TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

Abstract

The CD40/CD40 ligand (CD40L) pathway is involved in Crohn’s disease (CD) pathogenesis. In the patients’ circulation, soluble CD40L (sCD40L) levels are elevated and surface CD40L is increased in platelets and T cells, whereas in the intestine CD40 is overexpressed in the microvasculature and CD40L in platelets and T cells. The therapeutic effects of infliximab in CD are attributed to its systemic anti-TNF-α action, but because TNF-α modulates both CD40 and CD40L, we investigated whether infliximab affects the CD40/CD40L pathway in the intestine. Eighteen CD patients were evaluated before and after infliximab therapy. Plasma sCD40L was measured by ELISA and platelet and peripheral blood T cell (PBT) CD40L expression by flow cytometry. Microvascular CD40 and VCAM-1 expression were assessed in mucosal biopsies by immunohistochemistry and by flow cytometry in human intestinal microvascular endothelial cells (HIMEC). Cell cultures were performed in the presence and absence of infliximab. Infliximab treatment significantly reduced plasma sCD40L levels and eliminated CD40 and VCAM-1 from mucosal microvessels. In vitro infliximab prevented TNF-α-induced CD40 and VCAM-1 expression by HIMEC, and reduced PBT, but not platelet, surface CD40L expression and sCD40L release. In addition, infliximab decreased T cell-induced VCAM-1 expression in HIMEC by down-regulating CD40L in T cells and promoting T cells apoptosis. These findings point to a novel mechanism of action of infliximab, i.e., the disruption of CD40/CD40L-dependent cognate interactions between intestinal microvessels and T cells. Thus, in addition to neutralizing TNF-α and inducing T cell death, the therapeutic effects of infliximab in CD appear to be also mediated by inhibition of vascular inflammation in the gut.

Proteomics for prediction and characterization of response to infliximab in Crohn's disease: A pilot study

“…The sCD40L is another important platelet-derived factor that has been correlated with disease activity and extent in CD [23], as well as with tissue response to infliximab [24]. Similarly to PF4 determined by ELISA, sCD40L serum levels observed before treatment were not associated with response to infliximab, nor correlated to PF4 peaks on SELDI-MS.…”

TNFα blockade in human diseases: Mechanisms and future directions

“…1). Danese et al [51] showed that INF significantly reduced levels of intestinal endothelial expressed CD40 and VCAM-1 in treated patients with CD, as well as their levels of soluble CD40L.…”

The Intersection of TNF, IBD and the Microbiome

“…23 Anti-TNF therapeutics dampens inflammation in IBD, at least in part, by modulating the gut microbiota, inducing T cell apoptosis, and by inhibiting vasculitis. 25,26 With respect to the microbiota, this decreased inflammation is associated with modulation of the gut microbiota tending toward eubiosis. The microbiome of treated individuals was characterized by reduced Enterobacteriaceae (specifically E. coli) and Ruminococcus, and increased proportions of Bacteroidetes and Firmicutes, restoring the microbiome to a composition more reflective of healthy individuals.…”