JCV-specific cell-based assays for PML risk assessment in lupus and multiple sclerosis patients with and without
Qi Wu1,2, Elizabeth A Mills3, Qin Wang2
1Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, United States.
Background:
Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by the JC virus and often fatal. Natalizumab is a highly effective therapy for multiple sclerosis (MS) but is linked to a high incidence of PML. The current metrics used to stratify MS patients at risk for PML are incomplete, leading some patients to prematurely discontinue an effective treatment and others to develop PML despite perceived low risk.
Objective:
We sought to develop a combination of cell-based assays using peripheral blood which can be used to provide a more comprehensive assessment of immune system function and complement existing PML risk metrics.
Methods:
Our assays measure general and JCV specific responses in CD4+ and CD8+ T cells following antigen stimulation. We examined responses in systemic lupus erythematosus (SLE) and MS patients with and without PML. Our cytotoxicity index (CTI) measures expression of IFNγ and the degranulation marker CD107a on CD8+ T cells, while our OX40 immunity index (OII) measures CD4+ T cell activation, as determined by OX40 and CD25 co-expression.
Results And Conclusion:
We find that the combined metrics can be used to assess JCV immunocompetence, which can distinguish patients with and without PML, and could be used to predict and monitor PML patients from diagnosis onward to facilitate timely intervention.
Insights
New cell-based assays assess immune function to predict progressive multifocal leukoencephalopathy (PML) risk in multiple sclerosis (MS) patients. These assays can identify patients at risk for PML, enabling timely interventions.
Area of Science:
- Immunology
- Neurovirology
- Clinical Diagnostics
Background:
- Progressive multifocal leukoencephalopathy (PML) is a fatal opportunistic infection caused by the JC virus.
- Natalizumab, a multiple sclerosis (MS) therapy, increases PML incidence.
- Current PML risk stratification metrics are insufficient, leading to suboptimal patient management.
Purpose of the Study:
- Develop novel cell-based assays using peripheral blood for comprehensive immune assessment.
- Complement existing metrics for stratifying PML risk in MS patients.
- Improve prediction and monitoring of PML in at-risk individuals.
Main Methods:
- Assays measure JC virus (JCV)-specific T cell responses (CD4+ and CD8+).
- Cytotoxicity Index (CTI) quantifies CD8+ T cell degranulation and IFNγ production.
- OX40 Immunity Index (OII) assesses CD4+ T cell activation via OX40 and CD25 co-expression.
Main Results:
- Combined assay metrics effectively assess JCV immunocompetence.
- The assays distinguish between patients with and without PML.
- The metrics show potential for predicting and monitoring PML development.
Conclusions:
- Novel cell-based assays offer improved PML risk assessment in MS patients.
- These assays can aid in timely intervention for PML.
- Further application in predicting and monitoring PML is warranted.
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