“Thinking without thinking” about natalizumab and PML

  title={“Thinking without thinking” about natalizumab and PML},
  author={Richard M. Ransohoff},
  journal={Journal of the Neurological Sciences},
  • R. Ransohoff
  • Published 15 August 2007
  • Psychology, Medicine
  • Journal of the Neurological Sciences

Early relapses after the first dose of natalizumab in active multiple sclerosis patients

It is speculated that natalizumab can promote the release of inflammatory mediators from lymphocytes present in the central nervous system at the time of the first infusion, thus favoring the clinical manifestation of a pre-existing active lesion in patients with MS.

Update on PML: Lessons from the HIV uninfected and new insights in pathogenesis and treatment

Recent advances in understanding of PML in HIV-uninfected patients in oncology, rheumatology, organ transplantation, and idiopathic immune deficiency and in association with novel therapeutics are summarized.

A bird's-eye view of T cells during natalizumab therapy

The main observations are that the TCR repertoire seems to “normalize” during natalizumab treatment, that is, revert to the state observed in healthy subjects, and the onset of PML and immune reconstitution inflammatory syndrome (IRIS) is accompanied or preceded by the appearance of distinct clonal T-cell expansions in blood or CSF.

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

The need for PML risk stratification among natalizumab-treated patients and the need of effective therapeutic options are discussed under the light of the major viral models of PML etiopathogenesis.

Progressive multifocal leukoencephalopathy and other forms of JC virus disease

The controversies surrounding JCV infection are critically appraised, the practical management guidelines for PML are provided, and reconstitution of the immune system affords the best prognosis for this condition.

Natalizumab treatment perturbs memory‐ and marginal zone‐like B‐cell homing in secondary lymphoid organs in multiple sclerosis

The ability of natalizumab to influence B‐cell migration and homeostasis through the splenic MZ, where JCV has been detected, adds to the list of nalozumab effects and may contribute to PML development by disseminating JCV.

Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis

Circulating B cells and especially pre-B cells are most prominently elevated among the studied immune cell subsets, raising the possibility that the effects and side effects of natalizumab are partly mediated by actions on B cells.

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

The study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies.



Progressive multifocal leukoencephalopathy and natalizumab--unforeseen consequences.

Three patients in whom progressive multifocal leukoencephalopathy (PML) developed during treatment with natalizumab, a humanized monoclonal antibody against α4 integrins are described.

Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease.

Analysis of frozen serum samples showed that JC virus DNA had appeared in the serum three months after the initiation of open-label natalizumab monotherapy and two months before the appearance of symptomatic PML, suggesting that anti-alpha4-integrin therapy can result in JC virus-induced PML.

Natalizumab and PML

It is proposed that natalizumab treatment led to PML by mobilizing infected bone marrow cells, possibly in combination with reduced inflammatory and surveillance trafficking to the CNS, and if this hypothesis is correct, agents that do not affect bone marrow will lack this complication, whereas those affecting bone marrow and lymphoid organs require caution and surveillance.

Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab

  • L. Steinman
  • Medicine, Psychology
    Nature Reviews Drug Discovery
  • 2005
Three months after its expedited approval by the FDA, natalizumab was removed from the market after two cases of deadly progressive multifocal leukoencephalopathy were reported among the few thousand patients who had taken this drug in those clinical trials.

Immune surveillance in multiple sclerosis patients treated with natalizumab

Whether natalizumab, an antibody against very late activating antigen (VLA)‐4, interferes with central nervous system immune surveillance as assessed by leukocyte cell numbers and cellular phenotypes in cerebrospinal fluid (CSF) and peripheral blood is tested.

Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis.

Natalizumab therapy decreased the CSF CD4(+)/CD8(+) ratio of patients with MS to levels similar to those of human immunodeficiency virus-infected patients, which may have implications for the observation that some natalizUMab-treated Patients with MS developed progressive multifocal leukoencephalopathy.

Traffic of JC virus from sites of initial infection to the brain: the path to progressive multifocal leukoencephalopathy.

Results from investigations into cell-surface receptors, intracellular DNA-binding proteins, and variant viral regulatory regions suggest mechanisms that may regulate cellular susceptibility to JCV infection and elucidate how JCV may establish infection in various cell types, persist latently or become reactivated, and ultimately reach the brain to cause PML.

Viral variant nucleotide sequences help expose leukocytic positioning in the JC virus pathway to the CNS

In most literature, a dichotomy of the JCV regulatory region structure exists by tissue, but B lymphocytes have demonstrated the capacity to harbor JCV of diverse regulatory regions, which helps position their interaction with virus amid every stage of infection and implicates a lymphocytic role in latency.