Low-Dose Cyclosporine with Mycophenolate Mofetil Induces Similar Calcineurin Activity and Cytokine Inhibition as does Standard-Dose Cyclosporine in Stable Renal Allografts

Grinyó, Josep M.; Cruzado, Josep M.; Millán, Olga; Caldés, A; Sabaté, I; Gil-Vernet, S.; Serón, Daniel; Brunet, Mercè; Campistol, Josep M.; Torrás, Joan; Martorell, Jaume

doi:10.1097/01.tp.0000141227.63639.63

Cited by 30 publications

(24 citation statements)

References 19 publications

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“…Classically, CNIs downregulate IL-2 synthesis, which prevents Th1 and CD8 T-cell functions and IFN-γ synthesis (31,32). By contrast, cyclosphorin A (CsA) treatment promotes Th17 and Th2 responses after experimental lung transplantation and subsequently increases bronchiolitis obliterans (41).…”

Section: Mrna Expression After Transfer Of Ifn-γmentioning

confidence: 99%

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Inhibition of acute lethal pulmonary inflammation by the IDO–AhR pathway

Lee

Park

Suh

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The lung is a prototypic organ that was evolved to reduce immunopathology during the immune response to potentially hazardous endogenous and exogenous antigens. In this study, we show that donor CD4+ T cells transiently induced expression of indoleamine 2,3-dioxygenase (IDO) in lung parenchyma in an IFN-γ-dependent manner early after allogeneic hematopoietic stem cell transplantation (HSCT). Abrogation of host IDO expression by deletion of the IDO gene or the IFN-γ gene in donor T cells or by FK506 treatment resulted in acute lethal pulmonary inflammation known as idiopathic pneumonia syndrome (IPS). Interestingly, IL-6 strongly induced IDO expression in an IFN-γ-independent manner when deacetylation of STAT3 was inhibited. Accordingly, a histone deacetylase inhibitor (HDACi) could reduce IPS in the state where IFN-γ expression was suppressed by FK506. Finally, L-kynurenine produced by lung epithelial cells and alveolar macrophages during IPS progression suppresses the inflammatory activities of lung epithelial cells and CD4 + T cells through the aryl hydrocarbon receptor pathway. Taken together, our results reveal that IDO is a critical regulator of acute pulmonary inflammation and that regulation of IDO expression by HDACi may be a therapeutic approach for IPS after HSCT.acute lethal pulmonary inflammation | IFN-γ | Th2/Th17 cells | indoleamine 2,3-dioxygenase | aryl hydrocarbon receptor I ndoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme of tryptophan catabolism along the kynurenine pathway. The immunosuppressive mechanism of IDO is mediated by depletion of tryptophan and/or the accumulation of catabolites collectively known as kynurenines (1-5). Recently, L-kynurenine, a product of IDO, has been identified as an endogenous ligand for the aryl hydrocarbon receptor (AhR), which is a ligand-activated transcription factor belonging to the steroid receptor family (6, 7). It is now clear that the IDO-AhR pathway contributes to immune homeostasis by promoting modulation of innate and adaptive immune responses. Whereas IFN-γ is the most prominent inducer of IDO in various cell types, IL-6 also can induce the enzyme expression in astrocytes and neuronal and cancer cells by stimulating the JAK/ STAT3 signaling pathway (8, 9). By contrast, IL-6 has been implicated in the pathophysiology of Th17-mediated pulmonary inflammations such as idiopathic pulmonary syndrome (IPS) (10, 11). Thus, the IL-6-STAT3 pathway might be immunosuppressive or immunostimulatory in a context-dependent way.The lung was evolved to develop tolerance mechanisms to avoid severe immunopathology during the immune response to pathogens (12, 13). High levels of IDO are expressed in the lung during microbial infections. IFNs seem to be required for IDO expression by microbial components (14, 15) and IDO expressed in epithelial cells prevents immunopathology mediated by Th cells after microbial infections (16). It is clear that defects in IDO expression in cystic fibrosis and granulomatous disease is associated with unchecked inflammation cause...

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Section: Mrna Expression After Transfer Of Ifn-γmentioning

confidence: 99%

“…CNIs potently inhibit IFN-γ secretion from T cells (31,32) and are most widely used in the clinic for pharmacological GVHD prophylaxis (33). We examined whether CNI treatment influences the development of IPS associated with the inhibition of IDO expression.…”

Section: Cni Treatment Seems To Deteriorate Ips Through Inhibition Ofmentioning

confidence: 99%

Inhibition of acute lethal pulmonary inflammation by the IDO–AhR pathway

Lee

Park

Suh

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Earlier biomarker assays measured drug target enzyme activity in renal transplant recipients to predict efficacy of CsA [30] and SRL [31] or to evaluate the predictive value of pre-transplant values of MPA enzyme inhibition for the post-transplant outcome [32]. The enzyme assays, in general, do only measure enzyme activity, and not the numerous effects on immune cell function caused by enzyme inhibition.…”

Section: Clinical Studiesmentioning

confidence: 99%

Biomarkers in Transplantation Medicine: Prediction of Pharmacodynamic Drug Effects

Barten¹,

Gummert²

2007

Transfus Med Hemother

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Conventional therapeutic drug monitoring based on measuring of blood concentrations (pharmacokinetic) is important in the clinical management of immunosuppressive therapy in transplantation medicine. Since rejection or infection occurs at irregular drug concentrations, immunosuppressive drug therapy is often empiric and prophylactic in nature. In addition, blood immunosuppressant levels are only indirect predictors of the pharmacologic effects on immune cells (pharmacodynamic) because, due to the genetic heterogeneity, the immune systems of the transplant recipients are not equally sensitive to drug effects. Therefore, therapeutic drug monitoring requires the application of reliable and effective methods to study the pharmacodynamic variability by direct measurements of drugs effects on immune cell functions. Against this background we developed assays which are based on whole blood, flow cytometry and biomarkers of diverse functions of T cells and of dendritic cell subsets. These biomarker assays allow us to differentiate between synergistic and antagonistic pharmacodynamic effects of an immunosuppressive drug combination therapy in vitro and to predict the pharmacodynamic drug effects in heart-transplanted recipients. Such a pharmacodynamic drug monitoring based on biomarkers may offer the opportunity to complete conventional therapeutic drug monitoring and, therefore, to tailor immunosuppressive therapy more individually.

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“…CSA acts by binding to intracellular cyclophilin molecules -preventing the activation of the calcium-dependent phosphatase calcineurin -and inhibits the expression of immune-related cytokines such as IL-2 and IFN-γ (8,9). The use of these agents has been associated with an increased incidence of SCCs in particular primary cSCC, which occur proportionally to the intensity and duration of treatment (10,11).…”

Section: Introductionmentioning

confidence: 99%