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P657. Effects of isotretinoin treatment on epigenetic programming in T cells

E. Becker, C. Stanzel, K. Atrott, G. Rogler, I. Frey-Wagner, University Hospital Zurich, Gastroenterology & Hepatology, Zurich, Switzerland

Background

Retinoids are essential nutrients involved in the maturation of the immune system. The majority of in vitro and in vivo studies provided evidence that retinoid treatment exhibits anti-inflammatory properties and is effective acne therapy. However, there is a controversial discussion about a causal relationship between isotretinoin treatment and the onset of inflammatory bowel disease (IBD). Some patients have claimed that they developed acute intestinal inflammation during isotretinoin treatment or had an onset of IBD weeks or even years after cessation of the medication. We have previously shown that isotretinoin treatment has no adverse effects in two mouse models of inflammatory bowel disease [1]. Here we investigated the influence of isotretinoin treatment on genetic imprinting in two T cells subsets as a potential mediator of long-term effects of isotretinoin treatment on the immune system.

Methods

Balb/c mice were treated with isotretinoin (30 mg/kg bodyweight) or vehicle orally for 2 weeks and kept for further 4 weeks to study potential direct and long-term effects. Naive T cells and regulatory T cells were isolated directly after the treatment period and at the end of the study by magnetic cell sorting. After isolation of genomic DNA, microRNA and mRNA, samples were sequenced with the Illumina® technique to study changes in methylation patterns, microRNA and mRNA expression. For predicting target genes of determined microRNAs the software Target Scan and Traget Scan Custom were used. For identification of pathways significantly affected by isotretinoin treatment the software Meta Core® was applied.

Results

Analysis of epigenetic modifications in naive and regulatory T cells revealed potential long-term effects in both T cells subsets. In regulatory T cells mainly the methylation pattern was altered in T cells isolated four weeks after cessation of treatment. In naive T cells on the other hand predominantly microRNA expression was altered in T cells isolated after four weeks without treatment. Pathway analysis by Meta Core® revealed that pathways of immune responses, concerning antigen presentation and T helper cell differentiation were affected. Further functional analysis of affected pathways is currently under investigation.

Conclusion

Preliminary results identified changes in methylation pattern and microRNA expression in naive and regulatory T cells which might mediate potential long-term effects after isotretinoin treatment, yet differences between the different T cell subsets were far more pronounced than differences induced by isotretinoin treatment.

1. Frey-Wagner I. (2013), Effects of retinoids in mouse models of colitis: benefit or danger to the gastrointestinal tract?