Glucocorticoid receptors are down‐regulated in inflamed colonic mucosa but not in peripheral blood mononuclear cells from patients with inflammatory bowel disease

Rogler,; Meinel,; Lingauer,; Michl,; Zietz,; Lang, T. J.; Andus,; Schölmerich,; Palitzsch,

doi:10.1046/j.1365-2362.1999.00460.x

Cited by 47 publications

(27 citation statements)

References 29 publications

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“…The reason for the efficacy of relatively low dose intra-arterial corticosteroid infusion in acute gastrointestinal GVHD, refractory to high dose systemic steroid therapy, is currently unknown. Several studies suggest decreased number and affinity of steroid receptors in inflammatory mucosa of gastrointestinal tract [10], a process which may contribute to pathogenesis of steroid refractory acute GVHD. We believe intra-arterial infusion delivers high concentration of corticosteroids directly to the gastrointestinal mucosa, overcoming the refractoriness caused by decreased steroid receptor affinity and number.…”

Section: Discussionmentioning

confidence: 99%

Role of intra‐arterial steroid administration in the management of steroid‐refractory acute gastrointestinal graft‐versus‐host disease

et al. 2006

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We report here a case of severe steroid-refractory gastrointestinal graft-versus-host disease treated with intra-arterial administration of corticosteroids. A 53-year-old female with nonHodgkin's lymphoma received peripheral blood hematopoietic stem cell transplant from her HLA-matched sibling. She developed grade II skin and grade IV gastrointestinal graft-versus-host disease with no hepatic involvement. Therapy with oral prednisone easily controlled her skin rash but she had profuse diarrhea that did not respond to high dose intravenous corticosteroids and denileukin diftitox. Infusion of methyl-prednisolone into superior and inferior mesenteric arteries produced dramatic improvement of diarrhea, with complete resolution of gastrointestinal graft-versus-host disease. Am. J. Hematol. 81:959-962, 2006.

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Section: Discussionmentioning

confidence: 99%

Role of intra‐arterial steroid administration in the management of steroid‐refractory acute gastrointestinal graft‐versus‐host disease

et al. 2006

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“…In CD, a macrophage population is found with high expression of costimulatory molecules, which is presumably responsible for the perpetuated immune response [12]. This special population of CD iMACs also reveals increased activation of nuclear factor (NF)-κB in the inflamed mucosa [13], which might, at least in part, be due to decreased levels of human glucocorticoid receptor in mucosal CD iMACs and lead to decreased protection against NF-κB action [14]. Further, NADPH oxidase mRNA is downregulated or absent in macrophages from normal mucosa, which correlates with a lack of oxidative burst activity.…”

Section: - Loss Of Tolerance?mentioning

confidence: 99%

Crohn's Disease: Loss of Tolerance or a Disorder of Autophagy?

Spalinger

Rogler

Scharl

2014

Dig Dis

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Crohn's disease (CD) is characterized by a breakdown of the intestinal epithelial barrier function leading to an uncontrolled immune response to bacterial antigens. Available data demonstrate that appropriate response and early host defense against invading bacteria are crucial to maintain tolerance towards commensal bacteria. When the mechanisms of early removal of invading bacteria are disturbed, a loss of tolerance and a full-blown adaptive immune reaction, which is mounted against the usually harmless commensal flora, are induced. Dysfunction of autophagy caused by genetic variations within CD susceptibility genes, such as ATG16L1 and IRGM, results in defective handling of intracellular and invading bacteria and causes prolonged survival and defective clearance of those microbes. Dysfunction of ATG16L1 and IRGM has also been shown to cause aberrant Paneth cell function and uncontrolled secretion of proinflammatory cytokines finally resulting in increased susceptibility to bacterial infection and the onset of colitis. Interestingly, autophagy can also be regulated by other CD susceptibility genes, such as NOD2 (nucleotide oligomerization domain 2) or PTPN2 (protein tyrosine phosphatase nonreceptor type 2) and the presence of the CD-associated variations within these genes results in similar effects. Taken together, more and more evidence suggests a close functional correlation between loss of tolerance and defective autophagy in CD patients. Therefore, most likely, the onset of CD is triggered by both a loss of tolerance as well as a dysfunction of autophagy, which finally results in the onset of chronic intestinal inflammation.

