Abstract
Organ transplantation is often the unique solution for organ failure. However, rejection is still an unsolved problem. Although acute rejection is well controlled, the chronic use of immunosuppressive drugs for allograft acceptance causes numerous side effects in the recipient and do not prevent chronic allograft dysfunction. Different alternative therapies have been proposed to replace the classical treatment for allograft rejection. The alternative therapies are mainly based in pre-infusions of different types of regulatory cells, including DCs, MSCs, and Tregs. Nevertheless, these approaches lack full efficiency and have many problems related to availability and applicability. In this context, the use of extracellular vesicles, and in particular exosomes, may represent a cell-free alternative approach in inducing transplant tolerance and survival. Preliminary approaches in vitro and in vivo have demonstrated the efficient alloantigen presentation and immunomodulation abilities of exosomes, leading to alloantigen-specific tolerance and allograft acceptance in rodent models. Donor exosomes have been used alone, processed by recipient antigen-presenting cells, or administered together with suboptimal doses of immunosuppressive drugs, achieving specific allograft tolerance and infinite transplant survival. In this review, we gathered the latest exosome-based strategies for graft acceptance and discuss the tolerance mechanisms involved in organ tolerance mediated by the administration of exosomes. We will also deal with the feasibility and difficulties that arise from the application of this strategy into the clinic.
Highlights
Solid organ transplantation (SOT) is the unique solution for end-stage organ failure, and can be considered among the major accomplishments of the twentieth century in human health
It is well established that kidney transplantation, increases survival rates, guarantees a better quality-of-life and it is less costly in the long term compared to hemodialysis
Apoptotic lymphocytes would be a rich major histocompatibility complex (MHC) source [75, 76], easy to prepare, and would not require pre-loading dendritic cells (DCs) in vitro as their use per se has been proven sufficient. They have been used in transplant models in mice and rats, showing a prolonged allograft survival, promoting donor-specific tolerance, and proving to be safe by intravenous administration [75,76,77,78,79]
Summary
Solid organ transplantation (SOT) is the unique solution for end-stage organ failure, and can be considered among the major accomplishments of the twentieth century in human health. Apoptotic lymphocytes would be a rich MHC source [75, 76], easy to prepare, and would not require pre-loading DCs in vitro as their use per se has been proven sufficient They have been used in transplant models in mice and rats, showing a prolonged allograft survival, promoting donor-specific tolerance, and proving to be safe by intravenous administration [75,76,77,78,79]. These studies highlighted the importance of the right timing of the therapy and demonstrated apoptosis’ intrinsic immunoregulatory capabilities, as necrosis did not show the same beneficial effects [76]. Some studies proved the need of indirect presentation by DCs for exosomes to be able to stimulate T cells [93,94,95], while other groups did demonstrate direct functional presentation through exosomes themselves [96, 97]
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