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Celiac.com 05/19/2010 - Enteropathy-associated T cell lymphoma is a serious complication of celiac disease, and a major cause of mortality in untreated celiac disease. One possible trigger for Enteropathy-associated T cell lymphoma development is chronic exposure of intraepithelial lymphocytes (IELs) to strong anti-apoptotic signals, that is, signals that interfere in the normal mortality of the IEL cells. These signals are triggered by IL-15, a cytokine that is over-expressed in the enterocytes of people with celiac disease. However, researchers have not yet fully mapped the signaling pathway by which IL-15 transmits these anti-apoptotic signals. Researchers consider type II refractory celiac disease (RCDII) to be a middle step between celiac disease and enteropathy-associated T cell lymphoma. Eliminating abnormal IELs at the RCDII stage would likely block EATL development. So far, though, scientists have not found successful immunosuppressive and/or chemotherapeutic approaches able to accomplish this, and RCDII outcomes remain very poor. A team of researchers recently set out to map the IL-15–driven survival pathway in human IELs, and to determine whether IL-15 triggered pathway in human intraepithelial lymphocytes represents a possible new target in type II refractory celiac disease and enteropathy-associated T cell lymphoma. The research team was made up of Georgia Malamut, Raja El Machhour, Nicolas Montcuquet, Séverine Martin-Lannerée, Isabelle Dusanter-Fourt, Virginie Verkarre, Jean-Jacques Mention, Gabriel Rahmi, Hiroshi Kiyono, Eric A. Butz, Nicole Brousse, Christophe Cellier, Nadine Cerf-Bensussan, and Bertrand Meresse. The are variously affiliated with INSERM U989, the Université Paris Descartes, Faculté de Médecine René Descartes, the Department of Gastroenterology, AP-HP, Hôpital Européen Georges Pompidou, the Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), INSERM U1016, the Department of Pathology, AP-HP, of the Hôpital Necker-Enfants Malades in Paris, with the Division of Mucosal Immunology, Department of Microbiology and Immunology at the Institute of Medical Science at the University of Tokyo in Japan, and the Inflammation Department of AMGEN Inc., in Seattle, Washington, USA. Their current findings reveal that the survival signals IL-15 directs to freshly isolated human IELs, and to human IEL cell lines derived from celiac disease patients with type II refractory celiac disease, depend on anti-apoptotic factors Bcl-2 and/or Bcl-xL. The signals require IL-15RÎ², Jak3, and STAT5 for proper function, but functioned independently of PI3K, ERK, and STAT3. In support of these findings, the team recorded elevated levels of Bcl-xL, phospho-Jak3, and phospho-STAT5 in IELs from patients with active celiac disease and RCDII. Moreover, by incubating patient duodenal biopsies with a fully humanized human IL-15–specific Ab, the team effectively blocked Jak3 and STAT5 phosphorylation. Also, treatment with IL-15–specific Ab caused IEL cell mortality, and wiped out the massive IEL build-up in mice over-expressing human IL-15 in their gut epithelium. The study marks the first successful mapping of the IL-15–driven survival pathway in human IELs, and demonstrates that IL-15 and its downstream effectors are meaningful therapeutic targets in RCDII. These findings will likely help to pave the way for the development of successful immunosuppressive and/or chemotherapeutic treatments that destroy abnormal IELs at the RCDII stage and help to block EATL development, improving outcomes for RCDII patients. Source: Journal of Clinical Investigation doi:10.1172/JCI41344