Extracellular Vesicles from MSC Modulate the Immune Response to Renal Allografts in a MHC Disparate Rat Model.

M Koch,C Lange,A Lemke

doi:10.1155/2015/486141

Abstract

Application of mesenchymal stromal cells (MSC) has been proposed for solid organ transplantation based on their potent immunomodulatory effects. Since side effects from the injection of large cells cannot be excluded, the hypothesis rises that extracellular vesicles (EV) may cause immunomodulatory effects comparable to MSC without additional side effects. We used MSC-derived EV in a rat renal transplant model for acute rejection. We analysed peripheral blood leukocytes (PBL), kidney function, graft infiltrating cells, cytokines in the graft, and alloantibody development in animals without (allo) and with EV application (allo EV). There was no difference in kidney function and in the PBL subpopulation including Tregs between allo and allo EV. In the grafts T- and B-cell numbers were significantly higher and NK-cells lower in the allo EV kidneys compared to allo. TNF-α transcription was lower in allo EV grafts compared to allo; there was no difference regarding IL-10 and in the development of alloantibodies. In conclusion, the different cell infiltrates and cytokine transcription suggest distinct immunomodulatory properties of EV in allotransplantation. While the increased T- and B-cells in the allo EV grafts may represent a missing or negative effect on the adaptive immune system, EV seem to influence the innate immune system in a contrary fashion.

Highlights

Life-long drug-based immunosuppression still is the standard regime to induce clinical allograft acceptance, at the price of significantly reduced overall well-being of transplanted patients
Serum creatinine (SCr) in the allo extracellular vesicles (EV) group did not differ from the values in the allo group; that is, there was no difference in graft function, which was impaired due to acute rejection in both allo groups
It has previously been shown that application of Mesenchymal stromal cells (MSC) and MSC-derived EV can ameliorate ischemia-reperfusion injury (IRI) [13, 15,16,17]

Summary

Introduction

Life-long drug-based immunosuppression still is the standard regime to induce clinical allograft acceptance, at the price of significantly reduced overall well-being of transplanted patients. In the highly complex pathophysiology of acute renal allograft rejection, several components of the immune system are involved leading to vascular, glomerular, and tubular injuries. MSC influence all components of the immune system as shown for T-, B-, natural killer(NK-), monocytic and dendritic cells in vitro and in vivo [6, 7]. Our own group and others provided evidence for a negative impact on recipient survival in rat models of acute kidney allograft rejection [8, 9] and several questions have been rising about the role of MSC in SOT [10]

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Conclusion