It has long been known that apoptosis of T cells is an important mechanism for terminating inflammatory reactions.¹ It was proposed over 10 years ago that defective apoptosis could play a role in the pathogenesis of inflammatory bowel disease.² There is now substantial experimental and clinical evidence supporting this hypothesis.³

In Crohn’s disease there is an expansion in CD4 T-cell populations mediated by tumour necrosis factor (TNF) and γ-interferon (IFN-γ), which activate macrophages to release interleukin-6, interleukin-12 and TNF.^4,5 These cytokines act to perpetuate the inflammatory reaction by reducing the susceptibility of T cells to die by apoptosis.³ In the uninflammed state, lamina propria T cells have a higher susceptibility to apoptosis than unstimulated T cells from the peripheral blood because of high expression of the apoptosis-inducing receptor Fas.⁶ In contrast to this, lamina propria T cells from patients with Crohn’s disease are resistant to apoptotic stimuli.⁷ These observations suggest that apoptosis limits the number of CD4 T cells in healthy individuals whereas in Crohn’s disease expansion of T-cell populations can occur without the restriction of apoptosis.

This resistance to induction of apoptosis is mediated by interleukin-12, the interleukin-6 receptor and TNF. Interleukin-12 is one of the most important cytokines in Crohn’s disease promoting Th₁ T-cell differentiation. It also renders T cells resistant to Fas-induced apoptosis, possibly through inhibition of caspase 3 and 9, thereby prolonging T-cell survival.⁸ Early clinical studies have shown that antibodies that block the action of interleukin-12 reduce the severity of Crohn’s disease.⁹ Such antibodies also increase apoptosis in lamina propria T cells and reduce the severity of trinitrobenzene sulphonic acid experimental colitis.⁵

Interleukin-6 secreted by lamina propria macrophages and T cells also promotes the survival of T cells by inhibiting …