Immunomodulatory effects of thalidomide in an experimental brain death liver donor model
Alexandre Chagas Santana, Wellington Andraus, Filipe Miranda Oliveira Silva, Humberto Dellê, Rafael Pepineli, Edvaldo Leal de Moraes, Cristóforo Scavone, Larissa de Sá Lima, Sabrina Degaspari, Sérgio Brasil, Davi Jorge Fontoura Solla, Liliane Moreira Ruiz, Karina Andrighetti de Oliveira Braga, Natália Aparecida Nepomuceno, Paulo Manuel Pêgo-Fernandes, Stefan G. Tullius, Eberval Gadelha Figueiredo
Abstract
Brain death is characterized by a generalized inflammatory response that results in multiorgan damage. This process is mainly mediated through cytokines, which amplify graft immunogenicity. We investigated the immunological response in a brain death liver donor model and analysed the effects of thalidomide, a drug with powerful immunomodulatory properties. Brain death was induced in male Lewis rats. We studied three groups: Control (sham-operated rats in which trepanation was performed without inserting the balloon catheter), BD (rats subjected to brain death by increasing intracranial pressure) and BD + Thalid (BD rats receiving thalidomide after brain death). After 6 h, serum levels of AST, ALT, LDH, and ALP as well as systemic and hepatic levels of TNF-α, IL1-β, IL-6, and IL-10 were analysed. We also determined the mRNA expression of MHC Class I and Class II, NF-κB, and macrophage infiltration. NF-κB was also examined by electrophoretic mobility shift assay. Thalidomide treatment significantly reduced serum levels of hepatic enzymes and TNF-α, IL-1-β, and IL-6. These cytokines were evaluated at either the mRNA expression or protein level in liver tissue. In addition, thalidomide administration resulted in a significant reduction in macrophages, MHC Class I and Class II, and NF-κB activation. This study reveals that thalidomide significantly inhibited the immunologic response and graft immunogenicity, possibly through suppression of NF-κB activation.