One of the best-characterized types of iTreg is the type 1 regulatory T cell (Tr1). These cells are induced from naive T cells and control immune responses mainly through ICG-001 in vivo the production of immunosuppressive cytokines (IL-10 and TGF-β), but they can also act by lysing target cells of myeloid origin [35]. The mechanisms by which tolDC operate have been described amply in detail by others (e.g. [18, 36, 37]); only a few examples will be mentioned here. DC producing the tryptophan-degrading enzyme indoleamine 2,3 dioxygenase (IDO) block T cell clonal expansion [38]. Plasmacytoid DC in the liver promote antigen-specific tolerance through T cell deletion and/or the induction of T cell

anergy [39]. Mucosal CD103+ DC induce FoxP3+ Tregs through secretion of TGF-β and/or retinoic acid [40, 41], whereas mucosal CD8+ DC induce Tr1-like cells with regulatory properties [41]. Interestingly, it has been shown that Tregs, in turn, suppress DC maturation and enhance the expression of immunosuppressive PD0325901 molecules (e.g. IL-10, B7-H4), thus inducing tolerogenic function in DC [42, 43]. This bidirectional cross-talk between Tregs and DC further supports immune tolerance. The concept that maturation conditions determine the tolerogenicity of DC has facilitated

the development of tolDC therapies for disorders that are characterized by a failure in immune tolerance. TolDC treatment for the prevention of graft rejection

in transplantation has been reviewed extensively elsewhere [44, 45]; the current review focuses on development of this tolerogenic immunotherapy for autoimmune Ibrutinib solubility dmso diseases, in particular RA. TolDC have been developed as an autologous cellular therapy, in which DC precursors are isolated from the patient, differentiated ex vivo into tolDC, loaded with appropriate autoantigens (optional), and injected back into the patient. Many different methods are available for the ex-vivo generation of DC with potent tolerogenic function. One of the most important considerations in choosing the appropriate method is that the final tolDC product should be stable, i.e. tolDC should not differentiate into immunogenic DC in vivo when exposed to proinflammatory mediators. The stability of tolDC is, therefore, an especially important consideration if they are going to be used for the treatment of autoimmune diseases that are characterized by chronic inflammation, as is the case in RA. Certain types of tolDC (e.g. partially matured DC, also referred to as semi-mature DC) have indeed been shown to become immunogenic in vivo [46, 47], which is undesirable, as presentation of autoantigen by immunogenic DC can induce or exacerbate autoimmune disease [48, 49]. Methods for stable tolDC generation have been reviewed elsewhere [50], and will be summarized only briefly here.