Infusion of Mesenchymal Stem Cells and Rapamycin Synergize to Attenuate Alloimmune Responses and Promote Cardiac Allograft Tolerance

Abstract

The inherent immunosuppressive properties and low immunogenicity of mesenchymal stems cells (MSCs) suggested their therapeutic potential in transplantation. We investigated whether MSCs could prolong allograft survival. Treatment involving infusion of MSCs into BALB/c recipients 24 hours after receiving a heart allograft from a C57BL/6 donor significantly abated rejection and doubled graft mean survival time compared to untreated recipients. Furthermore, combination therapy of MSCs and low-dose Rapamycin (Rapa) achieved long-term heart graft survival (>100 days) with normal histology. The treated recipients readily accepted donor skin grafts but rejected third-party skin grafts, indicating the establishment of tolerance. Tolerant recipients exhibited neither intragraft nor circulating antidonor antibodies, but demonstrated significantly high frequencies of both tolerogenic dendritic cells (Tol-DCs) and CD4 + CD25 + Foxp3 + T cells in the spleens. Infusion of GFP + C57BL/6-MSCs in combination with Rapa revealed that the GFP-MSCs accumulated in the lymphoid organs and grafts of tolerant recipients. Thus, engraftment of infused MSCs within the recipient's lymphoid organs and allograft appeared to be instrumental in the induction of allograft-specific tolerance when administered in combination with a subtherapeutic dose of Rapamycin. This study supports the clinical applicability of MSCs in transplantation.

iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation

“…Previous published experimental studies suggested that MSCs can, under certain conditions, induce allograft tolerance together with immunomodulatory drugs [9,10,14,19]. In our study, iPSCMSCs + Rapa treatment effectively prolonged islet allograft survival time and even induced immune tolerance in 50% of the recipients, which was consistent with results using adult MSCs with 2 mg/kg/day Rapa treatment in heart allografts [9]. Our results demonstrated that the combined treatment had synergistic effects.…”

“…Several studies have shown that adult MSCs alone, or combined with immunosuppressive drugs, induce allograft immune tolerance through Treg induction in vivo [8,9,17]. Berman et al first reported that infusions of donor or thirdparty MSCs reversed rejection episodes and prolonged islet function, associated with increased numbers of Tregs in peripheral blood [60].…”

“…However, some studies showed that MSCs alone had no significant effect on graft survival in a completely allogeneic heart transplant model. In contrast, combining MSCs with mycophenolate mofetil led to prolonged allograft survival [10], and MSCs plus rapamycin (Rapa) induced immune tolerance of heart allografts [9]. Furthermore, MSCs combined with cyclosporine A (CsA) induced tolerance of islet allografts in immune-deficient mice [14].…”

“…The immunosuppressive effect and low immunogenicity of mesenchymal stem cells (MSCs) make them ideal candidates for immunosuppressive strategies [3,4]. Adult MSCs have been used widely in the allogeneic heart [5][6][7][8][9][10][11], liver [12], islet [13][14][15][16][17], kidney [18,19], and composite tissue transplants [20,21]. Bone marrow mesenchymal stem cells (BM-MSCs) alone prolong heart allograft survival [8].…”

Mesenchymal stem cells differentially mediate regulatory T cells and conventional effector T cells to protect fully allogeneic islet grafts in mice

“…Recently, we showed that MSCs exert potent immunosuppressive properties by reducing the surface expression of CD25, the alpha subunit of the IL-2 receptor, on T eff cells, thus blocking the IL-2 cytokine signalling pathway required for T lymphocyte activation, expansion and differentiation [8]. By targetting the detrimental alloreactive T cell response, MSCs have been shown to exhibit therapeutic potential in controlling or preventing graft rejection in many experimental animal models of organ transplantation [9][10][11].…”