Intraperitoneal Infusion of Mesenchymal Stem/Stromal Cells Prevents Experimental Autoimmune Uveitis in Mice

Autoimmune uveitis is one of the leading causes of blindness. We here investigated whether intraperitoneal administration of human mesenchymal stem/stromal cells (hMSCs) might prevent development of experimental autoimmune uveitis (EAU) in mice. Time course study showed that the number of IFN-γ- or IL-17-expressing CD4+ T cells was increased in draining lymph nodes (DLNs) on the postimmunization day 7 and decreased thereafter. The retinal structure was severely disrupted on day 21. An intraperitoneal injection of hMSCs at the time of immunization protected the retina from damage and suppressed the levels of proinflammatory cytokines in the eye. Analysis of DLNs on day 7 showed that hMSCs decreased the number of Th1 and Th17 cells. The hMSCs did not reduce the levels of IL-1β, IL-6, IL-12, and IL-23 which are the cytokines that drive Th1/Th17 differentiation. Also, hMSCs did not induce CD4+CD25+Foxp3+ cells. However, hMSCs increased the level of an immunoregulatory cytokine IL-10 and the population of IL-10-expressing B220+CD19+ cells. Together, data demonstrate that hMSCs attenuate EAU by suppressing Th1/Th17 cells and induce IL-10-expressing B220+CD19+ cells. Our results support suggestions that hMSCs may offer a therapy for autoimmune diseases mediated by Th1/Th17 responses.

[1]  Lingyun Sun,et al.  Allogeneic mesenchymal stem cell treatment alleviates experimental and clinical Sjögren syndrome. , 2012, Blood.

[2]  D. Prockop,et al.  Human Mesenchymal Stem/Stromal Cells Cultured as Spheroids are Self‐activated to Produce Prostaglandin E2 that Directs Stimulated Macrophages into an Anti‐inflammatory Phenotype , 2012, Stem cells.

[3]  T. Ikeda,et al.  Systemic transplantation of allogenic fetal membrane-derived mesenchymal stem cells suppresses Th1 and Th17 T cell responses in experimental autoimmune myocarditis. , 2012, Journal of molecular and cellular cardiology.

[4]  R. Zhao,et al.  Mesenchymal stem cells inhibit Th17 cell differentiation by IL-10 secretion. , 2012, Experimental hematology.

[5]  D. Prockop,et al.  Relearning the Lessons of Genomic Stability of Human Cells During Expansion in Culture: Implications for Clinical Research , 2012, Stem cells.

[6]  A. Zajícová,et al.  The role of mouse mesenchymal stem cells in differentiation of naive T-cells into anti-inflammatory regulatory T-cell or proinflammatory helper T-cell 17 population. , 2012, Stem cells and development.

[7]  A. Dick,et al.  Interplay between innate and adaptive immunity in the development of non-infectious uveitis , 2012, Progress in Retinal and Eye Research.

[8]  R. Cancedda,et al.  Mesenchymal stem cells induce functionally active T-regulatory lymphocytes in a paracrine fashion and ameliorate experimental autoimmune uveitis. , 2012, Investigative ophthalmology & visual science.

[9]  Min-jung Park,et al.  Transforming growth factor β-transduced mesenchymal stem cells ameliorate experimental autoimmune arthritis through reciprocal regulation of Treg/Th17 cells and osteoclastogenesis. , 2011, Arthritis & Rheumatism.

[10]  Z. Han,et al.  Mesenchymal stem cells ameliorate experimental autoimmune uveoretinitis by comprehensive modulation of systemic autoimmunity. , 2011, Investigative ophthalmology & visual science.

[11]  A. Rudensky,et al.  Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. , 2011, Immunity.

[12]  Francis J. Huber,et al.  Th17 cells express interleukin-10 receptor and are controlled by Foxp3⁻ and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. , 2011, Immunity.

[13]  Antonio Uccelli,et al.  Why should mesenchymal stem cells (MSCs) cure autoimmune diseases? , 2010, Current opinion in immunology.

[14]  K. Wood,et al.  Mesenchymal stromal cells: facilitators of successful transplantation? , 2010, Cell stem cell.

[15]  R. Caspi.  A look at autoimmunity and inflammation in the eye. , 2010, The Journal of clinical investigation.

[16]  C. Jorgensen,et al.  Mesenchymal Stem Cells Inhibit Human Th17 Cell Differentiation and Function and Induce a T Regulatory Cell Phenotype , 2010, The Journal of Immunology.

[17]  Philippe M. Campeau,et al.  Mesenchymal Stromal Cells Ameliorate Experimental Autoimmune Encephalomyelitis by Inhibiting CD4 Th17 T Cells in a CC Chemokine Ligand 2-Dependent Manner1 , 2009, The Journal of Immunology.

[18]  Yufang Shi,et al.  Species Variation in the Mechanisms of Mesenchymal Stem Cell‐Mediated Immunosuppression , 2009, Stem cells.

[19]  A. Uccelli,et al.  Multipotent mesenchymal stromal cells for autoimmune diseases: teaching new dogs old tricks , 2009, Bone Marrow Transplantation.

[20]  S. Fillatreau,et al.  Activated B cells in autoimmune diseases: the case for a regulatory role , 2008, Nature Clinical Practice Rheumatology.

[21]  A. P. Robinson,et al.  Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses , 2008, Proceedings of the National Academy of Sciences.

[22]  A. Uccelli,et al.  Mesenchymal stem cells in health and disease , 2008, Nature Reviews Immunology.

[23]  M. Fujimoto,et al.  A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. , 2008, Immunity.

[24]  Y. Bertrand,et al.  Human Mesenchymal Stem Cells License Adult CD34+ Hemopoietic Progenitor Cells to Differentiate into Regulatory Dendritic Cells through Activation of the Notch Pathway1 , 2008, The Journal of Immunology.

[25]  M. Kay,et al.  Sarcoma Derived from Cultured Mesenchymal Stem Cells , 2007, Stem cells.

[26]  R. Willemze,et al.  Mesenchymal Stem Cells Inhibit Generation and Function of Both CD34+-Derived and Monocyte-Derived Dendritic Cells1 , 2006, The Journal of Immunology.

[27]  H. Weiner,et al.  Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells , 2006, Nature.

[28]  R. J. Hocking,et al.  TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. , 2006, Immunity.

[29]  G. Mancardi,et al.  Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. , 2005, Blood.

[30]  Yi Zhang,et al.  Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. , 2005, Blood.

[31]  D. Gritz,et al.  Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study. , 2004, Ophthalmology.

[32]  B. Larson,et al.  Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. , 2004, Blood.

[33]  A. O’Garra,et al.  Cytokines induce the development of functionally heterogeneous T helper cell subsets. , 1998, Immunity.

[34]  P. Lehoang.  The gold standard of noninfectious uveitis: corticosteroids. , 2012, Developments in ophthalmology.

[35]  Cathy Frey,et al.  Investigative Ophthalmology and Visual Science , 2010 .

[36]  Krisztián Németh,et al.  Bone marrow stromal cells attenuate sepsis via prostaglandin E2–dependent reprogramming of host macrophages to increase their interleukin-10 production , 2009, Nature Medicine.

[37]  R. Caspi.  Experimental Autoimmune Uveoretinitis—Rat and Mouse , 1994 .