BLOCKAGE OF T-CELL COSTIMULATION INHIBITS T-CELL ACTION IN CELIAC-DISEASE

Background & Aims: Celiac disease is an exemplary model of T cell-medi ated pathology, Therefore, therapeutic approaches that target T cells may successfully control this disease. CTLA-4 immunoglobulin (CTLA-4Ig ) can inhibit T-cell activation by blocking the engagement of CD28, We took advantage of this tool to define the pathogenic role of gliadin- specific T cells in the induction of celiac disease, Methods: Duodenal biopsy specimens from 7 treated celiac patients were challenged in vi tro with gliadin and CTLA-4Ig or CD40-Ig. After 24 hours, the biopsy s pecimens were analyzed for the presence of characteristic modification s induced by gliadin challenge. Results: CTLA-4Ig down-regulated the e xpression of CD25, intercellular adhesion molecule 1, interleukin 2, a nd interferon gamma (stained lamina propria mononuclear cells/mm(2); P < 0.05) induced by gliadin challenge, caused apoptosis of gliadin-spe cific T cells (apoptotic T cells/mm2; P < 0.05), and inhibited the pro duction of antiendomysial antibody (P < 0.01). However, it did not con trol intraepithelial T-cell migration (P = NS) and Fas expression by e nterocytes, Conversely, CD40-Ig only controlled production of antiendo mysial antibody. Conclusions: In an organ culture model, CTLA-4Ig cont rols many but not all of the immunologic features of celiac disease.