Crohn's disease is an inflammatory disease of the gut in which tumour
necrosis factor (TNF) and T helper 1 (Th1)
cytokines (
interleukin (
IL)-12,
interferon (IFN)-gamma) are thought to play a major role. After the successes obtained with neutralisation of TNF, interest is now growing for
therapy aiming at neutralisation of Th1-associated
cytokines. Since
cytokines are linked in a delicate network, in vitro cultures of ileal lamina propria mononuclear cells (LPMC) were set up for evaluation of a) IFN-gamma and
IL-12 production, b) effects of rhIFN-gamma and rhIL-12 and c) effects of anti-IFN-gamma and anti-
IL-12 on pro-inflammatory
cytokines and IL-10 production. LPMC were isolated from surgical specimens of a total of 27
Crohn's disease and 17 caecum
carcinoma (control) patients. Cells were stimulated with
CD40L (which triggers myeloid CD40-expressing cells) or anti-CD3 +CD80 (which triggers T cells). LPMC from involved ileal,
Crohn's disease produced, in both non-stimulated and stimulated conditions, more IFN-gamma and IL-12p70 than LPMC from non-involved tissue or from control patients. rhIFN-gamma significantly enhanced TNF production in both controls and in ileal
Crohn's disease patients, while rhIL-12 enhanced IFN-gamma but not TNF production. LPMC from involved tissue were more sensitive to
IL-12 than control LPMC. LP-T cell-dependent activation of monocytes was then studied by co-culture of anti-CD3/CD80-stimulated LPMC with fresh monocytes, which resulted in high
IL-12, IFN-gamma, TNF and IL-10 production. The data show that neutralisation of either
IL-12 or IFN-gamma with mAb in these cultures also affects secretion of the reciprocal
cytokine and (in the case of anti-
IL-12) also that of the anti-inflammatory
cytokine IL-10. However, no effect of anti-
IL-12 or anti-IFN-gamma on production of TNF, a
cytokine with an important pathogenic role in
Crohn's disease, could be found.
Therapies aiming at neutralisation of IFN-gamma or
IL-12 are therefore unlikely to replace anti-TNF, but they might provide an additive or synergistic effect.