Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study

Abstract

Despite excellent short-term results, long-term survival of transplanted kidneys has not improved accordingly. Although alloimmune responses and calcineurin inhibitor-related nephrotoxicity have been identified as main drivers of fibrosis, no effective treatment options have emerged. In this perspective, mesenchymal stromal cells (MSCs) are an interesting candidate because of their immunosuppressive and regenerative properties. Of importance, no other clinical studies have investigated their effects in allograft rejection and fibrosis. We performed a safety and feasibility study in kidney allograft recipients to whom two intravenous infusions (1 million cells per kilogram) of autologous bone marrow (BM) MSCs were given, when a protocol renal biopsy at 4 weeks or 6 months showed signs of rejection and/or an increase in interstitial fibrosis/tubular atrophy (IF/TA). Six patients received MSC infusions. Clinical and immune monitoring was performed up to 24 weeks after MSC infusions. MSCs fulfilled the release criteria, infusions were well-tolerated, and no treatment-related serious adverse events were reported. In two recipients with allograft rejection, we had a clinical indication to perform surveillance biopsies and are able to report on the potential effects of MSCs in rejection. Although maintenance immunosuppression remained unaltered, there was a resolution of tubulitis without IF/TA in both patients. Additionally, three patients developed an opportunistic viral infection, and five of the six patients displayed a donor-specific downregulation of the peripheral blood mononuclear cell proliferation assay, not reported in patients without MSC treatment. Autologous BM MSC treatment in transplant recipients with subclinical rejection and IF/TA is clinically feasible and safe, and the findings are suggestive of systemic immunosuppression.

Trial registration: ClinicalTrials.gov NCT00734396.

Figures

Figure 1.

Study flowchart and MSC characteristics. (A): Study flowchart. Patients with SCR in the protocol biopsy 4 weeks after transplantation or with SCR and/or an increase in IF/TA approximately 6 months after transplantation received MSC infusions. If patients received MSCs because of SCR and/or an increase of IF/TA in the protocol biopsy at 6 months after transplantation, a follow-up renal biopsy was taken only if clinically indicated. (B): Overview of bone marrow collection, time needed for MSC culture, passage number, final MSC product infused, and timing of first MSC infusion. Abbreviations: BM, bone marrow; bmMSC, bone marrow-derived mesenchymal stromal cell; IF/TA, interstitial fibrosis/tubular atrophy; MSC, mesenchymal stromal cell; SCR, subclinical rejection; Tx, transplantation; W, week.

Figure 2.

Renal histology in two patients before and after autologous bone marrow-derived MSC infusions. In patient 4 the protocol renal biopsy 5 weeks post-transplantation demonstrated only small areas of interstitial fibrosis/tubular atrophy (IF/TA) without signs of tubulitis (A). The renal biopsy 26 weeks post-transplantation showed multiple foci of tubulitis and mild IF/TA (B, G) (in [G], left panel shows tubulitis, right panel shows IF/TA; arrow indicates infiltrating lymphocyte). A third renal biopsy 10 weeks after MSC infusions showed a complete normal renal histology (hematoxylin & eosin [H&E] stain) (C). In patient 5 the protocol biopsy 4 weeks post-transplantation showed no signs of allograft rejection (D). The standard renal biopsy at 24 weeks post-transplantation showed T-cell-mediated rejection with severe tubulitis (E, H) (in [H], arrow indicates infiltrating lymphocyte), which was resolved without signs of IF/TA 6 weeks after the MSC infusion (F) (H&E stain). Abbreviations: MSC, mesenchymal stromal cell; Pt, patient; TX, transplantation; wks post Tx; weeks after renal transplantation; wks post MSC, weeks after first mesenchymal stromal cell infusion.

Fig. 3.

Immune monitoring in MSC-treated patients. Twelve weeks after MSC treatment, proliferation of patient peripheral blood mononuclear cells (PBMCs) to donor antigen, but not third-party antigen, was reduced in five of the six patients as compared with the proliferation before MSC infusions (A). IFN-γ, IP-10, and MCP-1 levels measured in the supernatants of the PBMC proliferation assay declined upon stimulation with donor-specific PBMCs in the majority of the patients (B). ●, patient 1; ■, patient 2; ▴, patient 3; ×, patient 4; ▿, patient 5; ◊, patient 6. Abbreviations: cpm, counts per minute; IFN-γ, interferon γ; IP-10, interferon-γ induced protein-10; MCP-1, monocyte chemoattractant protein-1; MSC, mesenchymal stromal cell; w, weeks.