Harnessing Apoptotic Cells for Transplantation Tolerance: Current Status and Future Perspectives

Abstract

Purpose of review The use of donor apoptotic cells is an emerging therapy for inducing transplantation tolerance. In this review, we will discuss current understanding of mechanisms of this approach, as well as crucial aspects necessary for successful translation of this approach to clinical transplantation. Recent findings Transplantation tolerance by donor apoptotic cells is mediated by their homeostatic interaction with recipient phagocytes, and subsequent expansion of suppressor cell populations as well as inhibition of effector T cells via deletion and anergy. To ensure their tolerogenicity, it is critical to procure non-stressed donor cells, and to induce and arrest their apoptosis at the appropriate stage prior to their administration. Equally important is the monitoring of dynamics of recipient immunological status, and its influences on tolerance efficacy and longevity. Emerging concepts and technologies may significantly streamline tolerogen manufacture and delivery of this approach, and smooth its transition to clinical application. Summary Hijacking homeostatic clearance of donor apoptotic cells is a promising strategy for transplantation tolerance. Timing is now mature for concerted efforts for transitioning this strategy to clinical transplantation.

The role of efferocytosis and transplant rejection: Strategies in promoting transplantation tolerance using apoptotic cell therapy and/or synthetic particles

“…It is essential to ensure that the workload of eliminating ACs does not exceed the host's capacity for elimination, as this could result in residual ACs, allowing the progression to late‐stage apoptosis, which would cause inflammation rather than tolerance. According to earlier research, the optimum dose of donor ACs for successfully inducing tolerance in rodent models is 4 × 10 8 cells/kg 78 . As an alternative, repeated, low‐dose administration of donor ACs can be accomplished and is additively effective in causing graft protection 201 .…”

“…The profound influence of ACs as immunomodulators has prompted various laboratories to study the potential of donor ACs to improve graft tolerance. In rat models of allogeneic cardiac, aortic, and islet transplantation, such therapeutic intervention reduces acute allograft rejection without immunosuppression and, in some instances, chronic rejection 78 . In addition, when injected intravenously, the ACs of donors or patients' DCs rescue mouse cardiac allografts 79,80 …”

“…In rat models of allogeneic cardiac, aortic, and islet transplantation, such therapeutic intervention reduces acute allograft rejection without immunosuppression and, in some instances, chronic rejection. 78 In addition, when injected intravenously, the ACs of donors or patients' DCs rescue mouse cardiac allografts. 79,80 The first point of contact between the host and the injected apoptotic donor cells is through antigen-presenting cells (APCs).…”

Drugging the efferocytosis process: concepts and opportunities

“…In ECP, the leukocytes from a patient are removed, treated with UVA light along with 8-methoxysorelin and, then, reintroduced into the patient, which has been highly beneficial in dampening overall inflammation in many organs. Further, the benefits of apoptotic cell infusion for transplantations have been widely accepted, and experimental transplant models ranging from murine bone marrow to the heart, pancreatic islets and aortic transplants have shown much improved graft acceptance when the recipient was exposed to donor apoptotic cells 24 , 25 . However, how the donor cells given during ECP function has been a mystery.…”

Impact of infection on transplantation tolerance

“…181 There are several in vitro approaches of inducing apoptosis in donor cells, including γ irradiation, UV-B irradiation, and chemical treatments such as with ethylene carbodiimide (ECDI) or lytic anti-Fas monoclonal antibody. 182 Importantly, for tolerance induction, the donor cells infused must be at an early stage of apoptosis, as late stage apoptotic cells or further secondary necrotic cells engage receptors for damage-associated molecular patterns (DAMPs) and deliver inflammatory, instead of immunosuppressive signals. 181 Infusions of UV-B or γ irradiated donor cells have been shown to provide significant protection to allografts in rodent bone marrow, 183 heart 184,185 as well as aorta 186 and islet transplantation models 187 without any additional immunosuppressive treatment.…”