Immunomodulatory effects of thalidomide in an experimental brain death liver donor model

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.

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“…We also observed that the levels of IL-1β were greater in the BD and TLD groups than in the CTR group and greater in the BD group than in the TLD group, reinforcing the hypothesis that BD generates an inflammatory process and the effective action of thalidomide on this marker. These results are in agreement with findings in the literature and in previous studies by our group with samples of liver and kidney tissue 23 – 25 .…”

“…According to immunohistochemical analysis, BD increased the activation of NF-ĸB through the generated inflammatory process, while thalidomide significantly reduced this activation to levels equal to those of the control group. These findings are in agreement with published studies and were also demonstrated in a previous study by our group, which confirmed the anti-inflammatory effects of thalidomide on liver tissue through a significant reduction in the number of M1 macrophages 23 . Considering the mechanism of action of thalidomide, we expected an increase in IL-10 expression and a significant decrease in IL-6 expression in the TLD group.…”

“…In the kidney, we showed that thalidomide acted via a reduction in TNF-α and IL-6 levels. All of these acts to significantly inhibit the immunological response and immunogenicity of the graft 23 , 24 .…”

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“…As a first consequence, it remains unclear if the immune system is impacted by brain death and whether a deceased recipient does not precisely mirror the response of a living body to a xenograft. Robust evidence indicates an increase in systemic immune response and local inflammatory reactions in brain‐dead subjects 7 . This altered state may manifest as either an enhanced or, conversely, a diverted immune response in the context of brain death.…”

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“…This process is mainly mediated through cytokines, which amplify graft immunogenicity. (3) Common side effects include constipation, hypothyroidism, ACTH stimulation, hypoglycemia, xerostomia, fever, mood changes,, peripheral neuropathy, somnolence, sedation, rash, and deep vein thrombosis (4) Though the use of Thalidomide was banned in most countries at that time, it proved to be a useful treatment for leprosy and later, multiple myeloma. (5) Thalidomide increases the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients receiving treatment for multiple myeloma.…”