Enhanced immunoregulation of mesenchymal stem cells by IL-10-producing type 1 regulatory T cells in collagen-induced arthritis

Abstract

Mesenchymal stem cells (MSCs) possess immunomodulatory properties and have potential, however, there have been conflicting reports regarding their effects in rheumatoid arthritis (RA), which causes inflammation and destruction of the joints. Through a comparative analysis of regulatory T (Treg) and IL-10-producing type 1 regulatory T (Tr1) cells, we hypothesized that Tr1 cells enhance the immunoregulatory functions of MSCs, and that a combinatorial approach to cell therapy may exert synergistic immunomodulatory effects in an experimental animal model of rheumatoid arthritis (RA). A combination of MSCs and Tr1 cells prevented the development of destructive arthritis compared to single cell therapy. These therapeutic effects were associated with an increase in type II collagen (CII)-specific CD4+CD25+Foxp3+ Treg cells and inhibition of CII-specific CD4+IL-17+ T cells. We observed that Tr1 cells produce high levels of IL-10-dependent interferon (IFN)-β, which induces toll-like receptor (TLR) 3 expression in MSCs. Moreover, induction of indoleamine 2,3-dioxygenase (IDO) by TLR3 involved an autocrine IFN-β that was dependent on STAT1 signaling. Furthermore, we observed that production of IFN-β and IL-10 in Tr1 cells synergistically induces IDO in MSCs through the STAT1 pathway. These findings suggest co-administration of MSCs and Tr1 cells to be a novel therapeutic modality for clinical autoimmune diseases.

The Therapeutic Effect of Human Embryonic Stem Cell-Derived Multipotent Mesenchymal Stem Cells on Chemical-Induced Cystitis in Rats

“…In recent years, stem cell therapies have opened up new pathways toward the therapy of several previously intractable disorders [ 10 , 11 ]. Stem cell-based therapy has been considered a novel therapeutic approach when seeking to resolve disorders of lower urinary tract including stress urinary incontinence, detrusor overactivity or underactivity, and bladder or urethral injury [ 12 , 13 ].…”

Mesenchymal stem cells protect against the tissue fibrosis of ketamine-induced cystitis in rat bladder

“…Recently, administration of mesenchymal stem/stromal cells (MSCs) was found to stimulate the regeneration of damaged tissues and secrete growth factors and cytokines that promote angiogenesis and cell survival and prevent apoptosis of damaged tissues in several intractable disorders 11 12 13 14 15 16 . MSCs are adult multipotent progenitor cells derived from a variety of adult tissues (eg, bone marrow, adipose, peripheral blood, and dental pulp) and fetal ones (eg, umbilical cord blood [UCB], Wharton’s jelly, placenta, and amniotic fluid) 13 14 15 17 18 .…”

Osthole treatment ameliorates Th2-mediated allergic asthma and exerts immunomodulatory effects on dendritic cell maturation and function

“…Previous studies have noted that IL-10-producing Treg cells play a key role in immune tolerance, preventing uncontrolled inflammation and immunopathology. [34][35][36][37] These Treg cells can inhibit effector T-cell proliferation and cytokine production, reduce IgE production, suppress airway eosinophilia and downregulate the release of proinflammatory cytokines from mast cells by mechanisms involving IL-10 in allergic diseases. [38][39][40][41] Collectively, our findings suggest that osthole treatment dampened effector Th2 cell responses to limit allergen-induced immunopathology, at least in part by augmenting the numbers of IL-10 + Foxp3 + Treg cells.…”