Selective Inhibition of Adhesion Molecules

Adhesion molecules, up-regulated in inflamed CD mucosa, play a role in the trafficking of leukocytes and are involved in local lymphocyte stimulation and antigen presentation. Integrins are heterodimeric receptors consisting of an a4 subunit and either a pi or p7 subunit (a4 pi and a4 p7 integrins). Integrins bind leukocytes in the vascular endothelium and have a role in the migration of leukocytes across the vascular endothelium. Therefore, they contribute to recruitment, activation and survival of leukocytes within the parenchyma. There is evidence that in IBDs, integrins are overexpressed on the vascular endothelium at the site of inflammation. In animal models of colitis, antibodies against the a4 integrin are able to significantly reduce gut inflammation [166].

Recent double-blind placebo-controlled studies using natalizumab, a humanised mouse monoclonal antibody anti-a4 integrin (95% human, 5% murine), in patients suffering from CD administrated at dosage of 3 mg/kg per month twice improve clinical remission and clinical response rates, as well as quality of life [167-169]. However, three cases of progres sive multifocal leukoencephalopathy (PML), probably secondary to reactivation of latent JC poly-omavirus infection, have been reported [170-172]. Retrospective analysis of serum samples showed that JC virus became detectable only after three injections of natalizumab monotherapy, and the serum viral load increased by a factor of ten after two additional injections. Although the large number of patients enrolled in this clinical trial (over 3,000) and, consequently, the low incidence of neurologic disease in natalizumab-treated patients, the lack of diagnosis of latent infection before natalizumab treatment limits, due to ethical concerns, its clinical use [173]. In fact, there is no specific treatment for PML at the moment. A better understanding of the risk of PML in natal-izumab-treated patients and the diagnostic possibilities for a latent JC polyomavirus infection will define the role of the drug in the treatment of CD.

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