A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

Abstract

ObjectiveParaneoplastic 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.MethodsCSF 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.ResultsHere 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.InterpretationThese 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. Ann Neurol 2015;78:619–629

Noninvasive profiling of serum cytokines in breast cancer patients and clinicopathological characteristics

“…8 Here we report a positive correlation between IP10 tumorderived mRNA expression and circulating serum levels. IP10 act as a chemo-attractant for monocytes 38,39 which may explain the herein reported positive correlation between IP10 and type M1 Macrophages. IP10 has been reported as a pro-tumorigenic chemokine.…”

Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines

“…Serendipity (two-for-one benefit) is not to be discounted. Tacrolimus (FK506), a calcineurin and IL-2 inhibitor, has been found to selectively decrease CSF CXCL10 in an exploratory study of paraneoplastic cerebellar degeneration with anti-Yo and anti-Hu antibodies ( 99 ). As CSF CXCL10 is also increased in pOMS and not reduced by conventional agents or steroid sparers ( 80 ), the effect may be relevant for OMS and other neurological paraneoplastic syndromes, too.…”

“…Various biopharmaceutical immunomodulators that target CKs or other cytokines have been tried, are in clinical trials, or have been U.S. Food and Drug Administration (FDA)-approved (Table 8 ) ( 26 , 99 , 179 , 200 – 229 ). Reference to trials in non-neurologic disorders, such as asthma, cancer, Crohn’s disease, HIV, psoriasis, and rheumatoid arthritis (RA), initially may seem off topic, but the treatment of those disorders has fueled trials in neuroinflammatory disorders.…”

IFN-γ is a therapeutic target in paraneoplastic cerebellar degeneration

“…This could be explained by the weak expression of CCR5 on T cells that infiltrated in the cerebellum of PCD mice and/ or by the redundancy in molecules important for T cell trafficking to the CNS. For instance, the levels of CXCL10, an IFN-γ-induced chemokine, are elevated in the CSF of PCD patients; therefore, the CXCL10/ CXCR3 axis may contribute to the trafficking of T cells into the cerebellum of PCD patients (36). Furthermore, cytotoxic T cells encountering their antigen and producing IFN-γ in the CNS may be responsible for the increased levels of CXCL10 in the CSF from patients with PCD (36).…”