Inflammation /Progressive Multifocal Leukoencephalopathy

$100,800R01FY2006NSNIH

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Linked publications & trials

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Abstract

DESCRIPTION (provided by applicant): A controversy exists regarding the role of inflammation in PML. It has been suggested that an inflammatory reaction, demonstrated by contrast-enhancement of the CNS lesions on MRI or by lymphoplasmocytic infiltrates on brain biopsy may be beneficial in PML. This inflammatory reaction may be mediated by CD8+ cytotoxic T lymphocytes (CTL) that are specific for JCV. When detectable in the blood of PML patients, this cellular immune response is also associated with a favorable outcome. Recently however, cases of PML have been shown to develop in HIV+ patients shortly after introduction of HAART, in the context of inflammation associated with an immune reconstitution syndrome. Whether inflammation is harmful or beneficial in PML and if it should be treated with steroids is therefore not settled and has immediate clinical implications for the patients. We hypothesize that PML patients who have evidence of an inflammatory reaction on MRI/1H-MRS or on brain biopsy are able to mount a vigorous cellular immune response against JCV in their blood and CSF. They will develop smaller lesions and have a better clinical outcome. They will also be able to suppress JCV replication in their CSF, and control the emergence of more virulent isolates. Specifically, we will: 1) evaluate the inflammatory component and metabolism in PML lesions with contrast-enhanced MRI and 1H-MRS, and correlate these findings with the cellular immune response against JCV in the patient's blood and CSF. 2) characterize the inflammatory infiltrates in PML lesions of those patients who undergo brain biopsy and analyze the topographic distribution of CD8+ T lymphocytes with regard to JCV-infected cells 3) quantify JCV CSF viral load of PML patients by qPCR to study the evolution of JCV replication in the presence or absence of inflammatory reaction. 4) analyze the sequence of JCV regulatory region (RR) in CSF of PML patients to assess the effect of JCV-specific cellular immunity on the emergence of JCV RR mutations and rearrangements 5) correlate MRI/1H-MRS, histological, immunological and virological parameters over time with lesion volume, neurological deficit and clinical outcome of the PML patients.

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