Tysabri affects what the Immune response may see

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Warnke C, Mausberg AK, Stettner M, Dehmel T, Nekrich L, Meyer Zu Horste G, Hartung HP, Fogdell-Hahn A, Adams O, Kieseier BC.Natalizumab affects the T-cell receptor repertoire in patients with multiple sclerosis. Neurology. 2013 Sep 18. [Epub ahead of print]
OBJECTIVE: To assess changes in the T-cell receptor (TCR) repertoire in peripheral venous blood and CSF of patients with multiple sclerosis (MS) treated with natalizumab and the potential implication for developing progressive multifocal leukoencephalopathy (PML) and PML-immune reconstitution inflammatory syndrome (IRIS).METHODS:  The TCR repertoire in blood and CSF was assessed by complementarity determining region 3 spectratyping in 59 patients with MS treated with natalizumab for at least 18 months, 5 cases of natalizumab-associated PML, 17 age- and sex-matched patients with MS not treated with natalizumab, and 12 healthy controls.
RESULTS:Patients with MS presented with peripheral TCR repertoire expansions in blood, which appeared less prominent during therapy with natalizumab. TCR repertoire restrictions observed in CSF were most pronounced in patients with MS treated with natalizumab. In patients who developed PML with longitudinal samples available, new identical TCR receptor length expansions in blood and CSF were observed following plasma exchange, and preceded the development of IRIS.
CONCLUSIONS: Profound TCR repertoire restrictions in CSF of patients treated with natalizumab reflect an altered immune surveillance of the CNS, which may contribute to an increased risk of developing PML. Natalizumab seems to prompt an impaired or delayed peripheral expansion of antigen-specific T cells, whereas increased reconstitution of peripheral T-cell expansion following plasma exchange may trigger PML-IRIS. Our data suggest that treatment with natalizumab results in broader changes in the T-cell immune repertoire beyond lymphocyte migration.

Tysabri binds to α4 integrins expressed on lymphocytes and monocytes. It blocks the interaction of these integrins with their binding partners on vascular endothelial cells, and thereby prevents immune cells from entering inflamed tissues. 
Natalizumab is an effective treatment, but it carries the risk of progressive multifocal leukoencephalopathy (PML). 


This study looked  how Tysabri affects the T-cell receptor (TCR) repertoire of patients with multiple sclerosis (MS). This determines what the immune response recognises.. Their main observations were that 1) the TCR repertoire seems to “normalize” during natalizumab treatment, that is, revert to the state observed in healthy subjects, and 2) 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. In IRIS this would be expansions of T cells that can destroy the JC virus

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4 comments

    • No. PML is diagnosed using MRI and lumbar puncture. Most centres, including ours, will also check your blood tests before doing these tests. Your renal function needs to be normal or near normal to receive gadolinium as part of the MRI and your clotting profile needs to be normal before you have a lumbar puncture.

  • JC-PML-IRIS in western europe and north america is known for MS patients. In other regions of the world with endemic MTB infection is there a risk for other opportunistic infections causing IRIS in patients receiving natalizumab? Anything at ECTRIMS on PML-IRIS in these patients?

    • Unfortunately, not! You have to remember that JCV is not the only virus that affects the nervous system that cause problems in natalizumabers. The only way to deal with this is by increased vigilance. Don't ignore new symptoms; discuss them with your neurologist. If in doubt ask. If worried, discuss. Treating the complications of natalizumab treatment should be done earlier than later.

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