S.F.H. de Witte, M. Franquesa, T. Strini, S.S. Korevaar, F. Luk, S.J. Elliman, P.N. Newsome, M. Gargesha, D. Roy, A.M. Merino Rodriguez, C.C. Baan, M.J. Hoogduijn
Chair(s): prof. dr. Irma Joosten, immunoloog, Radboudumc, Nijmegen
Thursday 10 march 2016
13:30 - 14:00h at Foyer
Parallel session: Postersessies XI - Opgesplitst in 3 tijdblokken en 3 categoriëen (klinisch, basaal, donatie)
Mesenchymal stromal cells (MSC) are attractive candidates for cellular immunotherapy after organ transplantation and for diseases characterized by immune system alteration. MSC have shown to be low immunogenic and contain promising immunomodulatory capacities. These properties are favorable for the applicability of MSC for cellular therapy, however there is evidence that MSC are more immunogenic than previously thought. Furthermore, improving their immunomodulation would be advantageous. This study aims to optimize MSC by making them better immunomodulators and less immunogenic. During in vitro experiments, umbilical cord-derived MSC were treated for 3 days under various conditions, i.e. in the presence of pro-/anti-inflammatory cytokines, vitamins and serum-deprivation. Their immunogenicity and immunosuppressive capacity were examined by gene expression analysis, surface marker expressions, IDO activity and inhibition of CD4 and CD8 T-cell proliferation. Subsequently, susceptibility to NK cell lysis was investigated via CD107a expression on NK cells. Furthermore, treatment of liver inflammation and MSC survival was examined in a CCL4-induced liver disease mouse model. In vitro results showed significantly increased expression by MSC of the immunomodulatory factor PD-L1 after treatment with IFNγ, IFNβ and TGFβ, while culture under serum-deprivation conditions (Starv) decreased PD-L1 expression. IFNγ treated MSC were the most potent inhibitors of CD4 and CD8 T-cell proliferation as well as their IFNγ production. In addition, stimulation with IFNγ increased IDO activity. Furthermore, increased HLA type-I and -II levels were observed in IFNγ, IFNβ, vitamin B6 (VitB6) and Starv+VitB6 treated MSC. These MSC were significantly protected against NK lysis, which may correlate to the increased HLA type-I levels. In addition, TGFβ-MSC were significantly protected against NK cell lysis, even though HLA levels remained unchanged. In vivo, TGFβ-MSC had improved persistence after infusion compared to the other MSC while clearance of Starv-, VitB6- and Starv+VitB6-MSC was accelerated compared to untreated MSC. Nonetheless, liver function showed a trend of improvement after administration of TGFβ and Starv treated MSC. These data show the versatility of MSC to culture conditions and the possibility of optimizing MSC into less immunogenic cells with improved immunomodulatory properties, which is important for further development of MSC for cellular immunotherapy.