Stem Cells. 2015 Dec;33(12):3493-503.

Human Adipose-Derived Mesenchymal Stem Cells Modulate Experimental Autoimmune Arthritis by Modifying Early Adaptive T Cell Responses.

Mercedes Lopez-Santalla1, Pablo Mancheño-Corvo2, Ramon Menta2, Juan Lopez-Belmonte3, Olga Delarosa2, Juan A. Bueren1, Wilfried Dalemans4, Eleuterio Lombardo2, Marina I. Garin1

1Division of Hematopoietic Innovative Therapies (HIT) & Advanced Therapy Unit, CIEMAT/CIBERER /IIS Fundación Jiménez Díaz, Madrid, Spain; 2TiGenix SAU, Madrid, Spain; 3FARMACROS, Albacete, Spain; 4TiGenix NV, Leuven, Belgium

 

Abstract

Mesenchymal stem cells (MSCs) are multipotent stromal cells with immunosuppressive properties. They have emerged as a very promising treatment for autoimmunity and inflammatory diseases such as rheumatoid arthritis. Recent data have identified that GM-CSF-expressing CD4 T cells and Th17 cells have critical roles in the pathogenesis of arthritis and other inflammatory diseases. Although many studies have demonstrated that MSCs can either prevent or suppress inflammation, no studies have addressed their modulation on GM-CSF-expressing CD4 T cells and on the plasticity of Th17 cells. To address this, a single dose of human expanded adipose-derived mesenchymal stem cells (eASCs) was administered to mice with established collagen-induced arthritis (CIA). A beneficial effect was observed, soon after the infusion of the eASCs, as shown by a significant decrease in the severity of arthritis. This was accompanied by reduced number of pathogenic GM-CSF+CD4+ T cells in the spleen and peripheral blood and by an increase in the number of different subsets of regulatory T cells like FOXP3+CD4+ T cells and IL10+IL17CD4+ T cells in the draining lymph nodes (LNs). Interestingly, increased numbers of Th17 cells coexpressing IL10 were also found in draining LNs. These results demonstrate that eASCs ameliorated arthritis, after the onset of the disease, by reducing the total number of pathogenic GM-CSF+CD4+ T and by increasing the number of different subsets of regulatory T cells in draining LNs, including Th17 cells expressing IL10. All these cellular responses, ultimately, lead to the reestablishment of the regulatory/inflammatory balance in the draining LNs.

KEYWORDS: Adipose-derived mesenchymal stem cells; Arthritis; GM-CSF-expressing CD4 T cells; Plasticity of Th17 cells; Regulatory T cells

PMID: 26205964

 

Supplement

In this study, we define early T responses that occur after infusion of a single dose of human adipose-derived mesenchymal stem cells (eASCs) in established arthritis in mice. Over the last decade, cell therapy approaches have focused on the use of mesenchymal stem cells (MSCs) as multipotent progenitor cells as well as immune modulators [1]. Number of studies has endeavored deeply in the mechanisms underlying the effects of MSCs on the immune system and their potential applicability for treatment of autoimmune diseases and inflammatory disorders [2, 3]. In this sense, one of the key observations in our study relates to the fact that the therapeutic use of MSCs can control, in vivo, the development of the very pathogenic GM-CSF-secreting CD4+ T cells. Recent data have identified that GM-CSF-expressing CD4+ T cells are instrumental during the induction phase of rheumatoid arthritis (RA) [4] and, in phase II clinical trials, the use of strategies where specific blockade of GM-CSF or GM-CSF receptor are highly effective for treating RA [5-7]. Our study is the first report showing that cell therapy using MSCs can modulate GM-CSF-secreting CD4+ T cells in vivo after the onset of the disease.

Moreover, Th17 cells play a critical role during the pathogenesis of RA [8, 9]. Although MSCs have been extensively demonstrated to modulate inflammatory Th17 cells, up to date, no studies have addressed whether MSCs can modulate the plasticity of Th17 cells [10-12]. Our results show that cell therapy with MSCs induces the generation of IL10-producing Th17 cells which are known to have anti-inflammatory effects in RA and that these populations are mainly found in the draining LNs. In addition to this, we also found a preferential increase in the number of different populations of regulatory T cells in draining LNs.

