TGF-BETA PRODUCTION REGULATES THE DEVELOPMENT OF THE 2,4,6-TRINITROPHENOL-CONJUGATED KEYHOLE LIMPET HEMOCYANIN-INDUCED COLONIC INFLAMMATIONIN IL-2-DEFICIENT MICE

A severe, Th1-mediated experimental colitis with similarities to infla mmatory bowel disease in humans can be induced by a single injection o f 2,4,6-trinitrophenol (TNP)-substituted protein plus adjuvant in IL-2 (-/-) mice, To determine the early events involved in the pathogenesis of IL-2(-/-) colitis, we compared the function of lamina propria (LP) T cells from IL-2(-/-) and IL-2(+/+) mice subjected to disease-induci ng (TNP-conjugated keyhole limpet hemocyanin (TNP-KLH)) and disease-in hibiting (anti-CD3) immunization protocols, We show that LP T cells in TNP-KLH-immunized IL-2(-/-) mice fail to produce TGF-beta early (day 2), whereas LP T cells in TNP-KLH-immunized IL-2(+/+) mice exhibit an approximately eightfold rise in TGF-beta secretion, The critical impor tance of local TGF-beta production was further substantiated by the fo llowing findings, 1) LP T cells from TNP-KLH-immunized IL-2(-/-) mice administered anti-CD3 (i.p.) exhibit a significant rise in TGF-beta pr oduction but fail to produce IFN-gamma, and such mice do not develop c olitis. 2) TNP-KLH-immunized IL-2(-/-) mice administered anti-CD3 and coadministered anti-TGF-beta mAb again give rise to IFN-gamma-producin g LP cells, and such mice develop colitis, 3) TNP-KLH-immunized IL-2(/+) mice administered anti-TGF-beta mAb exhibit pockets of mononuclear cell infiltrates in the LP. These results indicate that the dispositi on of IL-2(-/-) mice to develop chronic colonic inflammation is due to a Th1 cell response in the LP that is not appropriately counter-regul ated by the production of the suppressor cytokine, TGF-beta.