The Optimal Dose of Tacrolimus in Combination Therapy with an Anti-TNFα Antibody in a Mouse Colitis Model

Abstract

An attempt to use combination therapy with anti-tumor necrosis factor α (TNFα) antibodies and tacrolimus (TAC) has been tried to induce remission in ulcerative colitis (UC). However, the optimal dose of TAC in combination therapy with anti-TNFα antibodies (TAC anti-TNFα therapy) remains unclear. We examined the efficacy of various doses of TAC anti-TNFα therapy in a mouse colitis model. Dextran sulfate sodium induced colitis model mice were divided into an anti-TNFα antibody monotherapy group and the groups that received various doses of TAC anti-TNFα therapy. The nuclear factor expression of activated T-cells, cytoplasmic 1 (NFATc1) in the nuclei and the mRNA expression of inflammatory cytokines were assessed by immunohistochemistry and RT-PCR, respectively. The serum anti-TNFα antibody concentration was measured with an enzyme-linked immunosorbent assay. The colon length and histological severity were significantly improved in the groups that received any dose of TAC anti-TNFα therapy. The nuclear expression of NFATc1 was inversely proportional to the administered doses of TAC. The expression levels of inflammatory cytokines tended to decrease in proportion to the dose of TAC. The serum concentration of anti-TNFα antibodies in the high-dose TAC anti-TNFα therapy was significantly higher than those in the other groups. Low-dose TAC exerted its immunosuppressive effect on T-cells, and additionally, high-dose TAC maintained the serum anti-TNFα antibody concentration. When administered in combination with anti-TNFα antibodies, the dose of TAC should be adjusted according to the disease severity.

TNF-α Mediated the Disruption of Hepatic Tight Junction Expression in Blood–Biliary Barrier of Colitis <i>via</i> Downregulating PI3K/AKT Signaling Pathway

“…in the inflamed colon. 32) Accumulated evidences showed that the serum TNF-α level as well as colonic TNF-α concentration were all significantly elevated in acute colitis, [33][34][35][36] and the elevated TNF-α is positively correlated with the severity of UC, 36) indicating the vital role of TNF-α in the pathogenesis of UC. 37) Results from our study showed that the serum TNF-α level was markedly increased in colitis rats, and the increased TNF-α level was positively correlated with elevated TBA and TBil, indicating that the increased TNF-α may contribute to the intrahepatic cholestasis of acute colitis.…”