Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells

Authors

  • Manuel A. González,

    Corresponding author
    1. Cellerix SA, Tres Cantos, and Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
    • Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Calle Melchor Fernandez Almagro, Madrid 28029, Spain
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    • Drs. González and Gonzalez-Rey contributed equally to this work.

    • Drs. González, Büscher, and Delgado are coinventors with Cellerix SA on a patent application for the use of adipose-derived mesenchymal stem cells in autoimmunity. The study reported herein is part of that patent application.

  • Elena Gonzalez-Rey,

    1. University of Seville, Seville, Spain
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  • Laura Rico,

    1. Cellerix SA, Tres Cantos, Spain
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  • Dirk Büscher,

    1. Cellerix SA, Tres Cantos, Spain
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    • Drs. González, Büscher, and Delgado are coinventors with Cellerix SA on a patent application for the use of adipose-derived mesenchymal stem cells in autoimmunity. The study reported herein is part of that patent application.

  • Mario Delgado

    Corresponding author
    1. Instituto de Parasitología y Biomedicina, CSIC, Granada, Spain
    • Instituto de Parasitología y Biomedicina, CSIC, Avenida Conocimiento, PT Ciencias de la Salud, Granada 18100, Spain
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    • Drs. González, Büscher, and Delgado are coinventors with Cellerix SA on a patent application for the use of adipose-derived mesenchymal stem cells in autoimmunity. The study reported herein is part of that patent application.


Abstract

Objective

Rheumatoid arthritis (RA) is a chronic autoimmune disease caused by loss of immunologic self tolerance and characterized by chronic joint inflammation. Adult mesenchymal stem cells (MSCs) were recently found to suppress effector T cell responses and to have beneficial effects in various immune disorders. The purpose of this study was to examine a new therapeutic strategy for RA based on the administration of human adipose-derived MSCs (AD-MSCs).

Methods

DBA/1 mice with collagen-induced arthritis were treated with human AD-MSCs after disease onset, and clinical scores were determined. Inflammatory response was determined by measuring the levels of different mediators of inflammation in the joints and serum. The Th1-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with the autoantigen. The number of Treg cells and the suppressive capacity on self-reactive Th1 cells were also determined.

Results

Systemic infusion of human AD-MSCs significantly reduced the incidence and severity of experimental arthritis. This therapeutic effect was mediated by down-regulating the 2 deleterious disease components: the Th1-driven autoimmune and inflammatory responses. Human AD-MSCs decreased the production of various inflammatory cytokines and chemokines, decreased antigen-specific Th1/Th17 cell expansion, and induced the production of antiinflammatory interleukin-10 in lymph nodes and joints. Human AD-MSCs also induced de novo generation of antigen-specific CD4+CD25+FoxP3+ Treg cells with the capacity to suppress self-reactive T effector responses.

Conclusion

Human AD-MSCs emerge as key regulators of immune tolerance by inducing the generation/activation of Treg cells and are thus attractive candidates for a cell-based therapy for RA.

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