Abstract
Current organ transplantation therapy is life-saving but accompanied by well-recognized side effects due to post-transplantation systematic immunosuppressive treatment. Dendritic cells (DCs) are central instigators and regulators of transplantation immunity and are responsible for balancing allograft rejection and tolerance. They are derived from monocyte-macrophage DC progenitors originating in the bone marrow and are classified into different subsets based on their developmental, phenotypical, and functional criteria. Functionally, DCs instigate allograft immunity by presenting donor antigens to alloreactive T cells via direct, indirect, and semidirect recognition pathways and provide essential signaling for alloreactive T cell activation via costimulatory molecules and pro-inflammatory cytokines. Regulatory DCs (DCregs) are characterized by a relatively low expression of major histocompatibility complex, costimulatory molecules, and altered cytokine production and exert their regulatory function through T cell anergy, T cell deletion, and regulatory T cell induction. In rodent transplantation studies, DCreg-based therapy, by in situ targeting or infusion of ex vivo generated DCregs, exhibits promising potential as a natural, well-tolerated, organ-specific therapeutic strategy for promoting lasting organ-specific transplantation tolerance. Recent early-phase studies of DCregs have begun to examine the safety and efficacy of DCreg-induced allograft tolerance in living-donor renal or liver transplantations. The present review summarizes the basic characteristics, function, and translation of DCregs in transplantation tolerance induction.
Highlights
Organ transplantation has progressed greatly over the past half-century to become the optimal treatment for a variety of end-stage organ diseases
Divito et al demonstrated that host Dendritic cells (DCs) mediated the therapeutic effects of the infused donor-derived DCregs [115], which are likely to be rapidly killed by host natural killer (NK) cells or captured and reprocessed by host splenic DCs, which induce Tregs and graft tolerance
We developed a novel small interfering RNAs (siRNAs) delivery system with a poly-dA extension at the 5′-end of the siRNA sense strand that was stably incorporated into 1,3-β-glucan [140]. siRNAs silencing the CD40 gene were delivered into DCs through its receptor, Dectin-1, resulting in antigen-specific Treg generation and permanent murine cardiac allograft tolerance
Summary
Organ transplantation has progressed greatly over the past half-century to become the optimal treatment for a variety of end-stage organ diseases. Many types of regulatory immune cells, such as regulatory T cells (Tregs) [6], type 1 regulatory T cells (Tr1) [7], regulatory macrophages, regulatory B cells (Bregs) [5, 8], myeloid-derived suppressor cells [9], and regulatory dendritic cells (DCregs) [10], have already been investigated in animal transplantation models, and entered the clinical trials in organ transplantation and shown clear benefits in terms of safety and graft survival [11, 12]. DCregs are attractive due to their role as central regulators of the immune response
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