A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease
Wendy K Roberts1, Nathalie E Blachère1,2, Mayu O Frank1
1Laboratory of Molecular Neuro-oncology, Rockefeller University, New York, NY.
Annals of Neurology
|July 31, 2015
Summary
Treatment with FK506 (tacrolimus) reduced CXCL10 levels in the cerebrospinal fluid (CSF) of paraneoplastic neurologic disorder (PND) patients. This suggests targeting T cells or CXCL10 may help interrupt CNS inflammation.
Area of Science:
- Neuroimmunology
- Oncology
- Immunology
Background:
- Paraneoplastic neurologic disorders (PND) are autoimmune conditions linked to cancer.
- PND patients exhibit high-titer antibodies and T cells targeting tumor antigens.
- FK506 (tacrolimus) is an immunosuppressant known to reduce CSF white blood cell counts in PND.
Purpose of the Study:
- To investigate the impact of FK506 on cerebrospinal fluid (CSF) chemokine levels in PND patients.
- To understand the role of CXCL10 in PND pathogenesis.
Main Methods:
- Analyzed CSF samples from PND patients before and after FK506 treatment using a multiplex assay for 27 cytokines.
- Conducted in vitro experiments to assess T cell secretion of CXCL10 in response to cognate antigen.
Main Results:
- PND patients showed elevated levels of the chemokine CXCL10 in their CSF.
- FK506 treatment significantly decreased CSF CXCL10 levels among the 27 cytokines tested.
- In vitro, CXCL10 production by T cells required antigen-specific interactions and interferon-γ (IFNγ) receptor presence.
Conclusions:
- Results support a model where PND antigen-specific T cell activation leads to IFNγ production, followed by CXCL10 secretion and lymphocyte recruitment.
- Targeting T cells or CXCL10 in the central nervous system (CNS) may offer a therapeutic strategy to disrupt inflammatory feedback loops in PND.
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