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IL-10 therapy in Crohn's disease: at the crossroads
  1. H Herfarth,
  2. J Schölmerich
  1. Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
  1. Correspondence to:
    Dr H Herfarth, Klinik und Poliklinik für Innere Medizin I, Klinikum der Universität Regensburg, 93042 Regensburg, Germany;
    hans.herfarth{at}klinik.uni-regensburg.de

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Treatment of Crohn's disease with the anti-inflammatory cytokine interleukin 10

Interleukin 10 (IL-10) was initially discovered and isolated on the basis of its ability to suppress cytokine synthesis by Th1 helper cells. Macrophages and their secreted mediators are the primary target of IL-10. IL-10 downregulates expression of class II and B7 molecules, as well as IL-12 production, thus impairing the macrophage dependent stimulation of antigen reactive Th-1 cells.1

The important regulatory role of IL-10 in the gut became obvious when IL-10 deficient mice (IL-10−/−), generated by gene targeting, developed chronic enterocolitis.2 More interestingly, IL-10−/− mice kept under germfree conditions do not develop enterocolitis, which suggests that in the absence of the immunomodulatory effects of IL-10, an unrestricted intestinal inflammatory response develops towards normal enteric antigens. The observations in the IL-10−/− mice lay the foundation for administration of IL-10 in several animal models. The results of these studies clearly showed prevention of intestinal inflammation by IL-10, mainly by downregulation of an intestinal proinflammatory Th1 response. However, systemic IL-10 administration was successful only when administered prior to the initiation of colitis but was ineffective at reversing any established inflammation.3,4

IL-10: THE CLINICAL EXPERIENCE

Based on the successful experimental findings in animal models of intestinal inflammation, IL-10 therapy was introduced as a potential new anti-inflammatory therapy in Crohn's disease (CD). Several large multicentre trials were performed testing multiple IL-10 dosages in patients with mild/moderate or therapy refractory CD, as well as in patients undergoing curative ileal or ileocolonic resection to prevent endoscopic postoperative occurrence by systemic administration.5–7 All data indicate that IL-10 therapy is safe and well tolerated. But IL-10 treatment did not result in significantly higher remission rates or clinical improvement compared with placebo treatment. There are several explanations for the disappointment with this therapeutic strategy:

(i) With the administered dose of IL-10 in the clinical trials, the ultimate local IL-10 concentrations in the intestine could be too low to result in downregulation of inflammation. Unfortunately, increasing the dose of systemically administered IL-10 is limited due to side effects (for example, anaemia, headache).

(ii) IL-10 administration is only successful for preventing and not treating an established disease, as was suggested by the results of the animal experiments.

(iii) Administration of IL-10 alone fails to effectively suppress the dysregulation of the wide variety of proinflammatory mediators that are involved in the perpetuation of chronic intestinal inflammation.

(iv) The immunostimulatory properties of IL-10 on B cells and on interferon γ (IFN-γ) production by CD4+, CD8+, and/or natural killer cells counterbalance its immunosuppressive properties.

In this issue of Gut, data are presented which may explain, at least in part, the dilemma of IL-10 therapy in CD [see191].8 Tilg et al have investigated the influence of subcutaneous administration of various doses of human recombinant IL-10 on lymphocytic IFN-γ production and lipopolysaccharide (LPS) induced tumour necrosis factor (TNF) secretion by macrophages in whole blood assays as well as on serum neopterin and nitrite/nitrate levels. The study was conducted using samples from two multicentre therapeutic trials in patients with steroid dependent chronic active CD and patients with mild to moderately active CD.

In patients treated with the highest dose of IL-10 (20 μg/kg), the study described a significant increase in neopterin, which is produced by human monocytes/macrophages in response to IFN-γ, as well as an increase in phytohaemagglutinin induced IFN-γ production compared with pretreatment levels. Furthermore, LPS induced TNF-α production was dose dependently downregulated by IL-10. Neither the elevation in neopterin or IFN-γ nor suppression of TNF correlated with the clinical response of the patients, which may also reflectthe divergence of the clinical (Crohn's disease activity index) and immunological (for example, proinflammatory mediators) readouts in trials employing cytokine or anticytokine strategies.

The immunopotentiating effects of IL-10 found by Tilg et al are corroborated by a study in healthy volunteers subjected to experimental endotoxaemia.9 Systemic IL-10 treatment enhanced endotoxin (LPS) induced IFN-γ release as well as the IFN-γ dependent chemokines IFN-γ inducible protein 10 (IP-10) and monokine induced by IFN-γ (MIG). The stimulatory effects were most pronounced when IL-10 administration was performed one hour after the LPS challenge.

IL-10 THERAPY IN CD: A DEAD END?

What then are the lessons to be learned from the experimental and clinical experiences with IL-10?

The clinical studies published so far clearly indicate no relevant advantage of systemic IL-10 therapy compared with placebo in active and postoperative CD. Furthermore, as the results of Tilg et al indicate, higher doses of systemically administered IL-10 (which were also used in the clinical trials) may be detrimental rather than helpful. Nevertheless, the concept of rebalancing the intestinal immunological homeostasis with IL-10 is still very compelling and applying IL-10 locally in high concentrations may result in strong immunosuppression and circumvent the systemic side effects. So far we do not know whether high IL-10 concentrations also have immunostimulatory properties in the intestine as the study of Tilg et al was performed using only whole blood or serum. Furthermore, as indicated above, IL-10 prevented intestinal inflammation in animal studies but could never completely cure an established disease, indicating that IL-10 therapy in CD would succeed rather in preventing relapses than abolishing acute or chronic inflammation.

Recently, a novel compelling approach of local IL-10 therapy, which could also be used as a long term therapeutic approach, has been described. Steidler et al demonstrated that intragastric administration of an IL-10 secreting Lactobacillus lactis, generated by genetic engineering, caused a significant reduction in colitis in two different mouse models.10 Thus with dietary supplementation it may be possible to deliver high concentrations of IL-10 within the gut, thus preventing the recurrence of CD. However, this work has just proved a therapeutic principle and there is still a long way to go until such a concept can be evaluated in clinical studies.

Treatment of Crohn's disease with the anti-inflammatory cytokine interleukin 10

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