G(I2)ALPHA PROTEIN-DEFICIENCY - A MODEL FOR INFLAMMATORY BOWEL-DISEASE

Mice deficient for the G protein subunit G(12)alpha were obtained by g ene targeting. They displayed a growth retardation that was apparent a t 6 weeks of age. They subsequently developed diffuse colitis with cli nical and histopathological features closely resembling those of ulcer ative colitis in humans. Seven of 20 G(12)alpha-deficient mice with co litis also developed adenocarcinomas of the colon. G(12)alpha-deficien t thymocytes displayed two- to fourfold increases in mature CD4(+)8(-) and CD4(-)8(+) phenotypes, an approximately threefold increase in hig h-intensity CD3 staining and enhanced proliferative responses to T-cel l receptor stimuli. Stimulation of G(12)alpha-deficient peripheral T c ells induced a hyperresponsive profile of interleukin-2, tumor necrosi s factor, and interferon-gamma production, which may reflect a heighte ned response of primed cells or a defective negative regulation. We su ggest that G12 alpha-deficient mice may represent a useful animal mode l for dissecting the pathomechanisms of inflammatory bowel disease and also for the development of novel therapeutic strategies.