Role of regulatory T cells in irinotecan-induced intestinal mucositis

Publication date: 30 March 2018
Source:European Journal of Pharmaceutical Sciences, Volume 115
Author(s): Camila Fernandes, Carlos Wagner Souza Wanderley, Camila Meireles Souza Silva, Heitor Amorim Muniz, Maraiza Alves Teixeira, Nathália Ribeiro Pinho Souza, André George Ferreira Cândido, Renata Brito Falcão, Marcellus Henrique Loiola Ponte Souza, Paulo Roberto Carvalho Almeida, Lilia Maria Carneiro Câmara, Roberto César Pereira Lima-Júnior
Intestinal mucositis (IM) is a common side effect of irinotecan-based chemotherapy. The involvement of inflammatory mediators, such as TNF-α, IL1-β, IL-18 and IL-33, has been demonstrated. However, the role of adaptive immune system cells, whose activation is partially regulated by these cytokines, is yet unknown. Thus, we investigated the role of regulatory T cells (Tregs) in irinotecan-induced IM. C57BL/6 mice were injected with saline or irinotecan (75mgkg⁻¹, i.p.), once a day for 4days, and euthanized at day 1, 3, 5 or 7 following the first dose of irinotecan. For Treg depletion, the mice were pretreated with a low single dose of cyclophosphamide (100mgkg⁻¹, i.p). Intestinal lamina propria lymphocytes were harvested and purified by Percoll gradient. Treg and Th17 cells were identified by flow cytometry. Blood leukocyte count was obtained and ileum samples were collected for histopathological analysis and myeloperoxidase assay. IM caused an accumulation of Tregs and Th17 cells over time. Treg depletion exacerbated intestinal damage, diarrhea, neutrophil infiltration and animal mortality, despite a reduction in Th17 cell number. The frequency of other Th cells increased and was positively correlated with neutrophil infiltration. Tregs showed a negative correlation with neutrophils and the frequency of non-regulatory Th cells. In conclusion, Tregs are important in the control of intestinal damage induced by irinotecan, and their depletion showed a deleterious effect on IM. Activation of these cells appears to be a compensatory mechanism for intestinal inflammation.

Graphical abstract

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