The tolerogenic modulation of dendritic cells in Crohn’s disease

Abstract

Crohn’s disease is a chronic relapsing remitting inflammatory disease of the gut. The aetiology is multifactorial, and incompletely understood. The immune system plays a key role as evidenced by animal and human studies, as well as the predominance of immune-targeting treatments amongst the Crohn’s disease therapeutic arsenal. Defects in the adaptive immune system in Crohn’s have been well described, and there is an increasing body of evidence that the innate immune system, including dendritic cells (DCs) may be involved as well. Vitamin D is of interest as a potential adjunctive therapy in IBD, and its potential mechanisms of action are incompletely understood. In this thesis, we utilised flow cytometry, ELISA, electron microscopy and PCR to explore the interactions between DCs, anti-TNF treatment and vitamin D in Crohn’s disease. We found abnormalities in circulating DCs in Crohn’s disease, especially in the expression of homing markers, and in the production of inflammatory cytokines. Expression of homing markers were discriminatory for both location of disease and degree of inflammation. There were abnormalities in the less well studied plasmacytoid DC (pDC) population. Abnormalities in intracellular DC production of inflammatory cytokines were mirrored by serum cytokine concentrations. The phenotype and function of circulating DCs was seen to alter after ex vivo treatment with anti-TNF. Anti-TNF therapy was associated with a switch away from gut-homing circulating DC phenotype towards skin homing, and with a decrease in on-going DC production of intracellular cytokines such as TNFa and IL-6. These findings may provide further mechanisms of action of anti-TNF treatment as well as an explanation for its high rates of dermatological complications. Vitamin D was seen to alter DC homing profile in both in vitro and ex vivo studies to non-skin homing, and in addition augmented down-regulation of TNFa production by DCs. This could have potential clinical applications.