Recombinant human interleukin 10 suppresses gliadin dependent T cell activation in ex vivo cultured coeliac intestinal mucosa

Abstract

Background: Enteropathy in coeliac disease (CD) is sustained by a gliadin specific Th1 response. Interleukin (IL)-10 can downregulate Th1 immune responses. Aim: We investigated the ability of recombinant human (rh) IL-10 to suppress gliadin induced Th1 response. Patients and methods: IL-10 RNA transcripts were analysed by competitive reverse transcriptionpolymerase chain reaction in duodenal biopsies from untreated and treated CD patients, non-coeliac enteropathies (NCE), and controls. CD biopsies were cultured with a peptic-tryptic digest of gliadin with or without rhIL-10. The proportion of CD80+ and CD25+ cells in the lamina propria, epithelial expression of Fas, intraepithelial infiltration of CD3+ cells, as well as cytokine synthesis (interferon c (IFN-c) and IL-2) were measured. Short term T cell lines (TCLs) obtained from treated CD biopsies cultured with gliadin with or without rhIL-10 were analysed by ELISPOT for gliadin specific production of IFN-c. Results: In untreated CD and NCE, IL-10 RNA transcripts were significantly upregulated. In ex vivo organ cultures, rhIL-10 downregulated gliadin induced cytokine synthesis, inhibited intraepithelial migration of CD3+ cells, and reduced the proportion of lamina propria CD25+ and CD80+ cells whereas it did not interfere with epithelial Fas expression. In short term TCLs, rhIL-10 abrogated the IFN-c response to gliadin. Conclusions: rhIL-10 suppresses gliadin specific T cell activation. It may interfere with the antigen presenting capacity of lamina propria mononuclear cells as it reduces the expression of CD80. Interestingly, rhIL-10 also induces a long term hyporesponsiveness of gliadin specific mucosal T cells. These results offer new perspectives for therapeutic strategies in coeliac patients based on immune modulation by IL-10.

IL-10 polymorphisms are associated with early-onset celiac disease and severe mucosal damage in patients of Caucasian origin

“…Although the role of anti-TG antibodies in the pathogenesis of CD and in the development of the intestinal lesions is still unclear, the higher levels of antitissue transglutaminase antibodies observed in the low IL-10 producers could be attributed to the presence of a more severe intestinal lesion. 38,39 The pivotal role of IL-10 in the development of the celiac lesion is also supported by a recent paper by Salvati et al, 13 which demonstrated that IL-10 was able to inhibit the cytokine production triggered by gliadin in duodenal biopsies of CD patients. Lastly, it must be noted that in our present study the A allele in position Ϫ1082 in the IL-10 promoter was significantly associated with an earlier diagnosis, possibly suggesting the existence of genetic differences between celiac patients diagnosed in childhood or adulthood.…”

“…Candidate genes may include those coding for cytokines, which have been demonstrated to play an important role in the immune response of CD patients. [11][12][13] Several polymorphisms have been detected both in the coding and non-coding regions of these genes, and in vitro and in vivo data showed a correlation between specific polymorphisms and the levels of the produced proteins or the phenotype of various immunomediated diseases. [15][16][17][18]29,30 In the present study, no significant difference in frequencies of the analyzed polymorphisms could be detected between the CD patients and population controls, apart from a significantly higher frequency of the A allele in position Ϫ308 in the TNF␣ promoter.…”

“…This response can be counteracted by the production of antiinflammatory cytokines such as IL-10, which inhibits monocytes/macrophages activation and IFN␥ production. 13 The production of cytokines can be modulated both by the stimuli present in the local environment as well as by genetic factors. 14 -18 In fact, the presence of polymorphisms within the coding or noncoding sequences of cytokine genes can alter the efficiency of transcription of these genes and thus the production of cytokines, as demonstrated by studies both in vitro and in vivo.…”

Gliadin-Specific Type 1 Regulatory T Cells from the Intestinal Mucosa of Treated Celiac Patients Inhibit Pathogenic T Cells

“…Indeed, addition of exogenous IL-10 to mucosal cultures from treated CD patients can suppress gliadin-induced T cell activation and cytokine production ex vivo. (22) Therefore, similar to what has been described with alloantigens, (24), IL-10 can induce hyporesponsiveness to food Ags, and under noninflammatory conditions may also induce the differentiation of Tr1 cells in the gut.…”

“…Interestingly, we and others have recently shown that, in addition to proinflammatory cytokines, the inflamed CD mucosa also contains high levels of T cell-derived IL-10 when compared with treated CD or normal donors (22,23). It is possible that in acute CD, although IL-10 is produced, the levels are insufficient to down-regulate the massive Th1/Th0 immune responses induced by gliadin.…”