Mesenchymal stem cells infusion prevents acute cellular rejection in rat kidney transplantation.

Mesenchymal stem cells (MSC) are multipotent cells that differentiate into various mature cell lineages. MSC show immunomodulatory effects by inhibiting T-cell proliferation. We evaluated the effect of the infusion of MSC in rats experimental kidney transplantation. Sprague-Dawley transgenic rats (SD) able to express the green fluorescent protein (EGFP) were used as MSC donors. Syngeneic (Lewis to Lewis, n = 10) and allogeneic (Fischer to Lewis, n = 10) kidney transplantations were performed after bilateral nephrectomy. Five transplanted rats who received syngeneic grafts, were treated with 3 x 10(6) MSC (Gr B), while the other 5 did not received MSC (Gr A). Five rats with allogenic grafts received 3 x 10(6) MSC (Gr C) and another 5 did not receive MSC (Gr D). The MSC were infused directly into the renal artery of the graft. No immunosuppressive therapy was provided. The animals were killed after 7 days. Biochemical analysis for renal function, histological (Banff criteria) and immunohistological analysis (ED1+ and CD8+) were performed on treated animals. MSC improved kidney function in Gr B and D vs Gr A and C. The tubular damage appeared to be less severe among Gr B and Gr D with respect to Gr A and C (P < .01). Vasculitis was more accentuated in Gr A and C (P < .01). MSCs reduced the inflammatory infiltrate; in Gr B and D, the number of ED1+ cells was lower than in Gr A and C (P < .005), which was also observed for CD8+ cells (P < .05). Our study demonstrated that the infusion of MSC attenuated histological damage from acute rejection by reducing the cellular infiltration.

Which is the most suitable and effective route of administration for mesenchymal stem cell-based immunomodulation therapy in experimental kidney transplantation: endovenous or arterial?

Immunomodulating cell therapy represents a new perspective for the control of cellular immune responses that determine the occurrence of acute rejection (ACR) in allo-transplantation. Mesenchymal stem cells (MSC) demonstrate immunoregulatory effects by inactivating T-cell components that regulate tissue damage in transplantation models. The presumed mechanism of action is recruitment of cells by a cytokine network. The purpose of this study was to test which route of administration (intra-arterial vs intravenous) was the most effective route to achieve immunomodulating effects in experimental rat kidney transplantation. Transgenic Sprague-Dawley rats (SD) expressing the enhanced green fluorescent protein (EGFP) at the somatic level were used as MSC donors: Allogeneic Fischer to Lewis grafts (n = 4 per group) were performed in rats after bilateral nephrectomy. In Gr B, 3 x 10(6) MSCs were infused into the renal graft artery, whereas in Gr C, they were infused into the tail vein. The untreated Gr A were a control group. No immunosuppressive therapy was administered. The animals were sacrificed at day 7 postoperatively. Biochemical analysis for renal function, histological (Banff criteria) and immunohistological (anti-EGFP-Immunoglobulin) analysis were performed on the transplanted animals. In Gr B, functional recovery was more rapid (creatinine: Gr B vs Gr C, P < .05). The inflammatory infiltrate in the graft was less in Gr B vs Gr C, with preservation of tubules, arteries, and glomeruli (P < .01). Intra-arterial infusion of MSCs was more effective to control ACR.