Ulcerative Colitis: Treton X

Allez M, Tieng V, Nakazawa A, Treton X, Pacault V, Dulphy N, Caillat-Zucman S, Paul P, Gornet JM, Douay C, Ravet S, Tamouza R, Charron D, Lémann M, Mayer L, Toubert A. · Service de Gastroentérologie, Hôpital Saint-Louis, Paris, France; INSERM Unité 662, Hôpital Saint-Louis, Paris, France. · Gastroenterology. · Pubmed #17570210 No free full text.

Abstract: BACKGROUND & AIMS: Crohn's disease (CD) is an inflammatory bowel disease characterized by uncontrolled immune responses to bacterial flora, with excessive activation of T lymphocytes. MICA is a stress-induced major histocompatibility complex-related molecule expressed on normal intestinal epithelial cells (IECs) and recognized by the NKG2D-activating receptor on CD8(+) T cells, gammadelta T cells, and natural killer cells. We examined the role of MICA-NKG2D interactions in the activation of T lymphocytes in CD. METHODS: MICA expression was analyzed by flow cytometry on IECs isolated from patients with active inflammatory bowel disease and controls. NKG2D expression and function were analyzed on lamina propria and peripheral blood lymphocytes. RESULTS: MICA expression was significantly increased on IECs in CD, with higher expression in macroscopically involved areas. A subset of CD4(+) T cells expressing NKG2D was increased in the lamina propria from patients with CD compared with controls and patients with ulcerative colitis. CD4(+)NKG2D(+) T cells with a Th1 cytokine profile and expressing perforin were increased in the periphery and in the mucosa in CD. CD4(+)NKG2D(+) T-cell clones were functionally active through MICA-NKG2D interactions, producing interferon-gamma and killing targets expressing MICA. IECs from patients with CD had the ability to expand this subset in vitro. CD4(+)NKG2D(+) lamina propria lymphocytes from patients with CD highly expressed interleukin-15R alpha, and interleukin-15 increased NKG2D and DAP10 expression in CD4(+)NKG2D(+) T-cell clones. CONCLUSIONS: These findings highlight the role of MICA-NKG2D in the activation of a unique subset of CD4(+) T cells with inflammatory and cytotoxic properties in CD.

Daniel F, Loriot MA, Seksik P, Cosnes J, Gornet JM, Lémann M, Fein F, Vernier-Massouille G, De Vos M, Boureille A, Treton X, Flourié B, Roblin X, Louis E, Zerbib F, Beaune P, Marteau P. · Department of Gastroenterology, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France. · Inflamm Bowel Dis. · Pubmed #17206635 links to  free full text

Abstract: BACKGROUND: Cyclosporine A (CsA) is inconstantly effective in inducing remission in acute attacks of ulcerative colitis (UC) not responding to steroids. This study aimed to establish whether multidrug resistance gene (MDR)1 polymorphisms would be associated with CsA failure. PATIENTS AND METHODS: The distribution of the different genotypes of single nucleotide polymorphisms (SNP) G2677T/A and C3435T of MDR1 exons 21 and 26, respectively, was studied in 154 patients (mean age, 44 yr) who had received CsA to treat severe attacks of steroid resistant UC in 11 centers in France and Belgium. Patients were classified as CsA failure (n = 50) when they needed colectomy within 30 days after CsA initiation. The SNPs were detected by use of a 5' nuclease allelic discrimination assay. RESULTS: There was a significant association between the G2677T/A polymorphism distribution (exon 21) and the risk for CsA failure (P = 0.0001). The TT genotype of exon 21 was significantly associated with the risk compared with the two other genotypes (odds ratio, 3.77; 95% confidence interval, 1.42-9.97, P = 0.007). There was no significant association between the genotype C3435T distribution (exon 26) and the risk of CsA failure (P = 0.23). CONCLUSION: The TT genotype of exon 21 MDR1 polymorphisms is associated with a higher risk of CsA failure in patients with steroid resistant UC. Further studies should be performed to establish whether other treatments could be more efficient to avoid surgery in this subset of patients.