Natalizumab in Multiple Sclerosis Treatment: From Biological Effects to Immune Monitoring

Abstract

Multiple sclerosis is a chronic demyelinating disease of the central nervous system (CNS) with an autoimmune component. Among the recent disease-modifying treatments available, Natalizumab, a monoclonal antibody directed against the alpha chain of the VLA-4 integrin (CD49d), is a potent inhibitor of cell migration toward the tissues including CNS. It potently reduces relapses and active brain lesions in the relapsing remitting form of the disease. However, it has also been associated with a severe infectious complication, the progressive multifocal leukoencephalitis (PML). Using the standard protocol with an injection every 4 weeks it has been shown by a close monitoring of the drug that trough levels soon reach a plateau with an almost saturation of the target cell receptor as well as a down modulation of this receptor. In this review, mechanisms of action involved in therapeutic efficacy as well as in PML risk will be discussed. Furthermore the interest of a biological monitoring that may be helpful to rapidly adapt treatment is presented. Indeed, development of anti-NAT antibodies, although sometimes unapparent, can be detected indirectly by normalization of CD49d expression on circulating mononuclear cells and might require to switch to another drug. On the other hand a stable modulation of CD49d expression might be useful to follow the circulating NAT levels and apply an extended interval dose scheme that could contribute to limiting the risk of PML.

Transcranial Magnetic Stimulation Improves Muscle Involvement in Experimental Autoimmune Encephalomyelitis

“…While the effect of TMS on skeletal muscle may be related to the activation induced in the central and peripheral nervous systems [23], NTZ works by selectively blocking the alpha chain of the VLA-4 integrin, which inhibits leukocyte migration across the blood-brain barrier [20]. Interestingly, as pointed out by Soellner et al [24], in the PLP-139-151-induced EAE model, axonal pathology but not the inflammatory myelin pathology increases with disease progression.…”

“…All the above suggests that TMS could have a myoprotective effect in patients with MS. To verify this hypothesis, we analyzed the effects of TMS on muscle involvement in the EAE model in terms of histological morphology and the expression of oxidative stress markers. For comparative purposes, we also analyzed the effects of natalizumab (NTZ) in this model as one of the current treatments for MS [20]. To the best of our knowledge, this is the first time the effects of TMS and NTZ on skeletal muscle in the EAE model have been studied.…”

IL-15 Is Overexpressed in γδ T Cells and Correlates with Disease Severity in Relapsing-Remitting Multiple Sclerosis

“…Moreover, not all patients are treatment free, thus complicating the image. In fact the majority of patients in the current study were treated with natalizumab, which is known for significantly altering the lymphocyte count (most significantly rising the number of B and NK cells, to a lesser extent T cells); fortunately, the CD4/CD8 ratio is preserved, suggesting that natalizumab-driven accumulation of lymphocytes is uniform for all T subsets [ 29 ]. Finally, we have used unconventional markers for T memory cells—CD44.…”

Can Novel Insights into the Pathogenesis of Myeloproliferative Neoplasm-Related Thrombosis Inform Novel Treatment Approaches?

“…Antibodies to block leukocyte integrin interactions are already in use in clinics to modulate inflammatory responses in various disease states. For example, natalizumab, a monoclonal antibody directed against the alpha chain of the VLA-4 integrin is used to treat multiple sclerosis [187] and Crohn's disease [188]. A humanized CD11a blocking antibody, Efalizumab, was developed to inhibit LFA-1 and was used to treat psoriasis [189] but was later withdrawn from the market due to reports of JC virus reactivation associated with this drug [190,191].…”