Macrophage Colony-Stimulating Factor Drives Cord Blood Monocyte Differentiation into IL-10highIL-12absent Dendritic Cells with Tolerogenic Potential

Abstract

Immature dendritic cells (DCs) induce tolerance and mature DCs induce inflammatory immune responses. However, the likelihood of maturation of immature DCs in vivo limits its potential application for suppression of unwanted immune reactions in vivo. The aim of this study was to generate DCs with anti-inflammatory properties in both the immature and mature states. GM-CSF combined with IL-4 drives monocyte differentiation into DCs. As M-CSF is a critical cytokine in development of the monocytic lineage and its level is dramatically elevated in immunosuppressive conditions, we investigated whether M-CSF could replace GM-CSF and generate DCs with distinct functions from umbilical cord blood monocytes. Highly purified umbilical cord blood monocytes cultured with M-CSF and IL-4, in a GM-CSF-independent fashion, differentiated into IL-10highIL-12absent cells with a DC phenotype (termed M-DC). Single time stimulation with immature DCs (both M-DCs and DCs) derived from cord blood induced hyporesponsive and regulatory CD4+ T cells. In contrast to mature DCs, mature M-DCs induced decreased Th1 differentiation and proliferation of naive CD4+ T cells in both primary and secondary allogeneic MLR and showed tolerogenic potential. These results demonstrate an unrecognized role for M-CSF in alternative differentiation of monocytes into anti-inflammatory M-DCs and suggest that M-CSF-induced DCs may be of use for suppressing unwanted immune responses.

Antigen presenting cells treated in vitro by macrophage colony-stimulating factor and autoantigen protect mice from autoimmunity

“…M-CSF-stimulated macrophages produce a large amount of IL-10, but a minimal level of IL-12 (Smith et al, 1998). Recently, Li et al demonstrated an unrecognized role of M-CSF in driving monocyte differentiation into IL-10 high IL-12 null DCs with tolerogenic potential (Li et al, 2005). Taken together, these results suggest that M-CSF has the potential to induce tolerogenic phenotype in APC.…”

“…M-CSF is constitutively present in human serum and is greatly elevated in immune suppressive conditions (Bartocci et al, 1986;Ikeno et al, 1996), probably playing a role in maintaining maternal tolerance toward embryos (Piccinni et al, 1997). M-CSF not only has the ability to drive monocyte differentiation into DCs with tolerogenic potential (Li et al, 2005), but also inhibits DC differentiation from CD34 + progenitors by downregulation of CD1a and upregulation of CD14 expression (Menetrier-Caux et al, 1998). Furthermore, M-CSF induces macrophages to constitutively produce low levels of IL-10 and high levels after activation (Smith et al, 1998).…”

M-CSF attenuates severity of chronic GVHD after unrelated BMT

“…15 Recent reports have shown that M-CSF induced DCs with IL-4 in a culture from human cord blood, and that these DCs produced high amounts of IL-10, but not IL-12, a pattern similar to that seen in M-CSF-induced macrophages. 8,9 The low incidence and severity of both acute and chronic GVHD after cord blood transplantation irrespective of HLA disparity, has been well documented. [16][17][18] M-CSF is elevated during pregnancy and in cord blood.…”

“…6,7 A tolerogenic action of M-CSF was reported during the induction of DCs from cord blood. 8,9 Most recently, M-CSF administration before conditioning reduced the severity of GVHD in a mouse model, and it is anticipated that this modality may be adopted as a new strategy for preventing GVHD. 10 In this study, we retrospectively analyzed data from patients who underwent unrelated BMT through the Japan Marrow Donor Program to study effects of M-CSF administration on long-term outcomes of UR-BMT, and we identified decreased severity of chronic GVHD after M-CSF administration.…”

Cell-Based Therapies in the Prevention of Solid Organ Transplant Rejection

“…Some tolerogenic DC express high levels of co-inhibitory molecules such as PD-L1 on their surface, or have a lower net ratio of co-stimulatory to co-inhibitory molecule expression (i.e., CD86 : PD-L1). Secretion of inhibitory cytokines/mediators also is variable, as some tolerogenic DC release IL-10, which has been shown to inhibit T cell expansion (Li et al, 2005). Further, tolerogenic DC can induce activation-induced cell death through FasL expression or induce Treg through IDO expression (Bohana-Kashtan and Civin, 2004;Mellor et al, 2004).…”