Therapeutic effect of a new immunosuppressive agent, everolimus, on interleukin-10 gene-deficient mice with colitis

Abstract

SummaryA limited number of therapeutic strategies are currently available for patients with inflammatory bowel disease (IBD). In particular, the maintenance therapy after remission in Crohn's disease (CD) is not satisfactory and new approaches are needed. Interleukin-10 gene-deficient (IL-10 -/-) mice, a wellcharacterized experimental model of CD, develop severe chronic colitis due to an aberrant Th1 immune response. Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), a new immunosuppressive reagent, has been used successfully in animal models for heart, liver, lung and kidney transplantation. In the present study, we examined the efficacy of everolimus in the treatment of chronic colitis in an IL-10 -/-mouse model. Everolimus was administered orally for a period of 4 weeks to IL-10 -/-mice with clinical signs of colitis. The gross and histological appearances of the colon and the numbers, phenotype and cytokine production of lymphocytes were compared with these characteristics in a control group. The 4-week administration of everolimus resulted in a significant decrease in the severity of colitis, together with a significant reduction in the number of CD4 + T cells in the colonic lamina propria as well as IFN-g production in colonic lymphocytes. Everolimus treatment of established colitis in IL-10 -/-mice ameliorated the colitis, probably as a result of decreasing the number of CD4 + T cells in the colonic mucosa and an associated reduction in IFN-g production.

A novel mTOR inhibitor is efficacious in a murine model of colitis

“…A growing body of evidence supports the notion that kinase inhibitors, which possess antiproliferative activities, are potential therapeutics for UC (15,34,39). In our search for anticancer therapeutics, we have found that P2281 inhibits mTOR activity in colon cancer cells and suppresses DSS-induced colitis.…”

“…Interestingly, a recent study showed that rapamycin, a mTOR inhibitor, blunts leukocyte adhesion and extravasation in the gut mucosa, leading to suppression of experimental chronic colitis (15). In a complementary study, treatment with everolimus (another mTOR inhibitor) reduced the number of T cells in lamina propria and blocked lymphocytic IFN-␥ release, thereby ameliorating established murine colitis (34). These findings suggest that mTOR inhibitors may be useful for treatment of UC.…”

“…The observations that rapamycin and everolimus (both mTOR inhibitors) are efficacious in animal models of colitis (15,34), combined with the findings that blocking IFN-␥ production elicits a therapeutic effect in experimental colitis (16), led us to hypothesize that P2281 (which inhibits mTOR activation as well as IFN-␥ Fig. 6.…”

“…Indeed, in various experimental models of acute and/or chronic colitis, 1) suppression of T cell function (e.g., by cyclosporin A) (37), 2) blockade of signal transduction pathways (e.g., mTOR pathway, NF-B pathway) (15,34,52), 3) inhibition of proinflammatory cytokine expression (3,46), and 4) attenuation of leukocyte-endothelial interactions (1) separately provide a beneficial effect.…”

ATG16L1: A multifunctional susceptibility factor in Crohn disease

“…115 A similar drug to sirolimus, everolimus, is also an inhibitor of MTOR and has previously been demonstrated to produce promising results in murine colitis. 116 However, everolimus treatment failed to produce a significant difference in a randomized, controlled clinical trial for Crohn disease that was prematurely terminated after only 96 patients were evaluated (36 of whom received everolimus), likely due to the influence of disease-related factors on pharmacokinetics and pharmacodynamics or on the dosage regimens applied. 117 Nevertheless, the successful use of sirolimus in a so far underpowered clinical setting suggests that the efficacy of MTOR-based pharmaceutical strategies should be evaluated in randomized clinical trials among patients with Crohn disease refractory to conventional treatment, i.e., immunomodulators and biologics.…”