Excessive Biologic Response to IFNβ Is Associated with Poor Treatment Response in Patients with Multiple Sclerosis 英文参考文献.docVIP

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Excessive Biologic Response to IFNβ Is Associated with Poor Treatment Response in Patients with Multiple Sclerosis 英文参考文献.doc

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Excessive Biologic Response to IFNβ Is Associated with Poor Treatment Response in Patients with Multiple Sclerosis 英文参考文献

ExcessiveBiologicResponsetoIFNbIsAssociatedwith PoorTreatmentResponseinPatientswithMultiple Sclerosis RichardA.Rudick1*.,M.R.SandhyaRani2,YaominXu3,Jar-ChiLee3,JieNa3,JenniferShrock2 ,Anupama Josyula2,ElizabethFisher4,RichardM.Ransohoff1,2. 1Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, United States of America, 2Department of Neurosciences, Neuroinflammation Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America, 3Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America, 4Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland,Ohio,UnitedStatesofAmerica Abstract Background:Interferon-beta(IFNb)isusedtoinhibitdiseaseactivityinmultiplesclerosis(MS),butitsmechanismsofaction areincompletelyunderstood,individualtreatmentresponsevaries,andbiologicalmarkerspredictingresponsetotreatment haveyettobeidentified. Methods:TherelationshipbetweenthemolecularresponsetoIFNbandtreatmentresponsewasdeterminedin85patients using a longitudinal design in which treatment effect was categorized by brain magnetic resonance imaging as good (n=70)orpoorresponse(n=15).MolecularresponsewasquantifiedusingacustomizedcDNAmacroarrayassayfor166 IFN-regulatedgenes(IRGs). Results: Themolecularresponse toIFNbdifferedsignificantlybetween patientsin thepatternandnumberofregulated genes. The molecular response was strikingly stable for individuals for as long as 24 months, however, suggesting an individual ‘IFN response fingerprint’. Unexpectedly, patients with poor response showed an exaggerated molecular response. IRG induction ratios demonstrated an exaggerated molecular response at both the first and 6-month IFNb injections. Conclusion: MS patients exhibit individually unique but temporally stable biological responses to IFNb. Poor treatment responseisnotexplainedbythedurationofbiologicaleffectsorthesp