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Fine-needle aspiration biopsy (FNAB) samples (containing mononuclear cells together with kidney parenchymal cells) obtained from kidney transplant recipients receiving sirolimus showed lower synthesis of many proinflammatory cytokines, including IL-6 and MCP-1, and higher production of TGF- than samples from patients whose regimen contained MMF (104)

Fine-needle aspiration biopsy (FNAB) samples (containing mononuclear cells together with kidney parenchymal cells) obtained from kidney transplant recipients receiving sirolimus showed lower synthesis of many proinflammatory cytokines, including IL-6 and MCP-1, and higher production of TGF- than samples from patients whose regimen contained MMF (104). to improve graft outcomes. This review discusses effects of currently used immunosuppressive brokers on innate immune responses in kidney transplantation. infections, indicating that CsA impairs specific anti-fungal functions in innate immune cells ZM 306416 hydrochloride (32). More specifically, mice lacking calcineurin activity in neutrophils were defective in the ability to kill indicating that CsA may directly influence neutrophil killing processes (32). Currently, overall mortality due to fungal infections in transplant patients varies between 25 and 80%, with Candida and Cryptococcus species being the most commonly recognized yeasts (33). The higher doses of immunosuppressive medications in the first 6 months after ZM 306416 hydrochloride transplantation are major causes of fungal infections. studies revealed that CsA damages human neutrophil clearance of (another important cause of post-transplant opportunistic infections) (34), and that this effect is more evident in patients reaching high CNI ZM 306416 hydrochloride trough levels. Inhibition of neutrophils activity by CNI may be, at least in part, responsible for increased risk of Rabbit polyclonal to Neuropilin 1 post-transplant fungal infections. CNI do also impact NK cells in kidney transplant recipients (35). Zhang et al. have demonstrated that this expression levels of TNF-related apoptosis-inducing ligand (TRAIL) and FasL, potent apoptosis inducers, increase in NK cells at day 5 after transplantation, while their levels return to baseline on day 13 post-kidney transplantation (36). The authors also exhibited that in supernatants generated from mixed lymphocytes culture (MLC) and on the surface of activated lymphocytes (particularly on NK cells) there was a significant increment of the expression of TRAIL and FasL. This condition was considerably reduced by adding CsA (500 ng/mL) at the beginning of MLC, an effect that could, at least in part, be implicated in the antirejection properties of CsA (36). CsA inhibits the NK cells proliferation in a dose-dependent manner (37). Morteau et al. showed that treatment of NK cells from healthy controls with CNI inhibits their degranulation and IFN- production. Similar functional impairment was observed in NK cells from CNI-treated patients. This could have dramatic effects around the NK cells capacity of killing transformed or virus-infected cells and generating pro-inflammatory cytokines and could, at least in part, explain the increased risk of opportunistic infections and tumors of CNI-treated patients (38). Mycophenolate Mofetil/Mycophenolic Acid Currently, mycophenolate mofetil (MMF) and its active metabolite mycophenolic acid (MPA), are the most widely used drugs in transplantation (39, 40). MMF/MPA are considered specific anti-lymphocytes brokers, since they reduce the guanosine nucleotide synthesis by selectively inhibiting the inosine monophosphate dehydrogenase (IMPDH), mainly expressed by T- and B- cells (41, 42). When exposed to MMF/MPA, monocytes show lower levels of pro-inflammatory cytokine IL-1 and altered polarization, with enhanced expression of surface markers (like CD163 and CD200R), generally associated with an anti-inflammatory function (M2 phenotype) (43). Additionally, MMF/MPA-exposed monocytes down-regulate several adhesion molecules, like ICAM-1, and display a weaker binding to cultured human umbilical vein endothelial cells (HUVEC) (44). Treating HUVECs alone with MMF/MPA does not reduce the adhesion of activated monocytes, reinforcing the idea of a direct effect of these compounds on monocytes (45). In a mouse model of renal IRI, MMF down-regulated TLR4 expression on monocytes surface, along with plasma level of several cytokines (IL-6, MCP-1, and TNF-). This ZM 306416 hydrochloride resulted in milder kidney damage, as defined by creatinine levels and histological findings at 48 h after IRI (46). MMF also reduces the LPS-induced expression of MHC-II on monocyte surface, suggesting a reduced activity as antigen presenting cells (44). In.