Mycophenolate mofetil-based immunosuppression and cytokine genotypes: effects on monokine secretion and antigen presentation in long-term renal transplant recipients

Weimer, Rolf; Mytilineos, Joannis; Feustel, Andreas; Preiss, Astrid; Daniel, Volker; Grimm, H.; Wiesel, M.; Opelz, Gerhard

doi:10.1097/01.tp.0000058808.37349.23

Cited by 36 publications

(26 citation statements)

References 57 publications

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“…Our study is the first to confirm the influence of the IL-6 promoter polymorphism at position Ϫ174 on the IL-6 production capacity in patients who receive immunosuppressive drugs. This result is in accordance with recent findings indicating that only high steroid doses influence IL-6 production in RTR (22). Our results also suggest that the impact of such IL-6 gene promoter polymorphism on circulating IL-6 levels is higher in overweight patients.…”

Section: Discussionsupporting

confidence: 83%

IL-6 Promoter Polymorphism −174 Is Associated with New-Onset Diabetes after Transplantation

Bamoulid

Courivaud

Deschamps

et al. 2006

Journal of the American Society of Nephrology

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New-onset diabetes after transplantation (NODAT) is a serious complication of transplantation. This study tested whether IL-6 production capacity may influence the development of NODAT in two different groups of patients. The occurrence of NODAT was analyzed with respect to IL-6 gene promoter polymorphism at position ؊174 (G3C) and other relevant risk factors retrospectively in 217 renal transplant recipients and prospectively in 132. A linear increase in both circulating IL-6 (P ‫؍‬ 0.09) and C-reactive protein (an indicator of basal IL-6 secretion; P ‫؍‬ 0.03) concentrations from the CC genotype to the GG genotype was observed. In the multivariate model, the CC genotype was associated with a decreased risk for NODAT compared with the GG genotype in the two cohorts. Homeostasis Model Assessment for Insulin Resistance also revealed lesser insulin sensitivity in the GG carriers than in the CC carriers (2.15 ؎ 2 versus 1.32 ؎ 1.03; P ‫؍‬ 0.03). Subgroup analysis showed that the influence of IL-6 gene promoter polymorphism on the development of NODAT was restricted mostly to overweight patients. These results highly suggest that IL-6 production capacity influences the development of NODAT and that diabetes-inducing drug administration should be limited in overweight patients who carry the GG genotype.

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Section: Discussionsupporting

confidence: 83%

IL-6 Promoter Polymorphism −174 Is Associated with New-Onset Diabetes after Transplantation

Bamoulid

Courivaud

Deschamps

et al. 2006

Journal of the American Society of Nephrology

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“…MMF has been demonstrated to improve graft and patient survival by reducing acute rejection, [21][22][23] and possibly by delaying chronic graft rejection. 24,25 However, MMF-related adverse events, most notably GI intolerance and BMT, frequently lead to dose reductions or drug discontinuation. [3][4][5] Few clinical demographic parameters have been found to predict MMF intolerance.…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms influence mycophenolate mofetil–related adverse events in pediatric heart transplant patients

Ohmann

Burckart

Brooks

et al. 2010

The Journal of Heart and Lung Transplantation

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“…12,13 On the contrary, glucocorticoids (GCs) have a high anti-inflammatory potential and, consequently, are crucial constituents of various immunosuppressive regimens applied in many inflammatory conditions. 14 GCs differentially affect cytokine production in monocytes/macrophages with a prominent shift toward an anti-inflammatory phenotype.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells

Weichhart

Haidinger

Karl

et al. 2011

Blood

122

107

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A central role for the mammalian target of rapamycin (mTOR) in innate immunity has been recently defined by its ability to limit proinflammatory mediators. Although glucocorticoids (GCs) exert potent anti-inflammatory effects in innate immune cells, it is currently unknown whether the mTOR pathway interferes with GC signaling. Here we show that inhibition of mTOR with rapamycin or Torin1 prevented the anti-inflammatory potency of GC both in human monocytes and myeloid dendritic cells. GCs could not suppress nuclear factor-B and JNK activation, the expression of proinflammatory cytokines, and the promotion of Th1 responses when mTOR was inhibited. Interestingly, long-term activation of monocytes with lipopolysaccharide enhanced the expression of TSC2, the principle negative regulator of mTOR, whereas dexamethasone blocked TSC2 expression and reestablished mTOR activation. IntroductionCurrent immunosuppressive regimens to avoid allogeneic rejection after organ or bone marrow transplantation largely rely on drugs with potent immunosuppressive effects predominantly affecting different steps during T-cell activation. There is, however, increasing evidence that also the innate immune system is critical for the fate of allografts and may as well exert detrimental effector functions. 1-9 For example, monocytes are the first cells to enter the allograft immediately after transplantation; and recently, monocyte influx, rather than T-cell influx, into the allograft has been proposed to correlate with graft rejection. 9 Monocytes, macrophages, and dendritic cells (DCs) initiate the inflammatory response after stimulation by Toll-like receptor (TLR) ligands and trigger the subsequent adaptive T-cell response. 10,11 However, the molecular pathways targeted by immunosuppressants in particular when they are used as combination therapy and the ensuing functional consequences are still incompletely defined.Among the currently used immunosuppressants calcineurin inhibitors (CNI), such as cyclosporine A (CsA) or FK506, and antimetabolites, such as mycophenolic acid (mycophenolate mofetil [MMF]) are thought to exert distinct but rather modest effects on innate immune cells. 12,13 On the contrary, glucocorticoids (GCs) have a high anti-inflammatory potential and, consequently, are crucial constituents of various immunosuppressive regimens applied in many inflammatory conditions. 14 GCs differentially affect cytokine production in monocytes/macrophages with a prominent shift toward an anti-inflammatory phenotype. 15 Furthermore, DC differentiation and maturation are profoundly suppressed by GCs, leading to DCs with a tolerizing capacity characterized by increased interleukin-10 (IL-10), but blocked IL-12 secretion. 16,17 At the molecular level, GCs profoundly inhibit nuclear factor-B (NF-B) signaling via the glucocorticoid receptor (GR) to prevent recruitment of active NF-B dimers to the B promoter. 18 Moreover, it has been demonstrated that the c-Jun N-terminal kinase (JNK) pathway that specifically leads to the activation of the tr...

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Mycophenolate mofetil-based immunosuppression and cytokine genotypes: effects on monokine secretion and antigen presentation in long-term renal transplant recipients

Cited by 36 publications

References 57 publications

IL-6 Promoter Polymorphism −174 Is Associated with New-Onset Diabetes after Transplantation

IL-6 Promoter Polymorphism −174 Is Associated with New-Onset Diabetes after Transplantation

Genetic polymorphisms influence mycophenolate mofetil–related adverse events in pediatric heart transplant patients

Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells

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