title: A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease.
abstract: OBJECTIVE
  Paraneoplastic neurologic disorders (PND) are autoimmune diseases associated with cancer and ectopic expression of a neuronal antigen in a peripheral tumor. Patients with PND harbor high-titer antibodies and T cells in their serum and cerebrospinal fluid (CSF) that are specific to the tumor antigen, and treatment with the immunosuppressant FK506 (tacrolimus) decreases CSF white blood cell counts. The objective of this study was to determine the effect of FK506 on CSF chemokine levels in PND patients.
  
  
  METHODS
  CSF samples before and after FK506 treatment were tested by multiplex assay for the presence of 27 cytokines. Follow-up in vitro experiments aimed to determine whether T cells secrete CXCL10 in response to cognate antigen.
  
  
  RESULTS
  Here we report that PND patients harbor high levels of the chemokine CXCL10 in their CSF. CXCL10 is a cytokine that recruits CXCR3(+) cells such as activated T cells, and we found that FK506 treatment specifically decreased CSF CXCL10 from among 27 cytokines tested. In vitro, CXCL10 was only produced during antigen-specific cognate interactions between T cells and antigen-presenting cells (APCs) when interferon-γ (IFNγ) receptors were present on the T cell.
  
  
  CONCLUSIONS
  These results support a model in which antigen-specific T cell stimulation by PND APCs triggers IFNγ, followed by CXCL10 production and further lymphocyte recruitment, suggesting that treatments targeting T cells or CXCL10 in the central nervous system (CNS) may interrupt a destructive positive feedback loop present in CNS inflammation.
authors.affiliation: Laboratory of Molecular Neuro-oncology, Rockefeller University, New York, NY.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Roberts
authors.affiliation: Laboratory of Molecular Neuro-oncology, Rockefeller University, New York, NY.|Howard Hughes Medical Institute, Rockefeller University, New York, NY.
authors.forename: Nathalie E
authors.initials: NE
authors.lastname: Blachère
authors.affiliation: Laboratory of Molecular Neuro-oncology, Rockefeller University, New York, NY.
authors.forename: Mayu O
authors.initials: MO
authors.lastname: Frank
authors.affiliation: Neurological Institute, Columbia University Medical Center, New York, NY.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Dousmanis
authors.affiliation: Cleveland Clinic, Cleveland, OH.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.affiliation: Laboratory of Molecular Neuro-oncology, Rockefeller University, New York, NY.|Howard Hughes Medical Institute, Rockefeller University, New York, NY.|New York Genome Center, New York, NY.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Darnell
mesh_terms: D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002493:Central Nervous System Diseases / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000188:drug therapy; D054357:Chemokine CXCL10 / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000502:physiology*; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000188:drug therapy; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D020361:Paraneoplastic Syndromes, Nervous System / Q000134:cerebrospinal fluid* / Q000175:diagnosis* / Q000188:drug therapy; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D016559:Tacrolimus