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Doctors Veny, Salas, and Panes correctly point out that in our reports (Gut 2009;58:1481–1489; Nat Immunol 2005;6:507–514) we have isolated epithelial cells from regions that were not macroscopically involved by the disease, but we cannot rule out that they were not affected by subtle—undetectable—inflammation in the same region or by overt inflammation in adjacent regions. Hence, the reduction in transforming growth factor (TGF)-β, thymic stromal lymphopoietin (TSLP), or ALDH1A1 expression by epithelial cells isolated from tissues of Crohn's disease patients could still be secondary to inflammation.

The authors highlight 1 of the important consequences of our work for therapeutic purposes: The possibility of using dendritic cells (DCs) “educated” by intestinal epithelial cells as a therapeutic tool for tolerance induction. As they point out, however, we have not demonstrated that DCs retain their tolerogenic phenotype when reinfused into the patients. We would propose another approach that is based on using T-regulatory (Treg) cells induced by intestinal epithelial cell “educated” DCs. In fact, given the capacity of “educated” DCs to confer suppressory function and the expression of gut homing markers on T cells (also Treg cells), this approach may be more powerful (Mucosal Immunol 2009;2:340–350). In the mouse system, we tested the therapeutic potential of Treg cells induced in this way and we have shown that they partially protect mice against colitis (Mucosal Immunol 2009;2:340–350). However, we do not know what is the antigen specificity of these Treg cells and whether they act in a bystander fashion on other T cells or on the inflamed tissue. In diseases where the immunogenic antigen is known (like gliadin in celiac disease), this strategy is very attractive to induce tolerance.

The use of TSLP as possible therapeutic agent could also be exploited in Crohn's disease patients but the findings that TSLP can be inflammatory in other body districts like the skin and the airways (Nat Immunol 2002;3:673–680; Nat Immunol 2010;11:289–293) pose some caution for its systemic administration. Up-regulation of TSLP and TGF-β expression in epithelial cells by probiotic bacteria as recently described (PLoS One 2009;4:e7056; Immunology 2008;123:197–208) could be an alternative to increase these 2 factors only locally and avoid their systemic effect.

In conclusion, we thoroughly agree with Drs Veny, Salas, and Panes that this is a new and fascinating area of research that could further our understanding of the mechanisms controlling intestinal immune homeostasis and on designing new therapeutic approaches.