Recipient Lymphocyte Sensitivity to Methylprednisolone Affects Cadaver Kidney Graft Survival

Langhoff, Erik; Jakobsen, B. K.; Ryder, Lars P.; Ladefoged, J; Platz, P.; Svejgaard, A.; Thaysen, Jørn Hess

doi:10.1016/s0140-6736(86)91220-1

Cited by 81 publications

(42 citation statements)

References 5 publications

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“…Similar correlations between in vitro T-lymphocyte sensitivity to glucocorticoid inhibition and the clinical response to glucocorticoid therapy have been reported in other inflammatory diseases such as asthma (Corrigan 1996), rheumatoid arthritis (Kirkham et al 1991) and renal allograft rejection (Langhoff et al 1986). These observations underscore the pivotal role of activated Tlymphocytes in the pathogenesis of these diseases and also emphasise that, in a subset of IBD patients, glucocorticoid therapy is not viable because systemic concentrations achieved even at high dosage are insufficient to inhibit T cell function significantly and, by inference, disease progression.…”

Section: Molecular Mechanisms Of Glucocorticoid Resistancesupporting

confidence: 67%

Glucocorticoid resistance in inflammatory bowel disease

Rj¹,

Kelleher²

2003

Journal of Endocrinology

218

122

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Glucocorticoids are potent inhibitors of T cell activation and proinflammatory cytokines and are highly effective treatment for active inflammatory bowel disease (IBD). However, failure to respond, acutely or chronically, to glucocorticoid therapy is a common indication for surgery in IBD, with as many as 50% of patients with Crohn's disease (CD) and approximately 20% of patients with ulcerative colitis (UC) requiring surgery in their lifetime as a result of poor response to glucocorticoids. Studies report that approximately one-third of patients with CD are steroid dependent and one-fifth are steroid resistant while approximately one-quarter of patients with UC are steroid dependent and one-sixth are steroid resistant. While the molecular basis of glucocorticoid resistance has been widely assessed in other inflammatory conditions, the pathophysiology of the glucocorticoid resistance in IBD is poorly understood. Research in IBD suggests that the phenomenon of glucocorticoid resistance is compartmentalised to T-lymphocytes and possibly other target inflammatory cells. This review focuses on three key molecular mechanisms of glucocorticoid resistance in IBD: (i) decreased cytoplasmic glucocorticoid concentration secondary to increased P-glycoprotein-mediated efflux of glucocorticoid from target cells due to overexpression of the multidrug resistance gene (MDR1); (ii) impaired glucocorticoid signaling because of dysfunction at the level of the glucocorticoid receptor; and (iii) constitutive epithelial activation of proinflammatory mediators, including nuclear factor kappa B, resulting in inhibition of glucocorticoid receptor transcriptional activity. In addition, the impact of disease heterogeneity on glucocorticoid responsiveness and recent advances in IBD pharmacogenetics are discussed.

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Section: Molecular Mechanisms Of Glucocorticoid Resistancesupporting

confidence: 67%

Glucocorticoid resistance in inflammatory bowel disease

Rj¹,

Kelleher²

2003

Journal of Endocrinology

218

122

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show abstract

“…We have previously provided evidence that failure to respond to steroids in UC correlates with failure of PHA-stimulated peripheral blood lymphocytes to be suppressed by dexamethasone in an in vitro assay (4), and others have made similar observations in other diseases (1,(5)(6)(7). In vitro steroid resistance measured in this way varies widely across the normal population with 20 -30% of individuals showing marked resistance.…”

mentioning

confidence: 58%

The Effects of Cytokines on Suppression of Lymphocyte Proliferation by Dexamethasone

