of secretome and exosomes. Biochimie [Epub ahead of print];.

Information & Authors

Information

Published In

cover image Stem Cells and Development
Stem Cells and Development
Volume 22Issue Number 24December 15, 2013
Pages: 3192 - 3202
PubMed: 23941289

History

Published in print: December 15, 2013
Published ahead of print: 4 October 2013
Published online: 13 August 2013
Accepted: 13 August 2013
Received: 14 January 2013

Permissions

Request permissions for this article.

Topics

Authors

Affiliations

Liming Wang
*
Cell Therapy Center, 323 Hospital of Chinese People's Liberation Army, Xi'an city, China.
Lihua Wang*
The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Graduate School of Chinese Academy of Medical Sciences and Peking Union of Medical College, Tianjin, China.
Xiuli Cong
Alliancells Institute of Stem Cells and Translational Regenerative Medicine of Zhongyuan Union Stem Cell Bioengineering Co. Ltd, Tianjin, China.
Guangyang Liu
Alliancells Institute of Stem Cells and Translational Regenerative Medicine of Zhongyuan Union Stem Cell Bioengineering Co. Ltd, Tianjin, China.
Jianjun Zhou
Cell Therapy Center, 323 Hospital of Chinese People's Liberation Army, Xi'an city, China.
Bin Bai
Cell Therapy Center, 323 Hospital of Chinese People's Liberation Army, Xi'an city, China.
Yang Li
Cell Therapy Center, 323 Hospital of Chinese People's Liberation Army, Xi'an city, China.
Wen Bai
Cell Therapy Center, 323 Hospital of Chinese People's Liberation Army, Xi'an city, China.
Ming Li
Cell Therapy Center, 323 Hospital of Chinese People's Liberation Army, Xi'an city, China.
Haijie Ji
Alliancells Institute of Stem Cells and Translational Regenerative Medicine of Zhongyuan Union Stem Cell Bioengineering Co. Ltd, Tianjin, China.
Delin Zhu
Alliancells Institute of Stem Cells and Translational Regenerative Medicine of Zhongyuan Union Stem Cell Bioengineering Co. Ltd, Tianjin, China.
Mingyuan Wu
Harold Hamm Diabetes Center and Section of Endocrinology and Diabetes in the Department of Internal Medicine, and Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
School of Life Sciences and Technology, Tongji University, Shanghai, China.
Yongjun Liu
Alliancells Institute of Stem Cells and Translational Regenerative Medicine of Zhongyuan Union Stem Cell Bioengineering Co. Ltd, Tianjin, China.
School of Life Sciences and Technology, Tongji University, Shanghai, China.

Notes

Address correspondence to:Dr. Yongjun LiuAlliancells Institute of Stem Cells and Translational Regenerative Medicine of Zhongyuan Union Stem Cell Bioengineering Co. LtdNo.45 East Nine RoadSpecial Economic Zone of KongGangTianjin, 300381China
E-mail: [email protected]
Dr. Mingyuan WuHarold Hamm Diabetes Center and Section of Endocrinology and Diabetes in the Department of Internal Medicine and Department of PhysiologyUniversity of Oklahoma Health Sciences Center941 Stanton L. Young BoulevardOklahoma City, OK 73104E-mail: [email protected]

Author Disclosure Statement

No competing financial interests exist.

Metrics & Citations

Metrics

Citations

Export citation

Select the format you want to export the citations of this publication.

View Options

Get Access

Access content

To read the fulltext, please use one of the options below to sign in or purchase access.

Society Access

If you are a member of a society that has access to this content please log in via your society website and then return to this publication.

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

View options

PDF/EPUB

View PDF/ePub

Full Text

View Full Text

Media

Figures

Other

Tables

Share

Share

Copy the content Link

Share on social media

Back to Top