Local Immune Regulation of Mucosal Inflammation by Tacrolimus

Abstract

PurposeTacrolimus 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.ResultsIn 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.ConclusionsTacrolimus 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.

Efficacy of Rectal Tacrolimus for Induction Therapy in Patients With Resistant Ulcerative Proctitis

“…Again no major side effects were reported and the preparation was well tolerated 29 . The mechanism of action of tacrolimus would also appear to be local, rather than systemic, immune suppression as the administration of rectal tacrolimus inhibits the activation of immune cells within the intestinal mucosa and not systemically 30 . Thus as the studies, and observations, demonstrate encouraging results in a difficult-to-treat patient population, a randomised double-blinded placebocontrolled trial was warranted.…”

Tacrolimus Suppositories in Therapy-Resistant Ulcerative Proctitis

“…Moreover, a study by van Dieren et al [13] showed that tacrolimus is adsorbed and active in human rectal mucosa. The same authors demonstrated that interleukin-2 can be suppressed in murine colonic (lamina propria) T cells [14] via topical administration of tacrolimus, thus confirming a local mechanism of action. Nonetheless, even with rectal application, raised tacrolimus levels and acute renal injury have been reported [15].…”

Advances in Therapeutic Development for Radiation Cystitis

“…Therefore, an immunosuppression approach that seeks to block the signaling responsible for release of cytokines and inflammatory mediators could be a reasonable approach to halt the inflammation of RC. Furthermore, urothelium is the primary site of tissue damage in the pathophysiology of non‐infectious hemorrhagic cystitis . The pre‐clinical efficacy of this approach was tested in a rodent model of chemically induced HC using tacrolimus.…”

“…Late endothelial cell damage and perivascular fibrosis occur as a result of vascular occlusion and bladder ischemia. 8,9 Late radiation tissue injury can take several months to many years to develop, and is largely a function of the total radiation dose and fraction size. The pathological hallmark of late radiation tissue injury is obliterative endarteritis resulting in atrophy and fibrosis.…”

“…Vascular endothelial cell edema also occurs early after radiation exposure, with endothelial cell proliferation seen months later. Late endothelial cell damage and perivascular fibrosis occur as a result of vascular occlusion and bladder ischemia …”