Reply to “‘Thinking without thinking’ about natalizumab and PML”

JC Polyomavirus (JCV) and Monoclonal Antibodies: Friends or Potential Foes?

“…To date, three main molecular mechanisms have been proposed. According to some authors, the blockage of VLA-4 by natalizumab may prevent the entry of JCV-specific cytotoxic T cells into the brain, necessary for the control of latent JCV within infected oligodendrocytes (the viral life cycle will be better explained in what follows) [20]. Another proposed possibility is that natalizumab may inhibit the VLA-4-dependent retention of lymphocytes in bone marrow and spleen (both sites of JCV latency), thus leading to an increase of JCV-infected peripheral leukocytes and to a possible increase of the peripheral JC viral load capable of crossing the BBB (this late aspect has not been confirmed, to date) [21].…”

Review: Natalizumab in the treatment of multiple sclerosis

“…This mechanism leads to an increase of peripheral leukocytes and possibly also to an increase of JC viral load. Retrospective analyses of 214 serum samples collected during the treatment with natalizumab showed detectable JCV DNA in only 2.3% of patients, which is not outside of the expected range in healthy individuals [Major et al 2005], but assaying blood plasma may underestimate the JCV viral load [Houff and Berger, 2008]. However, the presence of JCV DNA in the blood of MS patients on interferon-beta treatment did not seem to be a risk factor for PML [Delbue et al 2007].…”

“…The pathogenesis of PML in patients receiving natalizumab is complex and not fully understood. The issue of PML in patients with monoclonal antibodies is not restricted to natalizumab [Houff and Berger, 2008;Martin et al 2006;Uppenkamp et al 2002]. PML occurred in association with rituximab, a monoclonal antibody which induces B-cell depletion and efalizumab in a patient with psoriasis [Crowder et al 2005;Shitrit et al 2005].…”

“…First symptoms of PML occurred after a further five infusions of natalizumab. Houff and Berger [2008] postulated that by blocking VLA-4, natalizumab may prevent the entry of JCV-specific cytotoxic T cells into the brain, necessary for the control of latent JCV infection.…”