Frequent detection of IFN-gamma -producing memory effector and effector T cells in patients with progressive...

Area of Science:

• Neuroimmunology
• Virology
• Immunodiagnostics

Background:

• Progressive Multifocal Leukoencephalopathy (PML) is a rare, fatal demyelinating disease caused by JC virus (JCV) replication in the central nervous system.
• PML predominantly affects individuals with severe immune deficiencies, such as AIDS and hematological malignancies.
• The emergence of PML in patients receiving potent immunosuppressive biologics, like natalizumab for multiple sclerosis, highlights the need for risk stratification.

Purpose of the Study:

• To develop and validate an Interferon-gamma (IFN-γ) release assay (IGRA) for detecting JC virus (JCV)-specific T cell responses.
• To assess the utility of this IGRA in identifying patients with active PML and those at increased risk.

Main Methods:

• Development of an IGRA designed to detect JCV-specific effector memory T cells and effector T cells in peripheral blood.
• Evaluation of assay sensitivity and specificity in patients with confirmed PML and in healthy donors.
• Assessment of assay positivity rates in multiple sclerosis patients undergoing natalizumab treatment over time.

Main Results:

• The developed IGRA demonstrated high sensitivity (84%) in patients with active PML across various immunosuppression etiologies.
• The assay exhibited high specificity (97%), with only 3% of healthy donors testing positive.
• Assay positivity increased with prolonged natalizumab treatment duration in multiple sclerosis patients, reaching up to 36% in those treated for over 48 months, correlating with higher PML risk.

Conclusions:

• The JCV-specific IGRA is a sensitive and specific tool for detecting T cell responses in patients with PML.
• The assay's increased positivity in patients at higher risk of PML suggests its potential utility in risk stratification for this devastating opportunistic infection.
• This diagnostic approach may aid in managing patients on immunosuppressive therapies by identifying individuals who could benefit from closer monitoring or alternative treatment strategies.