Abstract
BackgroundThe use of natalizumab in multiple sclerosis (MS) may favour JC virus reactivation; this phenomenon is usually asymptomatic but can, albeit rarely, evolve into frank progressive multifocal leucoencephalopathy (PML).MethodsJCV-specific CD8+ T lymphocytes were evaluated by flow cytometry over a 24-month period in 24 natalizumab-treated MS patients in whom JCV DNA was or was not detected in blood using quantitative real-time polymerase chain reaction; all these cases were asymptomatic.ResultsPerforin- and grazymes-containing VP-1-specific CD8+ T lymphocytes were reduced whereas CD107a-expressing cells were increased in JCV positive patients, suggesting an active degranulation of these cells; naïve CD8+ T lymphocytes were also decreased whereas memory cells were increased in patients in whom JCV reactivation was observed.ConclusionThe presence of a CD8+ T lymphocyte-mediated effector immune response offers a greater insight into reactivation of JCV and its clinical sequelae, and may help the monitoring of patients on natalizumab therapy.
Highlights
The use of natalizumab in multiple sclerosis (MS) may favour JC virus reactivation; this phenomenon is usually asymptomatic but can, albeit rarely, evolve into frank progressive multifocal leucoencephalopathy (PML)
These results notwithstanding, a worrisome possible adverse effect of natalizumab is the development of progressive multifocal leucoencephalopathy (PML); recent results reported more than 200 cases of PML in natalizumab patients, with an overall incidence (1.01/1000 patients) with the greatest increase in risk occurring after 2 years of therapy [2]
That virus replication occurred in a subset of natalizumab-treated patients is further confirmed by the observation that a differentiation from naïve toward effector phenotypes of VP-1-specific CD8+ T lymphocytes was observed in such patients. Taken together these results indicate that the appearance of JC virus (JCV) DNA in blood of natalizumab treated MS patients is an event associated with the differentiation of virus-specific cells and the elicitation of a CD8+ T lymphocyte-mediated immune effector response
Summary
The use of natalizumab in multiple sclerosis (MS) may favour JC virus reactivation; this phenomenon is usually asymptomatic but can, albeit rarely, evolve into frank progressive multifocal leucoencephalopathy (PML). Results of longitudinal studies confirmed the efficacy of such treatment, as the annual relapse rate evaluated after 1 year was reduced by 68% whereas the disability progression over 2 years was diminished by 42% in natalizumab–treated compared to placebo patients [1]. These results notwithstanding, a worrisome possible adverse effect of natalizumab is the development of progressive multifocal leucoencephalopathy (PML); recent results reported more than 200 cases of PML in natalizumab patients, with an overall incidence (1.01/1000 patients) with the greatest increase in risk occurring after 2 years of therapy [2]. In the attempt to bypass this problem, a new assay (Viral-like particles – ELISA) was suggested to be a sensitive tool to identify patients at a reduced risk of PML development [12]; complementary tests of JCV DNA in urine were indicated as being useful for the stratification of risk of PML in patients [13], as the detection of urinary viral DNA identifies JCV infected subject when antibody are still undetectable
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