G-ALPHA-I2-DEFICIENT MICE WITH COLITIS EXHIBIT A LOCAL INCREASE IN MEMORY CD4(-CELLS AND PROINFLAMMATORY TH1-TYPE CYTOKINES() T)

Mice with targeted deletion of the G protein G alpha i2 develop an inf lammatory bowel disease closely resembling ulcerative colitis. To bett er define disease pathogenesis, the mucosal immune system in G alpha i 2-deficient mice was studied. Phenotypic analysis of large intestine l amina propria lymphocytes revealed a large increase in memory CD4(+) T cells (CD44(high), CD45RB(low), CD62L(low)). Furthermore, expression of the mucosal homing receptor integrin beta 7 was increased on mucosa l, but not systemic, CD4(+) T cells, Analysis of cytokine production r evealed a marked increase in proinflammatory Th1-type cytokines in inf lamed colons, as compared with wild-type mice or G alpha i2-deficient mice without colitis. Thus, IFN-gamma and IL-1 beta levels were increa sed 13-fold and 30-fold, respectively, with more modest increases in I L-6 levels (5-fold) and TNF levels (2-fold). Inflamed colons of G alph a i2-defrcient mice also demonstrated increased IL-12 p40 mRNA levels. No increase in IL-2, IL-4, IL-5, and IL-10 was seen. Large intestinal epithelial cells in G alpha i2-deficient mice with colitis were found by immunohistochemistry to express increased levels of both MHC class I and class II Ags. Colitis was associated with increased IgG levels (60-fold increase), predominantly IgG2a (135-fold increase), in large but not small intestinal secretions. This was shown by ELISPOT analysi s to result from local production within the lamina propria.