Table 1.

Main effects of the immunosuppressive drugs on innate cells.

Drug	Dendritic cells	Phagocytes	Natural Killer (NK)
CNIs	Reduce LPS-induced secretion of pro-inflammatory cytokines TNF-α, IL-12 (12, 18–20).	Impair IL-6 and TNF-α production in response to TLR2 and TLR7/8 activation in monocytes/macrophages (24).	Reduce the expression levels of TNF-related apoptosis-inducing ligand (TRAIL) and FasL (36).
	Increase LPS-induced production of IL-10 in bone marrow derived DCs (BMDCs) and human blood-derived DCs (12, 18, 21).	Inhibit inflammasome activation preventing membrane permeability transition (MPT) in monocytes/macrophages (28).	Inhibit proliferation of NK cells in a dose-dependent manner (37).
	These effects may promote an anti-inflammatory phenotype on DCs that may lead to differential regulation of effector T cells subsets.	Inhibit neutrophil's reactive oxygen species generation and the formation of Neutrophil Extracellular Traps (NET) (31). This effect on neutrophil activity may be responsible for increased risk of post-transplant fungal infections.	Inhibit degranulation and IFN-γ production (38).
MMF/MPA	Lower the expression of costimulatory molecules (CD40, CD80, CD86), adhesion proteins (ICAM-1) and maturation markers (CD83, CD206) (47).	Inhibit IL-1β production and enhance the expression of surface markers of M2 phenotype (CD163 and CD200R) in monocytes (43).	Reduce proliferation of NK cells and inhibit the expression of CD56 (50, 51).
	Decrease the synthesis of proinflammatory cytokines (TNF-α, IL-10, IL-12, IL-18) (47).	Down-regulate adhesion molecules, like ICAM-1 in monocytes and inhibit their adhesion to endothelial cells (44).	Reduce cytotoxicity against K562 bone marrow target cells and IFN-γ production upon target encounter (50, 51).
	MMF reduces IL-10 synthesis (49).	Down-regulate TLR-4 expression on monocytes surface in a mouse model of Ischemia reperfusion injury resulting in milder kidney damage (46).
		Reduce the LPS-induced expression of MHC-II on monocyte surface (44).
		Induce apoptosis in monocytes (48).
GCs	Reduce the production of TNF-α, IL-1β induced by CD40L and LPS (65, 66).	Increase expression of anti-inflammatory cytokines (IL-10) with concomitant down-regulation of TNF-α, IL-1β, IL-12 in monocytes (58–60).	Reduce NK cytolytic activity (80–82).
	Inhibit the LPS-induced up-regulation of costimulatory molecules (e.g., CD40, CD80, CD83, CD86, and MHC-II) (65, 66).	In monocytes GCs reduce the expression of CD80 in response to inflammatory stimuli which impairs their antigen-presenting activity (61).	Through an epigenetic mechanism GCs induce the synthesis of pro-inflammatory cytokines (83, 84).
	DC differentiated in the presence of GC are not able to induce the proliferation of allogeneic CD4 T cells (65, 66).	In kidney transplant patients, increase the number of CD14++CD16- and CD14++CD16+ monocytes while the CD14+CD16++ population is declined compared to patients receiving CNI, MMF/MPA or mTOR inhibitor (62).
		Down-regulate TLR4 expression on the surface of monocytes and their response to endotoxin (64).
		Inhibit activation process of neutrophils by reducing the expression of NADPH oxidase, iNOS, COX-2 (70–73).
		Reduce chemotaxis, phagocytosis and cytokines secretion in neutrophils (74, 75).
		Increase the expression of some receptors for interleukins and pro-inflammatory leukotrienes such as IL1R1 and BLT1 in neutrophils (76–78).
		Reduce sensitivity to apoptosis which increases neutrophils average life span (79).
mTOR inhibitors	Impair DC maturation after LPS stimulation by reducing translation, including that of MHC-II and costimulatory molecules (90).	In LPS-stimulated human monocytes reduce chemokines synthesis such as MCP-1, RANTES, IL-8, and MIP-1 (103).	Inhibit NK proliferation and cytotoxicity capacity (51).
	Prevent phenotypic and functional maturation induced by IL-4, LPS, or CD40 ligation (91–93).
	Inhibit DC development induced by Flt3L (93).
	Impair antigen uptake contributing to damage allogeneic T lymphocytes stimulation (95).	Induce the up-regulation of pathways involved in production of nitric oxide, reactive oxygen species and IL-12 in macrophages (105).	Inhibit the shift toward an overall NKG2A+KIR-NCR+ phenotype and maintain an overall NKG2A-KIR+NCR+/– (51).
	Disinhibit autophagy that contributes to both MHCII presentation and MHCI cross-presentation of exogenous peptides (96, 97).
	Induce apoptosis in immature DC by blocking GM-CSF signaling (99).
	Increase surface expression of chemokine receptor CCR7 promoting DC migration into lymphoid tissue (108).