Abatacept agrava a mucosite intestinal induzida por irinotecano em camundongos

Abstract

Intestinal mucositis (MI) is a very recurrent side effect in patients undergoing treatment with irinotecan, a drug used in first-line treatment regimens for the treatment of colorectal cancer. In the last decades many aspects related to the pathogenesis of MI have been elucidated, however, little is known about the lymphocyte cell profile and their role in its development. The objective of this work is, therefore, to investigate the role of lymphocytes in the pathogenesis of MI through immunosuppression with abatacept. Male swab mice, 20-25g, were divided into groups (n = 8) and treated for 4 days with saline (5 mL / kg, ip), irinotecan (75 or 45 mg / kg, ip), abatacept / Kg, ip 1h before irinotecan on the first day) or only abatacept (10 mg / kg, ip on the first day). The animals were evaluated daily for weight, diarrhea score and survival. Euthanasia occurred on day 5 on the first protocol and on day 7 on the second. Blood was collected for the total leukocyte count and after euthanasia, ileum samples were extracted for myeloperoxidase assay, histopathological analysis, and KC dosing in the ileum of the animals. Statistical analysis was used ANOVA / Bonferroni, Kruskal-Wallis / Dunn's or Log-rank (Mantel-Cox) tests, with p <0.05 accepted as significant. Results Abatacept reduced (p <0.05) the survival of the animals in the first protocol, making day 5 the ideal for euthanasia. Irinotecan caused significant weight loss (p <0.05) in relation to the saline group, however abatacept did not aggravate the loss. Pre-treatment with abatacept anticipated the appearance of moderate-grade diarrhea on the fourth day. Abatacept induced a reduction in villi / crypt ratio, villi height and crypt depth significantly in relation to the irinotecan alone (p <0.05) group, in addition to increasing the neutrophil infiltrate in the animals' ileum. Irinotecan increased the level of KC in the ileus of the animals in relation to the saline group, however abatacept did not significantly modify the level of this cytokine. In the second protocol, the subdose of irinotecan did not cause intense intestinal damage, but the treatment with abatacept proved its deleterious effect inducing the onset of diarrhea on the sixth day (p <0.05) in relation to the saline group, besides aggravating the Intestinal architecture. Abatacept increased neutrophil infiltration in the gut of irinotecan treated animals compared to the group injected with this drug alone (p <0.05), which was associated with elevated KC levels in the intestines of these animals. Irinotecan promoted myelotoxicity at all doses, but abatacept did not aggravate this toxicity. Abatacept alone caused no change in any of the evaluated parameters. Conclusion Abatacept aggravated intestinal mucositis induced by irinotecan in mice.