These early T cells responses induced by cell therapy with MSCs ultimately lead to the amelioration of the established arthritis in mice by shifting the inflammatory/regulatory balance from GM-CSF inflammatory predominance to IL10 regulatory predominance (see proposed model of action of the eASCs in the diagram).

This study further supports the use of MSC-based cell therapy for treatment of inflammatory disorders like rheumatoid arthritis by targeting pathogenic GM-CSF+CD4+ T cells and by inducing plasticity of Th17 cells towards a regulatory profile.

 

 

fig1Schematic model for early T cells responses induced by the expanded adipose-derived stem cells (eASCs) in established collagen-induced arthritis (CIA).

 

Upon challenge with type 2 collagen antigen, resting CD4+ T cells in healthy mice become activated and differentiated towards GM-CSF and IL17 inflammatory CD4+ T cells that gradually increase over time in arthritic mice. In response to the ongoing inflammation, CIA mice also show increase numbers of different subsets of regulatory T cells (FOXP3+ CD4+ T cells, IL10+ CD4+ T cells and Lag3+ Tr1 cells) in spleen.  Cell therapy with eASCs, during the onset of the disease, causes a declined in the pathogenic GM-CSF+CD4+ T cells in spleen and peripheral blood. eASC-treated CIA mice show increase frequencies of regulatory T cells mainly in draining lymph nodes at the expense of reducing their frequencies in the spleen. The ongoing inflammation also induces plasticity of IL17+ CD4+ T cells towards a regulatory phenotype as shown by the co-expression of IL10. Strikingly, cell therapy treatment with eASCs favors not only the plasticity toward a regulatory phenotype but also the migration of the IL10-producing Th17 cells from the spleen to the draining lymph nodes. Ultimately, eASC treatment induces the shifting the inflammatory/regulatory balance from GM-CSF inflammatory predominance to IL10 regulatory predominance.

 

References:

1- Glenn JD and Whartenby KA. Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy. World J Stem Cells 2014;6(5):526-539.

2- DelaRosa O, Dalemans W and Lombardo E. Mesenchymal stem cells as therapeutic agents of inflammatory and autoimmune diseases. Curr Opin Biotechnol 2012;23(6):978-983.

3- MacDonald GI, Augello A and De Bari C. Role of mesenchymal stem cells in reestablishing immunologic tolerance in autoimmune rheumatic diseases. Arthritis Rheum 2011;63(9):2547-2557.

4- Cook AD, Pobjoy J, Sarros S, et al. Granulocyte-macrophage colony-stimulating factor is a key mediator in inflammatory and arthritic pain. Ann Rheum Dis 2013;72(2):265-270.

5- Behrens F, Tak PP, Ostergaard M, et al. MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial. Ann Rheum Dis 2014;74(6)(1058-1064.

6- Greven DE, Cohen ES, Gerlag DM, et al. Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis. Ann Rheum Dis 2014;0:1-7.

7- Burmester GR, Feist E, Sleeman MA, et al. Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-alpha, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study. Ann Rheum Dis 2011;70(9):1542-1549.

8- Lamacchia C, Palmer G, Seemayer CA, et al. Enhanced Th1 and Th17 responses and arthritis severity in mice with a deficiency of myeloid cell-specific interleukin-1 receptor antagonist. Arthritis Rheum 2010;62(2):452-462.

9- Bettelli E, Korn T, Oukka M, et al. Induction and effector functions of T(H)17 cells. Nature 2008;453(7198):1051-1057.

10- Lee Y, Awasthi A, Yosef N, et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 2012;13(10):991-999.

11- Nakayamada S, Takahashi H, Kanno Y, et al. Helper T cell diversity and plasticity. Curr Opin Immunol 2012;24(3):297-302.

12- O’Shea JJ and Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 2010;327(5969):1098-1102.

 

 

 

 

Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann