Modulazione dell'espressione del recettore VLA4 in relazione a diverse terapie farmacologiche in pazienti affetti da sclerosi multipal

The development of monoclonal antibodies are an emerging therapy for the treatment of multiple sclerosis. Natalizumab (Tysabri ®) is a recombinant humanized IgG4 monoclonal antibody, directed against domain alpha 4 of alpha4beta1 integrin, expressed on the surface of all leukocytes except neutrophils. This molecule binds to VLA-4 antagonist acting mainly as vascular adhesion molecule (VCAM), inhibiting the binding of leukocytes to VCAM-1 and fibronectin. VCAM-1 upregulation, during the inflammatory process, induces a controlled migration of leukocytes to their target tissue. An emerging risk of therapy is the occurrence of progressive multifocal leukoencephalopathy (PML), demyelinating disease of the brain caused by human polyomavirus JC. In this context, expand the search for patient-specific predictors appears relevant to the success of this therapy. The identification of subjects responders poorly to therapy with natalizumab may provide a useful tool for decision based on the balance between risk of adverse reactions (PML) and therapeutic benefits. A preliminary study on selected MS patients treated with natalizumab as first- or second line therapy was performed. Patients were regularly followed-up during the therapy at both clinical and molecular levels. Some patients, enrolled in this preliminary study, have been treated with interferon (IFN) or glatimer acetate (GA) before starting natalizumab. We evaluated the cellular and molecular expression of VLA4 receptor through flow-cytometry and Real Time PCR. We analyzed the level of superficial expression of VLA4, on CD4+ and CD8+ lymphocytes, after the withdrawal of the therapy with IFN and GA at different times up to the beginning of the new therapy with natalizumab. We found a different kinetic of CD49d reappearance on the cell surface that could be important to determine the individual rest period before the start with a new therapy with natalizumab. In all patients, natalizumab, as expected, produced a drastic saturation of CD49d on CD3+ lymphocytes. During therapy, sometime, it was found a small percentage of lymphocytes with completely unsaturated CD49d. These completely unsaturated cells seem to present also an increment of superficial expression of the receptor. On the other side, at the transcriptional level, natalizumab didn’t produce a noticeable modulation of CD49d transcription.