Local immune regulation of mucosal inflammation by tacrolimus
Purpose: Tacrolimus is a potent immunomodulator that is effective in the treatment of inflammatory bowel disease (IBD). However, potential toxicity and systemic effects with oral intake limit its use. Local tacrolimus treatment is effective in a subgroup of proctitis patients. This study aimed to evaluate whether colonic mucosal immune cells are susceptible to locally applied tacrolimus in vitro. Our in vivo studies aimed at evaluating whether local tacrolimus treatment in mice would bring about local immune suppression and to compare colonic and systemic tacrolimus levels after locally and systemically applied tacrolimus. Results: In vitro tacrolimus inhibited the activation of multiple cell types present in colonic tissue; lamina propria T cells, NKT cells, and both classical- and non- classical antigen presenting cells. However, the cytokine production of epithelial cells was not inhibited by tacrolimus at these concentrations. After rectal administration in mice, tacrolimus blood levels were comparable to those obtained by oral intake. However, rectally treated mice exhibited a 14-fold higher concentration of tacrolimus within their colonic tissue than orally treated mice. Moreover, rectally applied tacrolimus resulted in a local but not a systemic immune suppression in mice. Conclusions: Tacrolimus inhibits activation of several pivotal immune cells of the intestinal mucosa. Murine studies indicate that colonic application of tacrolimus induces local rather than systemic immune suppression.
|Keywords||Colonic mucosa, Inflammatory bowel disease (IBD), Local immune suppression, Tacrolimus|
|Persistent URL||dx.doi.org/10.1007/s10620-009-1047-2, hdl.handle.net/1765/27707|
van Dieren, J.M., Lambers, M.E.H., Kuipers, E.J., Samsom, J.N., van der Woude, C.J., & Nieuwenhuis, E.E.S.. (2010). Local immune regulation of mucosal inflammation by tacrolimus. Digestive Diseases and Sciences, 55(9), 2514–2519. doi:10.1007/s10620-009-1047-2