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“…Several studies suggest that the number of steroid receptors and the affinity of the receptors to steroids are both decreased in the inflammatory mucosa of IBD such as UC. 9,10 Direct intraarterial steroid infusion may expose topical inflammatory mucosa to high concentrations of steroids and thus overcome the ineffectiveness of steroids caused by the decrease in the number of receptors and their affinity.…”

Section: Discussionmentioning

confidence: 99%

Intra-arterial steroid-injection therapy for steroid-refractory acute graft-versus-host disease with the evaluation of angiography

Nakai

Tajima

Tanigawa

et al. 2004

Bone Marrow Transplant

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Summary:We treated three patients with steroid-refractory acute graft-versus-host disease (aGVHD) with intra-arterial steroid-injection therapy (IAST). Two patients with gut aGVHD received IAST into both superior and inferior mesenteric arteries, while one patient with liver aGVHD received IAST into the proper hepatic artery. The volume of stools and the bilirubin level improved soon after IAST. Angiography of the superior and inferior mesenteric arteries was performed in the two patients with steroidrefractory gut aGVHD, and identical abnormal findings were obtained. IAST might be an earlier option for steroid-refractory aGVHD. Patients who do not respond to steroid therapy for acute graft-versus-host disease (aGVHD) are regarded as having steroid-refractory aGVHD, and their mortality is high. 1 A variety of salvage regimens, including mega-dose steroid therapy, anti-thymocyte globulin (ATG), 2 infliximab, 3 and daclizumab, 4 have been tried for steroid-refractory aGVHD. However, these agents have proven to be insufficiently effective, and there has been little improvement in the treatment related mortality (TRM). Furthermore, these agents cause profound immunosuppression, often resulting in fatal infections. Therefore, it remains critical to establish more effective treatment for steroidrefractory aGVHD without unwanted sequelae.Recently, Sato et al. 5 and Shapira et al. 6 reported that direct infusion of corticosteroid into arteries dominating the regions of the gut or liver was effective in treating steroid-refractory gut and liver aGVHD. Indeed, complete response was obtained in nine of 11 patients with gut aGVHD and three of seven patients with liver aGVHD. Furthermore, this procedure was shown to be safe. Based on the results of these studies, we applied the same approach to three patients with steroid-refractory aGVHD in this study. Case 1A 46-year-old man with adult T-cell leukemia (ATL) received peripheral blood stem cell transplantation (PBSCT) from his HLA-matched sister. The patient received donor lymphocyte infusion because of incomplete donor-type chimerism. The patient developed grade II aGVHD in the skin (stage III) and gut (stage I) on day 55 post-transplant. Methylprednisolone (mPSL) (1 mg/kg i.v. every 12 h), high-dose mPSL (20 mg/kg i.v. once daily for 3 days) and infliximab (5 mg/kg i.v. once monthly for 2 months) were all ineffective.We next performed intra-arterial steroid-injection therapy (IAST) according to the method described below. Briefly, selective angiography of both superior and inferior mesenteric arteries was performed through the femoral artery by Seldinger technique. In all, 30 ml of nonionic contrast media (Iopamiron 300, Nihon Schering, Osaka, Japan) was injected into the superior mesenteric artery at a rate of 6 ml/s, and 15 ml into the inferior mesenteric artery at the rate of 3 ml/s. Following the angiography, 10 ml of 1 mg/kg mPSL, which was diluted by adding physiological saline, was slowly infused for 1 min by hand into both the superior and inferior mesenteric arter...

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Glucocorticoid receptors are down‐regulated in inflamed colonic mucosa but not in peripheral blood mononuclear cells from patients with inflammatory bowel disease

Cited by 47 publications

References 29 publications

Role of intra‐arterial steroid administration in the management of steroid‐refractory acute gastrointestinal graft‐versus‐host disease

Role of intra‐arterial steroid administration in the management of steroid‐refractory acute gastrointestinal graft‐versus‐host disease

Crohn's Disease: Loss of Tolerance or a Disorder of Autophagy?

Intra-arterial steroid-injection therapy for steroid-refractory acute graft-versus-host disease with the evaluation of angiography

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