Creed

Lee

Newcomb

et al. 2009

The Journal of Immunology

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Treatment failure occurs in up to 30% of patients treated with steroids for inflammatory diseases. The aim of this study was to explore the potential role of 21 cytokines in steroid-resistant inflammatory disease and to develop methods to restore steroid sensitivity through cytokine manipulation. The dexamethasone inhibition of lymphocyte proliferation assay correlates with the outcome of steroid therapy in ulcerative colitis (UC) and other inflammatory diseases. Using this assay, PBMC production of 21 cytokines, assayed by cytokine bead array, was correlated with percentage of suppression of proliferation by 10−6 M dexamethasone (Imax) in 26 healthy volunteers. Effects of the addition of exogenous cytokines to induce steroid resistance in PBMCs from healthy volunteers and cytokine blockade to improve steroid sensitivity in PBMCs from patients with steroid-resistant UC were then explored. Production of IL-1α, IL-10, IL-17, IFN-γ, G-CSF, GM-CSF, TNF-α, and IFN-inducible protein 10 (IP-10) correlated significantly with in vitro steroid sensitivity; however, only IL-2 and TNF-α reduced steroid sensitivity when added exogenously. Addition of IL-10 enhanced steroid suppression. Immunoneutralization or receptor blockade of IL-2, but not TNF-α, IFN-γ, IL-4, IL-17, or IP-10 increased steroid sensitivity in cells from steroid-resistant UC patients. Neutralization of IL-10 reduced steroid sensitivity. Of the large panel of cytokines studied, IL-2 appears to have the greatest antagonistic effect on the antiproliferative effect of steroids. These data suggest that IL-2 inhibition in vivo may improve the response to steroids in steroid-resistant individuals.

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“…7,[14][15][16] Lymphocyte proliferative responses to liver-derived antigens are a feature of human alcoholic liver disease, 17 and steroid therapy is effective in a proportion of patients with AAH.…”

Section: Discussionmentioning

confidence: 99%

Theophylline improves steroid sensitivity in acute alcoholic hepatitis

et al. 2010

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Corticosteroid therapy has shown some benefit in severe acute alcoholic hepatitis (AAH); however, this is limited by uncertainty in patient selection and variable clinical response. Theophylline has been shown to ameliorate impaired steroid sensitivity in chronic obstructive pulmonary disease by facilitating corticosteroid-induced silencing of proinflammatory genes. We aimed to explore the mechanistic basis of the variable response to corticosteroid therapy seen in patients with AAH and to address the extent to which theophylline can improve this response. The ability of dexamethasone to inhibit phytohemagglutinin-induced lymphocyte proliferation was assessed by 3 H-thymidine incorporation in 12 severe AAH patients and age-matched and sex-matched controls. Steroid sensitivity was measured in terms of I max , the maximum inhibition of proliferation. The effect of 10 25 M theophylline and, in survivors, change in I max during recovery were observed. Lymphocyte steroid sensitivity was found to be significantly reduced in AAH compared with controls (I max 67[64.5]% versus 95[62.3]%, P 5 0.0002) and correlated with clinical markers of steroid responsiveness. In survivors, I max increased in recovery. Theophylline 10 25 M significantly increased lymphocyte steroid sensitivity (I max 86[66.6]% versus 67[65.0]%, P 5 0.027). Conclusion: Acute alcoholic hepatitis is associated with significant lymphocyte steroid insensitivity, which improves in recovery and can be ameliorated ex vivo by theophylline. This offers potential to rationalize corticosteroid prescribing in AAH and, furthermore, justifies investigation of this novel role for an existing pharmacological agent in this common and frequently fatal condition. (HEPATOLOGY 2010;52:126-131)

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Recipient Lymphocyte Sensitivity to Methylprednisolone Affects Cadaver Kidney Graft Survival

Cited by 81 publications

References 5 publications

Glucocorticoid resistance in inflammatory bowel disease

Glucocorticoid resistance in inflammatory bowel disease

The Effects of Cytokines on Suppression of Lymphocyte Proliferation by Dexamethasone

Theophylline improves steroid sensitivity in acute alcoholic hepatitis

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