Abstract
Survival after solid organ transplantation (SOT) is limited by chronic rejection as well as the need for lifelong immunosuppression and its associated toxicities. Several preclinical and clinical studies have tested methods designed to induce transplantation tolerance without lifelong immune suppression. The limited success of these strategies has led to the development of clinical protocols that combine SOT with other approaches, such as allogeneic hematopoietic stem cell transplantation (HSCT). HSCT prior to SOT facilitates engraftment of donor cells that can drive immune tolerance. Recent innovations in graft manipulation strategies and post-HSCT immune therapy provide further advances in promoting tolerance and improving clinical outcomes. In this review, we discuss conventional and unconventional immunological mechanisms underlying the development of immune tolerance in SOT recipients and how they can inform clinical advances. Specifically, we review the most recent mechanistic studies elucidating which immune regulatory cells dampen cytotoxic immune reactivity while fostering a tolerogenic environment. We further discuss how this understanding of regulatory cells can shape graft engineering and other therapeutic strategies to improve long-term outcomes for patients receiving HSCT and SOT.
Highlights
Solid organ transplantation is a lifesaving therapeutic strategy for numerous end-stage organ failures
To further extend chimeric antigen receptor (CAR) technology to Treg application in mice, Pierini et al [206] showed that Tregs with transient expression of mAbCAR promoted suppressive function once incubated with FITC-monoclonal antibodies (mAb) in vitro and in vivo and induced homing of mAbCAR Tregs to specific cells and organs [206] Adoptive transfer of mAbCAR Tregs reduced allograft responses such as GvHD, prolonged major histocompatibility complex (MHC)-mismatched pancreatic islet allograft survival, and increased alloantigen-specific tolerance to secondary skin grafts [206]
The transplantation tolerance field has dramatically advanced over recent decades to improve organ engraftment and survival and abate the mortality and morbidity caused by immune suppressive (IS)
Summary
Solid organ transplantation is a lifesaving therapeutic strategy for numerous end-stage organ failures. CD5 has been shown as a marker to promote extrathymic Treg development in response to self or tolerizing agents in the periphery [120,121,122], while lack of CD45RA indicates a memory phenotype in kidney transplanted patients [123] This shows that these induced Tregs in the periphery can have high plasticity to immune responses [120, 122] and be generated in a tolerogenic environment. Despite the removal of ab T cells, the presence of mature donor-derived effector cells provides anti-infectious control while minimizing the risk of severe acute GvHD [172, 173] In both malignant and non-malignant disorders, abhaplo-HSCT recipients have experienced excellent clinical outcomes including rapid immune reconstitution, low risk of infections, and low incidence of graft failure [170, 171, 174,175,176]. 2.5-125 × 106 cells 90-500 × 106 cells 300-500 × 106 cells 50 × 106 cells 224-384 × 106 cells
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