FK506 increases permeability in rat intestine by inhibiting mitochondrial function

doi:10.1016/0016-5085(95)90274-0

Gastroenterology

Volume 109, Issue 1, July 1995, Pages 107-114

https://doi.org/10.1016/0016-5085(95)90274-0 Get rights and content

Abstract

$Background & Aims:$ Under normal physiological conditions, the intestine presents an adenosine triphosphate (ATP)-dependent barrier to luminal contents. Disruption of this barrier function can occur when cellular metabolism is compromised. This study examined the effects of FK506 on intestinal permeability and enterocyte metabolic function in Lewis rats. $Methods:$ Rats were administered FK506 at a dose of 0.1, 0.5, or 2 mg/kg on alternate days for 6 weeks. Intestinal permeability was assessed by measuring urinary recovery of ^99mTc-diethylenetriamine pentacetate, and electrophysiological conductance measurements were performed in Ussing chambers. Metabolic function was assessed in isolated enterocytes by measuring total ATP and CO₂ release from [¹⁴C]pyruvate and [¹⁴C]glucose. $Results:$ Rats treated with FK506 showed a dose-dependent reduction in weight gain as well as increased in vivo and in vitro intestinal permeability. There was no difference in plasma creatinine or urinary output. Changes in permeability correlated with reduced ATP levels and CO₂ release because of diminished mitochondrial function. Lactate production, as a measure of glycolytic activity, was not altered by FK506. $Conclusions:$ In a dose-dependent manner, FK506 treatment in rats reduces weight gain, increases intestinal permeability, and decreases the ability of the small intestine to use glucose as an energy source.

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Après transplantation hépatique (TH), les enfants sous tacrolimus peuvent développer une allergie alimentaire IgE-médiée (AAIM).
Des enfants TH ont été adressés par les hépatologues à un allergologue pour suspicion d’AAIM. Une évaluation allergologique avant et après la TH a été réalisée. Les résultats des données ont été comparés.
La cohorte comporte 30 enfants d’âge moyen de 2,8 ans, tous traités par basiliximab et tacrolimus en post-TH. Pour 10 enfants, l’histoire clinique et/ou les tests cutanés et biologiques et/ou le test de provocation oral ont pu éliminer le diagnostic d’AAIM. Le diagnostic d’AAIM a été confirmé pour 20 enfants (67 %), parmi lesquels 70 % (n = 14) présentaient une atopie familiale. Treize enfants ont été switchés du tacrolimus à la ciclosporine dont 3 ont guéri et 6 ont une allergie persistante. Les enfants qui présentaient une sensibilisation en post-TH ont présenté des AAIM (n = 13, 76 %) dont 54 % (n = 7) ont guéri spontanément. Les enfants présentant une sensibilisation avant et après la TH ont présenté des AAIM dans 63 % des cas (n = 7). Seuls 29 % d’entre eux (n = 2) ont guéri. Pour 71 % (n = 5) d’entre eux, l‘allergie persiste. Les aliments les plus fréquemment incriminés étaient par ordre décroissant, les petits pois, le poisson, les lentilles, l’arachide et l’œuf.
Les enfants sensibilisés en pré- et post-TH ont majoritairement des AA persistantes alors que ceux qui ont une sensibilisation apparue en post-TH ont tendance à devenir tolérants spontanément. Un suivi au long court en collaboration entre hépatologue et allergologue est essentiel.
After liver transplantation (LT), children treated with tacrolimus may develop IgE-mediated food allergy (IMFA).
LT children were referred by hepatologists to an allergist for suspected IMFA. An allergological evaluation before and after LT was performed. The results of the data were compared.
The cohort included 30 children with a mean age of 2.8 years, all treated with basiliximab and tacrolimus combo in post-LT. For 10 children, the clinical history and/or skin and biological tests and/or oral challenge test could rule out the diagnosis of IMFA. The diagnosis of IMFA was confirmed in 20 children (67%), of whom 70% (n = 14) had familial atopy. Thirteen children were switched from tacrolimus to cyclosporine, of whom 3 were cured and 6 had persistent allergy. Children with post-LT sensitization presented IMFA (n = 13, 76%) of which 54% (n = 7) healed spontaneously. Children with pre- and post-LT sensitization had IMFA in 63% (n = 7). Only 29% of them (n = 2) recovered. For 71% (n = 5) of them, the allergy persisted. The most frequently incriminated food allergens were, in decreasing order, peas, fish, lentils, peanuts and eggs.
Children sensitized in pre- and post-LT settings have mostly persistent IMFA, whereas those with sensitization that appeared in post-LT tend to become tolerant spontaneously. Long-term follow-up in collaboration between hepatologist and allergist is essential.
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Citation Excerpt :
It was also determined that the use of tacrolimus as an immunosuppressant agent and tacrolimus blood levels were not associated with IgE-mediated food allergies, but peripheral eosinophil and serum total IgE levels were significantly higher in patients who developed IgE-mediated food allergies. Previous studies have reported that the incidence of IgE- and/or non-IgE-mediated food allergy after liver transplantation ranges from 8.5% to 37.6%.1,5,9 It was reported in these studies that patients mostly developed allergic reactions to eggs and milk.
In recent years, the number of studies regarding newly-diagnosed food allergies after liver transplantation has been increasing. In this study, we aimed to investigate the frequency, aetiology, risk factors, and severity of IgE-mediated food allergies after liver transplantation in children.
Paediatric patients who underwent liver transplantation at Inonu University Faculty of Medicine, Organ Transplantation Institute were included in the study.
Forty-nine paediatric patients were enrolled in the study; 26 (53.1%) were female, the median age at transplantation was five years, and median follow-up time after transplantation was 16 months. Six patients (12.2%) developed IgE-mediated food allergies after transplantation; four had urticaria and/or angio-oedema and two developed anaphylaxis after food intake. Patients with and without IgE-mediated food allergies were similar in terms of sex, age at transplantation, comorbid atopic disease, immunosuppressant therapy with tacrolimus, and blood tacrolimus level (p > 0.05 for each). Serum total IgE levels ≥100 IU/mL (p = 0.02) and peripheral eosinophilia (p = 0.026) were more common in the patients who developed IgE-mediated food allergies. In five of the six patients who developed IgE-mediated food allergies, reaction occurred within the first year after transplantation; the risk of developing a reaction was 2.7 times higher within the first year after transplantation than in subsequent years (95% CI, 1.546–4.914; p = 0.026). No Epstein–Barr virus or cytomegalovirus infections were detected in any of the patients who developed IgE-mediated food allergies after liver transplantation.
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The gastrointestinal (GI) mucosal immune response is characterized by an intricate balance between host defense and immunoregulation. A principal element of this normal response is acquisition of oral tolerance. Aberrations in oral tolerance induction can lead to food allergy, an increasingly prevalent disorder that causes significant medical and psychosocial stressors for patients and families. At present there is no definitive therapy for food allergy and the mainstays of treatment are allergen avoidance, nutritional support, and ready access to emergency medications. Significant progress toward an active therapy for food allergy has been made with the advent of novel therapies such as oral immunotherapy (OIT) and sublingual immunotherapy (SLIT), which modulate the GI mucosal immune response with the goal of promoting oral tolerance. In this review, we will examine the mechanisms of oral tolerance induction and its relation to food allergy and explore novel immunotherapeutic strategies for treatment and prevention of food allergy.
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^☆: Supported by the Medical Research Council of Canada and the Alberta Heritage Foundation.

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FK506 increases permeability in rat intestine by inhibiting mitochondrial function☆

Abstract

Immunol Today

Cell

Trends Biochem Sci

Diabetes Res Clin Pract

Biochem Pharmacol

J Nutr

J Nutr

Lancet

Lancet

Gastroenterology

Gastroenterology

Cell

FK506 (Tacrolimus), a novel immunosuppressant in organ transplantation: clinical, biomedical, and analytical aspects

Clin Chem

The immunosuppressant FK506 selectively inhibits the expression of early T cell activation genes

J Immunol

Evidence that the immunosuppressive effects of FK506 and cyclosporin are identical

Transplantation

Selective suppression of an early step in human B-cell activation by cyclosporin A

J Exp Med

The use of FK506 for small intestine allotransplantation: inhibition of acute rejection and prevention of fatal graft-versus-host disease

Transplantation

Effect of FK506 on bowel transplantation in rats

Transplant Proc

A randomized trial of primary liver transplantation under immunosuppression with FK506 vs cyclosporin

Transplant Proc

Clinical intestinal transplantation: three year experience

Intestinal transplantation in humans under FK506

Transplant Proc

Kidney transplantation under FK506

JAMA

Uncoupling of the molecular ‘fence’ and paracellular ‘gate’ functions in epithelial tight junctions

Nature

Gastrointestinal mucosal injury in experimental models of shock, trauma and sepsis

Crit Care Med