NIV Congres

Introduction CD28/B7 co-stimulation blockade with belatacept is used to prevent allo-reactivity in kidney transplant patients. Cells that lose CD28 during differentiation are not sufficiently controlled by belatacept. Yet, these CD28- T cells have cytotoxic capacities and pathogenic potential. Mesenchymal stem cells (MSC) possess various immunosuppressive properties, inhibit effector cell proliferation and therefore are interesting candidates for cellular therapy in organ transplantation. Our study aimed to investigate the effect of MSC on allo-reactive CD28- T cells and to elucidate the relevant mechanisms of action.

Methods MSC were isolated from perirenal adipose tissue of kidney donors; PBMC were derived from blood bank donors. Mixed lymphocyte reactions (MLR; 7-days) were used to mimic allo-reactivity. Flow cytometric analyses were performed (n = 5).

Results Belatacept (1µg/mL) and MSC (1:10; ratio MSC : effector cells) reduced effector cell proliferation by 40% (mean; p = 0.002) and 63% (p = 0.001), respectively. The combination of both inhibited proliferation by 78% (p < 0.0001). Belatacept treatment did not influence the proliferation of CD4+CD28- T cells and CD8+CD28- T cells when compared to MLR. MSC, however, reduced the proliferation of CD4+CD28- T cells by 67% (p = 0.002). The same effect was observed when MSC were separated from the MLR by permeable cell culture inserts. In both systems the influence of MSC on the proliferation of CD8+CD28- T cells was less profound. Combined treatment of belatacept and MSC did not impair the suppressive function of MSC on CD4+CD28- T cells or CD8+CD28- T cells.

Conclusion Allo-activated CD28- T cells that remain unaffected by belatacept treatment are inhibited by MSC in a cell-cell-contact independent manner. Although further investigation of specific contributing mechanisms is required, the anti-proliferative effect of MSC on CD28- T cells strongly emphasizes the potential of a MSC-belatacept combination therapy to prevent graft rejection.