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We read with great interest the paper by Gao et al, where the authors elegantly proved the efficacy of a CD40 antisense oligonucleotide for the treatment of trinitrobenzene sulphonic acid (TNBS) induced colitis in rats (
). Their results are in keeping with previous reports in which immunoblockade of CD40 ligand (L) was also able to ameliorate experimental colitis. The authors conclude that interruption of interactions between CD40 bearing monocytes and endothelial cells and CD40L positive T cells is crucial for the beneficial effect exerted by CD40 antisense oligonucleotide in TNBS induced experimental colitis.
In the past few years we have been investigating the role of the CD40/CD40L pathway in the pathogenesis of inflammatory bowel disease (IBD).1 We and others have recently shown that, apart from endothelial cells and monocytes, human intestinal fibroblasts (HIF) also express CD40 on their surface.2,3 HIF significantly upregulate CD40 expression, both at the mucosal and submucosal levels, in patients with active IBD. Moreover, we and others have shown that coculture of CD40 expressing HIF with CD40L T cells induces fibroblast activation, leading to chemokine and cytokine production, cell adhesion molecule upregulation, and activation of the intracellular signalling machinery, by triggering MAP kinases and nuclear factor κB activation. All of these events are biologically relevant for the inflammatory process as fibroblast derived chemokines mediate T cell recruitment.2,3 Another intriguing observation is the demonstration that CD40L T cells modulate collagen synthesis by HIF, thus suggesting the potential involvement of the CD40/CD40L pathway in stricture formation in Crohn’s disease (CD).4 Therefore, blockade of HIF CD40 is another potential mechanism for the therapeutic efficacy of CD40 antisense.
We have also shown that platelets express high levels of biologically active surface CD40 in a constitutive manner.5 This molecule provides a novel pathway for platelet activation, as shown by the observation of RANTES release after platelet stimulation.5 These events are particularly relevant at sites of intense immune activation where local inflamed endothelial cells retain RANTES on their surface and mediate T cell adhesion, thus locally amplifying the inflammatory response.5 Moreover, Vowinkel and colleagues recently showed that the CD40/CD40L system also plays a critical role in mediating platelet adhesion to and activation of intestinal microvasculature or leucocytes.6
) suggest that CD40L positive T cells could stimulate CD40 endothelium, and that CD40 antisense could prevent such cell interactions. Recently, we have described that apart from T cells, activated platelet also express CD40L.7 Platelets display enhanced levels of membrane bound CD40L in CD and ulcerative colitis patients, and secrete higher amounts of soluble CD40L, compared with healthy controls.8 These phenomena have biological relevance in terms of intestinal microvascular activation as IBD activated platelets trigger chemokine production, VCAM-1, ICAM-1, and CD40L upregulation, and T cell adhesion to the gut endothelium.7,9 Therefore, abrogation of endothelial or platelet CD40 expression would not only block T cell-endothelial interactions but also interrupt platelet-endothelial and platelet-leucocyte cell crosstalk in the gut microvasculature.
Taken together, these observations suggest that the CD40 antisense oligonucleotide used by Gao et al exerts its beneficial effect not only by disrupting the interaction between CD40 bearing monocytes and endothelial cells and CD40L positive T cells, but also by acting on a much wider array of cell types able to express either CD40 or CD40L. We conclude that the use of CD40 antisense oligonucleotides appears to be a very promising therapeutic approach to turn off intestinal inflammation, by disconnecting a crucial and almost ubiquitous communication system used by multiple cell types during inflammation.
Conflict of interest: None declared.
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