Efeito da modulação imune por Abatacept em modelo de carcinogênese oral induzida por 4-Nitroquinolina-N-Óxido

Abstract

Abatacept (ABA) is a drug that consists of a soluble protein resulting from the fusion of the constant fragment of human IgG1 and a CTLA-4 molecule present in TCD4+ lymphocytes negatively modula-ting the T helper response. However, this modulation can impair the development of immunity aga-inst tumors, since it is not certain at what stage of the immune response the plasticity of a Th1 or Th2 response is capable of interfering in carcinogenesis. The objective of this work was to evaluate the effect of immune modulation by Abatacept in an oral carcinogenesis model induced by 4-nitroquinoline-n-oxide (4NQO). The study included 60 Swiss mice divided into six groups: a negative control group (GCN); an Abatacept control group (GCABA); a positive control group (GCP) and three test groups, group 4NQO co-treated with Abatacept in the last 6 weeks, group 4NQO co-treated with Abatacept in the last 10 weeks and group 4NQO co-treated with Abatacept for 18 weeks. The animals were euthanized after 18 weeks and the tongues were collected for processing and making histological slides to analyze the presence and / or severity of cellular and architectural changes in the lesions (dysplastic and neoplastic). Blood and organs were collected for toxicity analysis. In addition, the micronucleus analysis and the variation in body mass was verified. For all analyzes, the statistical software GraphPad Prism 5.0® was used, with a significance level of p <0.05. Exposure to 4NQO promoted high-grade dysplasias and in animals submitted to ABA-associated carcinogen for longer periods revealed the development of microinvasive carcinoma (p <0.001). Haematological analysis revealed significant leukocytosis in the groups co-treated with ABA for 10 and 18 weeks (p <0.001). In reference to systemic toxicity, the non-exposure to the carcinogen led to a significant gain in body mass (p <0.001) in relation to the others. Microscopic changes in the esophagus [groups 4NQO and co-treatment with ABA (p <0.001)] and in the intestine [group 4NQO co-treated with ABA (p = 0.009)] were observed. Focal necrosis in the liver of animals in the 4NQO group co-treated with ABA was significantly less when compared to GCP (p <0.001). The increase in the number of mega-karyocytes was greater in the co-treatment (4NQO / ABA) for ten weeks (p <0.001). Renal changes, on the other hand, increased in the 4NQO group (p <0.001). Regarding genotoxicity, it was observed that the associated 4NQO and ABA caused an increase in Micronucleated Polychromatic Erythrocytes (p <0.001). It is concluded that the oral carcinogenesis model, induced by 4NQO, is ca-pable of producing dysplasias and carcinomas, in addition to causing mild systemic toxicity in the esophagus, visceral organs and genetic damage. Co-treatment with CTLA-4-Ig accelerated the process of carcinogenesis in a time-dependent manner, in addition to potentiating hematological dysregulation and structural chromosomal damage induced by 4NQO.