Marrow Mesenchymal Stem Cells Effectively Reduce Histologic Changes in a Rat Model of Chronic Renal Allograft Rejection

Background

Chronic allograft rejection remains as the leading cause of the chronic renal grafts loss post-transplantation. No therapy has been found really effective to prevent and treat chronic allograft rejection. Mesenchymal stem cells (MSCs) have characteristics of immunomodulation and are expected to be used for inducing graft immune tolerance in organ transplantation. We investigated the efficacy and safety of early infusion of donor-derived marrow MSCs in a rat model of chronic renal allograft rejection.

Methods

Orthotopic kidney transplantations were performed in a rat strain combination of Sprague-Dawley (SD) → Wistar. The native right kidneys of recipient rats were kept intact as internal control of each graft. Twenty-three successfully transplanted recipient rats were divided into 3 groups: group 1 (the MSCs therapy group) (n = 8) and group 2 (the control group) (n = 8) both received a 10-day course of cyclosporine (CsA) (2 mg/kg intraperitoneally) to prevent initial acute rejection. MSCs (1 × 10⁷) of first dosage and an additional dosage were injected into group 1 postoperative days (PODs) 0, 3, and 7. Group 2 received 0.9% saline solution in addition to CsA as the control group. Group 3 consisted of recipients (n = 7) receiving neither immunosuppression nor MSCs. Renal histopathology and immunohistochemistry of transforming growth factor β1 (TGF-β1) was examined at week 12. Safety of MSC infusion was determined by observing symptoms and signs after infusion and performing gross anatomy at week 12.

Results

All the grafts of group 3 developed acute rejection and were rejected within 4 weeks. Bone marrow MSCs significantly decreased the severity of mononuclear cell interstitial inflammation, tubular atrophy, interstitial fibrosis, and vascular fibrous intimal thickening in renal grafts (P < .001). MSCs also greatly reduced the glomerulosclerosis rate of the transplanted kidneys of group 1 (P < .001). The TGF-ß1 expression of group 1 was weaker than that of group 2 (P = .043). There were no symptoms or signs of severe adverse side effects observed.

Conclusions

Early bone marrow MSCs infusion on PODs 0, 3, and 7 are effective and safe for chronic renal allograft rejection in rats. MSCs hold significant promise for clinical transplantation to treat chronic renal allograft rejection and prolong the renal graft survival.