Pharmacologically Modified Dendritic Cells: A Route to Tolerance‐associated Genes

Tolerogenicity is not an absolute property of a dendritic cell

“…More complete explanations advocate some balance of the two, with micro-environmental context of antigenic encounter, and the nature of the Ag itself proposed as key determinants in establishing this balance of signaling [9,10]. We addressed the degree to which ''universal'' mechanisms are invoked by tolerogenic DC by comparing a set of male CBA-derived BMDC including DC modulated by VD3, IL-10 or TGF-b.…”

“…Immunological outcome was thought to be related directly to the maturation status of DC, with immature DC presenting for tolerance [4][5][6]; however, this simple view rapidly failed to account for accumulating experimental observations [7,8]. The functional diversity of DC has more recently been explained by the integration of multiple factors within a particular anatomical location causing the differentiation of appropriately tuned ''effector'' DC [9,10]. Although key co-inhibitory receptors, such as ILT3/4, PIR-B, PD-L1 and ICOSL, and immunoregulatory molecules, such as IDO and histone deacetylase HDAC11, have been variously implicated in driving tolerance [11][12][13][14][15][16], it is still not clear to what degree such molecules are universal players.…”

“…DC in vitro to generate maturation-resistant cells for adoptive cell therapy [2,9]; however, attempts to induce tolerance to allografts in conventional models have generally failed unless combined with other immunosuppressive agents [1], necessitating a move to reductionist models. We previously showed that we could induce tolerance to male skin grafts in female TCR transgenic A1.RAG mice by transferring either ''immature'' BMDC or BMDC modulated using 1a, 25-dihydroxyvitamin D 3 , (BMDC-VD3), but only the modulated cells retained their capacity to induce tolerance after maturation with the TLR4-ligand LPS [17].…”