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Abstract

We appreciate these comments, with which we partly agree. The thrust of our work was to examine the effects of the lack of interleukin (IL)-21 in animal models of colitis, because we had previously shown that IL-21 is important in maintaining the Th1 response in Crohn's disease, induces fibroblasts to make matrix metalloproteinases, and stimulates epithelial cells to secrete chemokines, which attract T cells into the gut.1Monteleone G. Monteleone I. Fina D. et al.Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn's disease.Gastroenterology. 2005; 128: 687-694Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 2Monteleone G. Caruso R. Fina D. et al.Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21.Gut. 2006; 55: 1774-1780Crossref PubMed Scopus (168) Google Scholar, 3Caruso R. Fina D. Peluso I. et al.A functional role for interleukin-21 in promoting the synthesis of the T-cell chemoattractant, MIP-3alpha, by gut epithelial cells.Gastroenterology. 2007; 132: 166-175Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar Our demonstration that genetic ablation of IL-21 protects mice from colitis adds to the body of evidence that IL-21 overexpression in inflammatory bowel disease (IBD) is involved in tissue damage; therefore, we feel that IL-21 could be a therapeutic target in these conditions. At the same time we were completely aware that IL-21 is involved in the generation of Th17 cells4Zhou L. Ivanov I.I. Spolski R. et al.IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.Nat Immunol. 2007; 8: 967-974Crossref PubMed Scopus (1676) Google Scholar, 5Korn T. Bettelli E. Gao W. et al.IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells.Nature. 2007; 448: 484-487Crossref PubMed Scopus (1508) Google Scholar, 6Nurieva R. Yang X.O. Martinez G. et al.Essential autocrine regulation by IL-21 in the generation of inflammatory T cells.Nature. 2007; 448: 480-483Crossref PubMed Scopus (1236) Google Scholar and so we carried out the rather obvious experiments to show that blocking IL-21 or lack of IL-21 markedly impairs IL-17 production, which it did.7Fina D. Sarra M. Fantini M.C. et al.Regulation of gut inflammation and th17 cell response by interleukin-21.Gastroenterology. 2008; 134: 1038-1048Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar We appreciate that IL-17 may cause injury via neutrophils, but the mechanisms of action of IL-17 in tissue damage in the gut was not our primary aim. Where we disagree rather profoundly with the authors is their statement that our data are not particularly applicable to IBD, notwithstanding our published papers on IL-21 in Crohn's disease where we show this applicability. This statement seems to be based on the idea that if IL-17 is involved in neutrophil recruitment into the gut, a reduction in neutrophil infiltrate owing to the block of the IL-21/Th17 axis becomes problematic, because it is claimed that “Reduced innate responses seem to cause Crohn's disease rather than ameliorate pathology.” In our view, this is an oversimplification of a rather controversial hypothesis suggesting that patients with Crohn's disease have a systemic defect in innate immunity and particularly in neutrophil function.8Bendixen G. Specific inhibition of the in vitro migration of leucocytes in ulcerative colitis and Crohn's disease.Scand J Gastroenterol. 1967; 2: 214-221Crossref PubMed Scopus (36) Google Scholar, 9Marks D.J. Harbord M.W. MacAllister R. et al.Defective acute inflammation in Crohn's disease: a clinical investigation.Lancet. 2006; 367: 668-678Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar The idea that there is such a rather obvious “abnormality” in patients with Crohn's disease shows no real appreciation of the complexity of the genetics, immunology, and environmental influences that lead to patients in the Western world developing this serious and debilitating condition. Moreover, if this abnormality is actually relevant in the pathogenesis of Crohn's disease, one should expect that the immunosuppressive therapy accentuates the immune defect and makes worse the course of the disease: however, this is not the case in Crohn's disease. The analogy with pediatric disorders of neutrophil dysfunction where some patients develop a disease like, but not the same as Crohn's disease, is equally overstretched. One might as well say that yersiniosis or intestinal tuberculosis give clues to the cause(s) of Crohn's disease(s) because they produce similar pathology and symptoms. Role of Neutrophil Recruitment in the Amelioration of Experimental Colitis by Genetic Ablation of Interleukin-21GastroenterologyVol. 135Issue 4PreviewWe have read with great interest the article by Fina et al,1 which provides urgently needed data on the role of interleukin (IL)-21 on the Th17 cell responses and the development of colitis in experimental murine models. In this article, the authors show that genetic ablation of IL-21 substantially ameliorates both DSS- and trinitrobenzene sulfonic acid (TNBS)-induced colitis and the authors conclude from these data that the IL-21/IL-17 system is an attractive target for clinical intervention in inflammatory bowel disease (IBD). Full-Text PDF