α4-Integrin antagonism with natalizumab: EEEffects and adverse effects

Based on the results of two phase III clinical trials, the humanized recombinant monoclonal antibody natalizumab was approved for the treatment of relapsing forms of multiple sclerosis (MS). Since its initial approval in November 2004, it has been announced that six patients who received natalizumab in the context of clinical studies acquired an infection with the human polyoma virus JC and were diagnosed with progressive multifocal leukoencephalopathy (PML). Two of these individuals had a fatal outcome. Our groups recently showed that natalizumab therapy results in a reduction of CD4⁺ T cells within the cerebrospinal fluid (CSF) that is ten-fold more pronounced than the reduction in the number of CD8⁺ T lymphocytes. Interestingly, it appears that the effect of natalizumab on cell numbers in the CSF persists for at least 6 months after cessation of treatment. More recently, we studied the expression of major histocompatibility complex (MHC) I and II, and the number and phenotypes of leukocytes in cerebral perivascular spaces (CPVS). We observed that natalizumab therapy was associated with a significant decrease in the cell surface expression of MHC class II molecules, and the numbers of dendritic cells in CPVS. In addition, no CD4⁺ T cells were detectable in this compartment. Our observations may explain the differential and prolonged effects of natalizumab therapy on different leukocyte subsets in the central nervous system. They also suggest that natalizumab treatment may result in prolonged immunosuppression in peripheral organs, and the delayed onset of adverse events.