Why interleukin-10 supplementation does not work in Crohn’s disease patients

Abstract

Inflammatory bowel diseases (IBD) such as Crohn's disease (CD) or ulcerative colitis are chronic intestinal disorders, which are on the increase in "Westernised" countries. IBD can be caused by both genetic and environmental factors. Interleukin-10 (IL-10) is an immunoregulatory cytokine that has been identified as being involved in several diseases including IBD. Studies have shown that polymorphisms in the promoter region reduce serum levels of IL-10 and this reduction has been associated with some forms of IBD. Mouse models have shown promising results with IL-10 supplementation, as such IL-10 supplementation has been touted as being a possible alternative treatment for CD in humans. Clinical trials have shown that recombinant human IL-10 is safe and well tolerated up to a dose of 8 μg/kg. However, to date, the results of the clinical trials have been disappointing. Although CD activity was reduced as measured by the CD activity index, IL-10 supplementation did not result in significantly reduced remission rates or clinical improvements when compared to placebo. This review discusses why IL-10 supplementation is not effective in CD patients currently and what can be addressed to potentially make IL-10 supplementation a more viable treatment option in the future. Based on the current research we conclude that IL-10 supplementation is not a one size fits all treatment and if the correct population of patients is chosen then IL-10 supplementation could be of benefit.

Design Advances in Particulate Systems for Biomedical Applications

“…Vascular endothelial growth factor has been used to promote angiogenesis and for ischemia treatment; [ 15,16 ] bone morphogenic proteins for bone regeneration; [ 17,18 ] epidermal growth factor for treatment of skin lesions resultant from burns or chronic ulcers; [ 19 ] glial cell-line neurotrophic factor for spinal cord injuries or peripheral nerves regeneration; [ 20 ] and IL-10 for treatment of infl ammatory bowel disease and to suppress infl ammation. [21][22][23] The main limitation of the delivery systems relies on the over simplifi cation of the release design because typically only one bioactive agent is delivered with the risk of providing supraphysiological doses or even being not enough for the complete and fast desired effect. Currently, it is known that in the natural milieu multiple signals act in a spatiotemporal controlled manner.…”

Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells

“…Unfortunately, well-tolerated doses of recombinant IL-10 therapy did not show efficacy in clinical trials for Crohn's disease (7). Potential explanations of this lack of efficacy include insufficient delivery recombinant IL-10 to the gut mucosa by systemic administration and/or the need to combine IL-10 supplementation with neutralization of inflammatory cytokines (8). Of note, disease activity is reduced in Crohn's disease patients following oral administration of Lactococcus lactis engineered to express IL-10 (9), which suggests that specifically increasing IL-10 levels in the gut microenvironment can be therapeutically beneficial in the absence of toxicities (e.g., headache, anemia, and thrombocytopenia) that limit systemic treatment.…”

IL-10: A Paradigm for Counterregulatory Cytokines

“…In contrast, despite favorable results in mouse models and encouraging phase I clinical trials, human rIL-10 failed to improve inflammatory bowel disease or rheumatoid arthritis (22)(23)(24)(25). Apart from the natural complications that arise when transitioning from preclinical mouse studies to human clinical trials, investigators have speculated that these negative results may be due to variation in host genetics, and multiple endophenotypes in complex diseases such as Crohn's disease (26). It is also possible that the tested doses of IL-10 supplementation were not sufficient to suppress the excessive inflammatory environment, particularly in severe disease states (26).…”

“…Apart from the natural complications that arise when transitioning from preclinical mouse studies to human clinical trials, investigators have speculated that these negative results may be due to variation in host genetics, and multiple endophenotypes in complex diseases such as Crohn's disease (26). It is also possible that the tested doses of IL-10 supplementation were not sufficient to suppress the excessive inflammatory environment, particularly in severe disease states (26). There are ongoing studies modifying IL-10 to increase its potency.…”