Mesenchymal stromal cells (MSC) possess immunomodulatory properties and are low immunogenic, which are both important for their development into an effective cellular immunotherapy after organ transplantation. The efficacy of MSC therapy will benefit from improvement of the immunomodulatory and immunogenic properties of MSC.

Human umbilical cord derived MSC were 3 days treated in vitro with various inflammatory factors, interleukins, vitamins and serum deprivation. Their immunogenicity and immunomodulatory capacity were examined by gene-expression analysis, surface-marker expressions, IDO activity, PGE₂ secretion and inhibition of Tcell proliferation and IFNγ production. Furthermore, their activation of NKcell cytotoxicity was investigated via CD107a expression on NKcells. Immunomodulatory capacity of treated MSC was investigated in an ex vivo liver inflammation model and a CCl₄-induced liver disease mouse model. In this mouse model, the bio-distribution and survival of pre-treated MSC was also examined.

IFNγ and a multi cytokine cocktail (MC) consisting of IFNγ, TGFβ and retinoic acid upregulated the expression of immunomodulatory factor PD-L1 and IDO activity. Subsequently, both treatments enhanced the capacity of MSC to inhibit CD4 and CD8 T-cell proliferation and IFNγ production. The susceptibility of MSC for NKcell lysis was decreased by IFNβ, TGFβ and MC treatment. In vivo, no immunomodulation was observed by the MSC. Four hours after intravenous infusion in mice with CCl₄ induced inflammatory liver injury, the majority of MSC were trapped in the lungs. Rapid clearance of MSC(VitB6), MSC(Starv+VitB6) and MSC(MC) and altered bio-distribution of MSC(TGFβ) was observed compared to MSC(-). In the ex vivo co-culture model with liver tissue slices, MSC(MC) showed enhanced immunomodulatory capacity compared to MSC(-).

The present study demonstrates the responsiveness of MSC to in vitro optimization treatment. The observed improvements in immunomodulatory capacity seen after IFNγ and MC treatment and decreased immunogenicity after TGFβ and MC treatment may improve the efficacy of MSC as immunotherapy after organ transplantation.

CITATION INFORMATION: de Witte S, Merino A, Franquesa M, Strini T, van Zoggel J, Korevaar S, Luk F, Gargesha M, Roy D, Elliman S, Newsome P, Baan C, Hoogduijn M. In Vitro Optimisation of the Immunotherapeutic Effects of Umbilical Cord Derived MSC. Am J Transplant. 2017;17 (suppl 3).

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