<<Disclaimer: Verify this information before applying it to your situation.>> Here are two somewhat technical but important CD studies. In previous studies (Science Magazine, Vol 297, Sept 27, 2002), a gliadin peptide was identified as an initiator of the CD T cell response. It was found to be highly resistant to breakdown by normal digestive enzymes. The following study shows that this peptide can, in fact, be fully digested by the enterocytes in the intestines of normal controls and treated-celiac patients, but not in patients with ACTIVE celiac disease. Enterocytes are epithelial cells which comprise the villi and crypts of the intestine lining. See: http://biology.about.com/library/organs/bldigestsmallint2.htm Another study identifies over expressed IL-15 (interleukin-15) as an immune system chemical that contributes to villous atrophy, suggesting that blocking IL-15 may be a way of treating complications of CD. ---------- Gastroenterology, Sept 2003, Vol 125, No 3, p 696-707 Alterations of the intestinal transport and processing of gliadin peptides in celiac disease Tamara Matysiak-Budnik, Celine Candalh, Christophe Dugave, Abdelkader Namane, Christophe Cellier, Nadine Cerf-Bensussan, Martine Heyman INSERM EMI 0212, Faculté Necker-Enfants Malades, Paris, France Laboratoire DIEP, CEA/Saclay, Gif sur Yvette, France Proteomic Platform, Institut Pasteur, Paris, France Hôpital Européen G. Pompidou, Paris, France Supported by the Nutricia Research Foundation, the Princess Grace de Monaco Foundation, INSERM, PROGRES, and IRMAD. Address requests for reprints to: Martine Heyman, Ph.D., INSERM EMI 0212, Faculté Necker-Enfants Malades, 156 rue de Vaugirard, 75730, Paris, France fax: (33) 1 40 61 56 38; Email: [log in to unmask] Abstract Background & aims: The hypothesis of a defect in the intestinal transport and processing of toxic (31-49) or immunostimulant (57-68 and the 33-mer 56- 89) gliadin peptides was tested in patients with active celiac disease (ACD), patients with treated celiac disease (TCD), and controls. Methods: Using duodenal biopsy specimens mounted in Ussing chambers, we measured electrical resistance, mucosal-to-serosal radiolabeled-peptide fluxes, and peptide processing during transport using radio-reverse-phase high-performance liquid chromatography. Results: Peptide 31-49 fluxes (24.7 µg · 3 h(-1) · cm(-2)) were increased in patients with ACD compared with controls and patients with TCD (12.7 and 12.3 µg · 3 h(-1) · cm(-2); P < 0.01). In contrast, no increase was observed for peptide 57-68 or 56-89 (33-mer). Electrical resistance was decreased in patients with ACD versus controls (15.3 vs. 23.9 ohms · cm(2); P < 0.001). Peptide 57-68 was partially degraded by brush-border peptidases in controls but not in patients with celiac disease. However, it was totally degraded after intestinal transport both in controls and patients with celiac disease. Peptides 31-49 and 56-89 were resistant to brush- border peptidases in all groups of patients but were totally degraded during intestinal transport in controls and patients with TCD. In patients with ACD, however, 50% of peptide 31-49 was delivered intact into the serosal compartment and only partial degradation of the 33-mer was observed. These abnormalities were not related to a nonspecific paracellular leakage. Conclusions: Our data indicate that gliadin peptides, although poorly or not digested by intraluminal enzymes, can be fully digested by enterocytes in controls and patients with TCD. In patients with ACD, incomplete degradation of the 33-mer and protected transport of the peptide 31-49 might favor their respective immunostimulatory and toxic effects. ---------- Gastroenterology, Sept 2003, Vol 125, No 3, p 730-745 Interleukin 15: A key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease Jean-Jacques Mention, Mélika Ben Ahmed, Bernadette Bègue, Ullah Barbe, Virginie Verkarre, Vahid Asnafi, Jean-frédéric Colombel, Paul-henri Cugnenc, Frank M. Ruemmele, Elisabeth Mcintyre, Nicole Brousse, Chistophe Cellier, Nadine Cerf-Bensussan INSERM EMI-0212, Faculté Necker, Paris, France Department of Pathology, Hôpital Necker-Enfants Malades, Paris, France Department of Hematology, Hôpital Necker-Enfants Malades, Paris, France Department of Gastroenterology, Hôpital Huriez, Lille, France Department of Surgery, Hôpital Georges Pompidou, Paris, France Department of Gastroenterology, Hôpital Georges Pompidou, Paris, France Supported by INSERM (Réseau Progrès), Assistance Publique des Hôpitaux de Paris (PHRC96096), La Fondation pour la Recherche sur le Cancer (ARC9216), and La Fondation Princesse Grace de Monaco. J.-J.M. has a fellowship from the Institut Danone, and M.B.A. has a fellowship from INSERM. Address requests for reprints to: Nadine Cerf-Bensussan, M.D., Ph.D., INSERM EMI-0212, Faculté Necker 156, rue de Vaugirard, 75730 Paris Cedex 15, France fax: (33) 1-40-61-56-38; Email: [log in to unmask] Abstract Background & Aims: The mechanism of intraepithelial lymphocyte hyperplasia, a hallmark of celiac disease, is unknown. We have investigated the role of epithelium-derived interleukin (IL)-15 in the alterations of epithelial homeostasis in refractory celiac sprue, a privileged situation to study the first step of lymphoid transformation and the contribution of intraepithelial lymphocytes to villous atrophy in celiac disease. Methods: IL-15 expression was assessed in biopsy specimens and isolated enterocytes by combining immunohistochemistry, flow cytometry, and real- time quantitative polymerase chain reaction. The ability of IL-15 to induce growth and survival of clonal intraepithelial lymphocytes lacking surface CD3 and to induce their cytotoxicity and secretion of interferon gamma was tested using soluble IL-15 and coculture in the presence of epithelial cell lines expressing membrane IL-15. Results: IL-15 was massively overexpressed not only in lamina propria but also in the intestinal epithelium of patients with active celiac disease and refractory celiac sprue. IL-15 was not secreted but delivered at the surface of enterocytes. IL-15 specifically induced the expansion and survival of the clonal abnormal intraepithelial lymphocytes that characterize refractory celiac sprue and triggered their secretion of interferon gamma and their cytotoxicity against intestinal epithelial cells. Comparable activating signals could be delivered by IL-15 expressed at the membrane of the T84 enterocyte cell line. Conclusions: These data provide strong evidence that uncontrolled overexpression of IL-15 in refractory celiac sprue perpetuates epithelial damage and promotes the emergence of T-cell clonal proliferations. Blocking IL-15 might prove useful to treat this severe complication of celiac disease. * * * *Support summarization of posts, reply to the SENDER not the CELIAC List*