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Editorial |

Central Nervous System Immune Surveillance On Natalizumab, Dendritic Cells, and Dangerous Immune Privilege

Burkhard Becher, PhD
Arch Neurol. 2008;65(12):1566-1567. doi:10.1001/archneur.65.12.1566.
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Multiple sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS), leading to progressive neurological deficit.1 While most diseases of the CNS display some degree of inflammation involving CNS-resident innate immune cells (ie, microglia), MS is characterized by the invasion of adaptive immune cells (ie, lymphocytes) into the CNS parenchyma. It is now widely held that MS is an autoimmune disease in which encephalitogenic myelin-reactive T lymphocytes invade the neuropil and initiate an inflammatory cascade leading to demyelination and axonal loss. Current therapies for MS include immunomodulatory drugs such as glatiramer acetate or interferon β, and while some degree of alleviation can be achieved this way, we are still far away from a satisfactory therapeutic effect.2 Rather than nonspecifically modulating immunity, an ideal therapeutic strategy would be to specifically inhibit autoimmunity while preserving the immune system's protective function against microbes and environmental hazards. One such specific approach would be to prevent inflammatory lymphocytes from entering the CNS by preventing their transmigration across the blood-brain barrier (BBB). Transmigration across endothelial barriers (diapedesis) involves changes in the expression of adhesion molecules on both blood vessels and leukocytes (for review, see the article by Muller3). In 1992, Yednock et al4 discovered that antibodies against α4β1 integrin (also known as very late activation antigen 4 [VLA-4]) can block the development of experimental autoimmune encephalomyelitis in mice. VLA-4 is upregulated on inflammatory effector cells and binds to its ligand vascular cell adhesion molecule 1, which is expressed by vascular endothelial cells. Under the assumption that the therapeutic intervention in mice specifically inhibited the transmigration of pathogenic T cells across the endothelial barrier, in the years after this discovery, a human anti–VLA-4 monoclonal antibody, natalizumab (Tysabri; Elan Pharmaceuticals Inc, Dublin, Ireland), was generated and patients with Crohn disease and MS were treated. While clinical trials showed a drastic reduction in the relapse rate in MS, 3 of 3000 patients developed lethal progressive multifocal leukoencephalopathy (PML). The manufacturer swiftly reacted and the drug was taken off the market pending further investigation. Why did that happen? What went wrong?

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