TYPE-1 T-HELPER CELL PREDOMINANCE AND INTERLEUKIN-12 EXPRESSION IN THE GUT OF PATIENTS WITH CROHNS-DISEASE

Crohn's disease (CD) is a chronic bowel inflammatory disorder in which the pathogenic role of immune alterations has been suggested, but the immunologic mechanisms responsible for the inflammatory reaction are still poorly understood, We investigated the profile of cytokine secre tion by T-cell clones generated from gut tissue specimens of four pati ents with active CD, five patients with ulcerative colitis, and four p atients with noninflammatory gut disorders (NIGDs). The great majority of CD4(+) T-cell clones generated from the gut of patients with CD pr oduced high levels of interferon-gamma (IFN-gamma) but low or undetect able amounts of interleukin-4 (IL-4), whereas substantial proportions of CD4(+) T-cell clones derived from the gut of patients with either u lcerative colitis or NIGDs produced IL-4 in addition to IFN-gamma. The immunohistochemical analysis revealed high numbers of activated CD4() T cells showing IFN-gamma but not IL-4 reactivity, as well as substa ntial proportions of IL-12-containing macrophages, in the intestinal l amina propia and muscularis propria of patients with CD, whereas these cells were very rare or undetectable in patients with NIGDs. Culturin g T cells from gut biopsy specimens of a patient with CD in the presen ce of a neutralizing anti-IL-12 antibody down-regulated the developmen t of IFN-gamma-producing CD4(+) T cells. These findings suggest that a critical event in the initiation of bowel inflammatory lesions in CD may involve up-regulation of IL-12 production, resulting in conditions that maximally promote type 1 T-helper immune responses.