Apoptotic Donor Cells in Transplantation

Abstract

Despite significant advances in prevention and treatment of transplant rejection with immunosuppressive medications, we continue to face challenges of long-term graft survival, detrimental medication side effects to both the recipient and transplanted organ together with risks for opportunistic infections. Transplantation tolerance has so far only been achieved through hematopoietic chimerism, which carries with it a serious and life-threatening risk of graft versus host disease, along with variability in persistence of chimerism and uncertainty of sustained tolerance. More recently, numerous in vitro and in vivo studies have explored the therapeutic potential of silent clearance of apoptotic cells which have been well known to aid in maintaining peripheral tolerance to self. Apoptotic cells from a donor not only have the ability of down regulating the immune response, but also are a way of providing donor antigens to recipient antigen-presenting-cells that can then promote donor-specific peripheral tolerance. Herein, we review both laboratory and clinical evidence that support the utility of apoptotic cell-based therapies in prevention and treatment of graft versus host disease and transplant rejection along with induction of donor-specific tolerance in solid organ transplantation. We have highlighted the potential limitations and challenges of this apoptotic donor cell-based therapy together with ongoing advancements and attempts made to overcome them.

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

“…Before transplantation, 5 × 10 7 apoptotic donor splenocytes were injected per recipient. This treatment increased graft survival from 7 days in the untreated control group to 53 days in the treatment group 197 …”

“…Cell apoptosis can be induced in vitro using a variety of techniques. These include chemical treatments like ECDI or paraformaldehyde and radiation techniques like γ‐radiation or ultraviolet B irradiation 197,198 . The benefits of ECDI‐treated cells include increased viability when kept at 4°C and the cells undergoing rapid and efficient early apoptosis 198,199 .…”

“…These include chemical treatments like ECDI or paraformaldehyde and radiation techniques like γ-radiation or ultraviolet B irradiation. 197,198 The benefits of ECDI-treated cells include increased viability when kept at 4°C and the cells undergoing rapid and efficient early apoptosis. 198,199 When administered intravenously, they quickly trigger strong donor-specific tolerance in allogeneic and xenogeneic transplantation murine models and are phagocytized by recipient splenic APCs.…”

The significance of mixed chimaerism and cell lineage chimaerism monitoring in paediatric patients post haematopoietic stem cell transplant

“…The level of chimaerism is influenced by disease and conditioning regimens which can range from fully myeloablative to reduced-intensity conditioning (RIC) to the use of unconditioned HSCT infusions. [10][11][12] In RIC and unconditioned HSCTs, recipient and donor cells often coexist post HSCT, 13 but whether mixed chimaerism (MC) is a cause for concern or not depends entirely on the underlying disease. It is vital for laboratories to perform cell fractionation permitting chimaerism analysis of individual cell lineages.…”

Immune Modulatory Cell Therapy in Kidney Transplantation: Hints of a Durable Mechanism of Action

“…Tregs have also been proposed as a primary active mediator of immune regulation induced by tolerogenic cell therapies, including donor-derived apoptotic cells 12 and mesenchymal stromal cells. 3 Morath et al 5 analyzed the longitudinal Treg profiles of their trial participants, finding that, despite an early expansion of Tregs during the first post-transplant year, the longer-term proportions of the circulating level of Treg were rather low.…”