Human Gingiva-Derived Mesenchymal Stromal Cells Attenuate Contact Hypersensitivity via Prostaglandin E2-Dependent Mechanisms

Abstract

The immunomodulatory and anti-inflammatory functions of mesenchymal stromal cells (MSCs) have been demonstrated in several autoimmune/inflammatory disease models, but their contribution to the mitigation of contact hypersensitivity (CHS) remains unclear. Here, we report a new immunological approach using human gingiva-derived MSCs (GMSCs) to desensitize and suppress CHS and the underlying mechanisms. Our results showed that systemic infusion of GMSCs before the sensitization and challenge phase dramatically suppress CHS, manifested as a decreased infiltration of dendritic cells (DCs), CD8 1 T cells, T H -17 and mast cells (MCs), a suppression of a variety of inflammatory cytokines, and a reciprocal increased infiltration of regulatory T cells and expression of IL-10 at the regional lymph nodes and the allergic contact areas. The GMSC-mediated immunosuppressive effects and mitigation of CHS were significantly abrogated on pretreatment with indomethacin, an inhibitor of cyclooxygenases. Under coculture condition of direct cell-cell contact or via transwell system, GMSCs were capable of direct suppression of differentiation of DCs and phorbol 12-myristate 13-acetate-stimulated activation of MCs, whereas the inhibitory effects were attenuated by indomethacin. Mechanistically, GMSC-induced blockage of de novo synthesis of proinflammatory cytokines by MCs is mediated partly by the tumor necrosis factor-alpha/prostaglandin E 2 (PGE 2 ) feedback axis. These results demonstrate that GMSCs are capable of desensitizing allergic contact dermatitis via PGE 2 -dependent mechanisms.

Human Oral Mucosa and Gingiva

“…Similar immunomodulatory mechanisms mediated by elevated IDO have also been reported for other types of oral MSCs, particularly human periodontal ligament stem cells (Wada et al, 2009). Additionally, findings from both in vitro and in vivo studies have indicated that GMSCs could significantly inhibit Th17 cells and simultaneously promote the expansion of CD4 + CD25 + FoxP3 + regulatory T-cells (Tregs) (Zhang et al, 2009(Zhang et al, , 2010Su et al, 2011;Tang et al, 2011). However, further studies are needed to elucidate the underlying mechanisms of interplay between gingivaderived MSCs and specific types of T-helper cells.…”

“…Similar to BMSCs (English and Mahon, 2011;Lee et al, 2011), GMSCs exhibit potent immunomodulatory effects on several types of innate immune cells, particularly dendritic cells (DCs), macrophages, and mast cells (Zhang et al, 2010;Su et al, 2011). (Galli et al, 2011).…”

“…Most recently, it has been shown that mouse BMSCs and human GMSCs exhibit striking suppressive effects on specific functions of MCs in vitro and in vivo (Brown JM et al, 2011;Su et al, 2011). We found that human BMSCs and GMSCs suppressed de novo synthesis of the major pro-inflammtory cytokine, TNF-α, from activated human HMC-1 mast cells in a cell-cell contact-independent manner; however, it had no obvious inhibitory effects on their degranulation in vitro (Su et al, 2011). However, mouse BMSCs suppressed not only the production of pro-inflammatory cytokines by MCs, but also their degranulation, chemokinesis, and chemotaxis (Brown JM et al, 2011).…”

“…Using a hapten (oxazolone)-induced murine CHS model, we showed that both prophylactic and therapeutic administration of GMSCs could mitigate clinical signs of CHS (Su et al, 2011). Following GMSC treatment, we observed a reduced infiltration of dendritic cells (DCs), CD8 + T-cells, Th17, total and degranulated mast cells (MCs), a decreased level of a variety of inflammatory cytokines, and a reciprocal increased infiltration of Tregs and expression of IL-10 at regional lymph nodes and inflammatory areas.…”

“…Following GMSC treatment, we observed a reduced infiltration of dendritic cells (DCs), CD8 + T-cells, Th17, total and degranulated mast cells (MCs), a decreased level of a variety of inflammatory cytokines, and a reciprocal increased infiltration of Tregs and expression of IL-10 at regional lymph nodes and inflammatory areas. The underlying mechanism of GMSCmediated attenuation of CHS involves the COX2/PGE 2 axis (Su et al, 2011). These findings suggest that GMSCs suppress CHS through targeting multiple types of innate and adaptive immune cells (Su et al, 2011), and the use of MSCs in cell-based therapy potentially contributes a novel modality for the treatment of allergic diseases.…”