Wednesday, 28 November 2012

Research: JC virus responses & natalizumab

#MSBlog: Steroids reduce the immune response to the JC virus that causes PML. Therefore steroids should only be used to treat not prevent IRIS. 

#MSBlog: MSers with natalizumab-associated PML have a deficit in the cells that attack the JC virus.

"These two studies demonstrate that MSers with natalizumab-associated PML have a problem with the cells that attack the JC virus, the causes of PML. In addition, steroids that are often given to treat and/or prevent the inflammation that occurs when natalizumab is stopped or washed out blunts the cells ability to kill or destroy the cells infected with the virus. These studies provide some new insights into some of the immune function that is awry in MSers on natalizumab who develop PML. Can we use this information to test or furthe stratify the PML risk in individual MSers on Natalizumab? Maybe. Doing cellular tests like this are difficult to standardise. But they have been developed to help diagnose TB or tuberculosis. So may be we can do the same for PML?"

Epub
: Antoniol et al. Impairment of JCV-specific T-cell response by corticotherapy: Effect on PML-IRIS management? Neurology. 2012 Nov.

OBJECTIVE: To investigate the impact of corticosteroids (CS) on the viral-specific T-cell response, in particular the JC virus (JCV)-specific one, in an attempt to determine the optimal timing of CS in the management of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS).

METHODS: A blood draw was performed before and 7 days after the administration of IV CS to 24 RRMSers. The phenotypic pattern of T cells was determined by CCR7 and CD45RA. To assess the impact of CS treatment on proliferative response of JCV-, influenza-, and Epstein-Barr virus (EBV)-specific T cells, a thymidine incorporation proliferation assay was performed. An intracellular cytokine staining assay was performed to determine the effect of CS treatment on the production of cytokine by virus-specific T cells. JCV T-cell assays were performed only in JCV-infected MSers as detected by serologies (Stratify) or detection of JCV DNA in the urine by PCR.

RESULTS: CS led T cells, CD4+ and CD8+, toward a less differentiated phenotype. There was a significant decrease of EBV-, influenza-, and JCV-specific T-cell proliferative response upon CS treatment. There was a significant decrease in the frequency of interferon (IFN) γ- and tumor necrosis factor (TNF) α-producing JCV-specific CD8+ T cells, but not EBV- or influenza-specific CD4+ or CD8+ T cells.
CONCLUSIONS: CS have a profound impact on the virus-specific T-cell response, especially on JCV, suggesting that when CS are considered, they should not be given before the onset of clinical or radiologic signs of IRIS. Studies addressing directly patients with MS with natalizumab-caused PML are warranted.

CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that methylprednisolone treatment decreases the frequency of JCV specific CD8+ T cells producing IFN-γ and TNFα, impairing control of JCV, suggesting this should be used to treat but not to prevent PML-IRIS. No clinical outcomes were measured.




Epub: Perkins et al. Changes in JC Virus-Specific T Cell Responses during Natalizumab Treatment and in Natalizumab-Associated Progressive Multifocal Leukoencephalopathy.PLoS Pathog. 2012 Nov;8(11):e1003014. Epub 2012 Nov.

Background: Progressive multifocal leukoencephalopathy (PML) induced by JC virus (JCV) is a risk for natalizumab-treated MSers. 

Objectives: Here we characterize the JCV-specific T cell responses in healthy donors and natalizumab-treated MSers to reveal functional differences that may account for the development of natalizumab-associated PML. 

Results: CD4 and CD8 T cell responses specific for all JCV proteins were readily identified in MSers and healthy volunteers. The magnitude and quality of responses to JCV and cytomegalovirus (CMV) did not change from baseline through several months of natalizumab therapy. However, the frequency of T cells producing IL-10 upon mitogenic stimulation transiently increased after the first dose. In addition, MSers with natalizumab-associated PML were distinguished from all other subjects in that they either had no detectable JCV-specific T cell response or had JCV-specific CD4 T cell responses uniquely dominated by IL-10 production. Additionally, IL-10 levels were higher in the CSF of individuals with recently diagnosed PML. 

Conclusion: Thus, natalizumab-treated MSers with PML have absent or aberrant JCV-specific T cell responses compared with non-PML patients, and changes in T cell-mediated control of JCV replication may be a risk factor for developing PML. Our data suggest further approaches to improved monitoring, treatment and prevention of PML in natalizumab-treated MSers and other patients.

2 comments:

  1. In the news today--a Citizen's Petition to the FDA, asking them to refrain from approving any more MS treatments until they have been reviewed by advisory committees. The petition includes serious safety problems with Tysabri, Gilenya and other MS medications which were identified after they went to market, and cautions approval of BG 12. (Irony here, the petition was filed by Teva) http://freepdfhosting.com/efaf2ebf45.pdf

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    Replies
    1. We posted on this last friday and have posted on the link...read the letter from one of our "elephant in the room champions" me thinks

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