Abstract
Myeloid regulatory cell-based therapy has been shown to be a promising cell-based medicinal approach in organ transplantation and for the treatment of autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, Crohn’s disease and multiple sclerosis. Dendritic cells (DCs) are the most efficient antigen-presenting cells and can naturally acquire tolerogenic properties through a variety of differentiation signals and stimuli. Several subtypes of DCs have been generated using additional agents, including vitamin D3, rapamycin and dexamethasone, or immunosuppressive cytokines, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). These cells have been extensively studied in animals and humans to develop clinical-grade tolerogenic (tol)DCs. Regulatory macrophages (Mregs) are another type of protective myeloid cell that provide a tolerogenic environment, and have mainly been studied within the context of research on organ transplantation. This review aims to thoroughly describe the ex vivo generation of tolDCs and Mregs, their mechanism of action, as well as their therapeutic application and assessment in human clinical trials.
Highlights
New immunological therapies have been developing rapidly over the last few years, and one approach has focused on the immunoregulatory function of myeloid regulatory cells
These cells had a high capacity to capture and present antigen, and induced low proliferation of allogeneic T cells. They resisted maturation and increased graft survival after in vivo injection [97]. We focused on this simple protocol to derive tolerogenic bone marrow-derived rat Dendritic cells (DCs) based on cell adherence and granulocytes-macrophage colonystimulating factor (GM-CSF) + IL-4 treatment
We observed that human Autologous Tolerogenic Dendritic Cells (ATDC) display an immature phenotype by expressing low levels of costimulatory factors (CD80/86), low HLA-DR and low CD40. These ATDCs maintain their immature state after exposure to LPS or other Toll-like receptors (TLRs) ligands. We showed that these ATDCs expressed enhanced CCR7 after TLR stimulation, which lead to enhanced migration of these cells to secondary lymphoid organs, and importantly, maintenance of their tolerogenic potential
Summary
New immunological therapies have been developing rapidly over the last few years, and one approach has focused on the immunoregulatory function of myeloid regulatory cells. Whilst it had already been proposed that immature DCs could induce tolerance to transplantation antigens and contact allergens (in vitro/in vivo) [13,14], the DEC-205 approach showed that DCs could induce profound antigen-specific tolerance in vivo [15] This led to the possibility of isolating, targeting and expanding specific immune cell populations ex vivo to generate cell-based medicinal products (CBMPs) for the treatment of a range of immune diseases [16,17]. Knowledge of tolerogenic DCs (tolDCs) and regulatory macrophages (Mreg) has been expanding over recent years, and has shown promising results in animal models This has extended to several phase I clinical trials to assess tolDCs in the treatment of autoimmune diseases and the prevention of transplantation rejection [26,27,28,29,30,31,32,33]. We highlight the completed and ongoing clinical trials using tolDCs and Mregs to treat autoimmune diseases such as rheumatoid arthritis (RA), type 1 diabetes, multiple sclerosis, and Crohn’s disease, as well as to prevent transplantation rejection
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