Multiple sclerosis (MS), a central nervous system (CNS) inflammatory demyelinating disease, is a leading cause of disability in the young adult population. While dramatic progress has been made in our understanding of the disease pathogenesis, the initial disease-triggering events remain poorly understood. Since immunomodulatory therapies are most effective when administered early in the courseofthedisease,weareseekingbiomarkersoftheclinicallyisolatedsyndrome(CIS)suggestive ofMS,theearliestphaseofthedisease.OurpreliminarystudieshaveidentifiedIL-11,anewTh17 cell-polarizing cytokine, as the most significantly increased cytokine in the serum and cerebrospinal fluid (CSF) of CIS patients, whose serum levels are increased during clinical exacerbations of the disease. CD4+ cells are the main source of IL-11 in the peripheral circulation. The percentage of IL- 11+CD4+ cells is increased in the peripheral circulation of CIS patients in comparison to matched healthycontrols(HCs),andtheysignificantlyaccumulateintheCSFandtheactivebrainMSlesionsin comparisontomatchedbloodsamples.AnimalstudieshaveconfirmedthecausalroleofIL-11inthe exacerbation of relapsing remitting (RR) experimental autoimmune encephalomyelitis (EAE), since IL- 11administrationworsenedclinicalcourseandinducedincreasednumbersofIL-17A+CD4+cellsinthe central nervous system (CNS) inflammatory infiltrates. Our central hypothesis is that IL-11 induces CD4+cellmigratorycapacityandencephalitogenicity,mediatedviaup-regulationofCCR6,ICAM-1and VLA-4,whichmediateCD4+cellstrans-endothelialmigration.WeproposethatIL-11+CD4+cells,which are also expanded in the presence of IL-11, may represent a pathogenic cell subset, whose transcriptionalprofilingandTcellreceptor(TCR)Vb?repertoirewillelucidatetheirfunctionandantigen specificity. a?IL-11R mAb treatment of RRAEA will provide pre-clinical data and identify markers of therapeuticeffectforthisnewtherapeuticapproach.Theobjectiveofthisstudyis(1)toidentifythe molecular mechanisms involved in IL-11-induced migration of CD4+ cell subsets to the CNS in CIS patients, (2) to characterize the phenotype, transcriptional profile and TCRVb? repertoire of CSF- enriched IL-11+CD4+ cells in CIS patients, and (3) to examine the potential of IL-11 to induce encephalitogenicCD4+cellscapableofpassivelytransferringdisease,andtodeterminethetherapeutic effectofa?IL-11RmAbinRREAE,ananimalmodelofthedisease.Theresultsareexpectedtoprovide biomarkers of early autoimmune response in CIS patients and to identify selective therapeutic targets forthisdisablingdisease.
This study will characterize the role of IL-11 in the pathogenesis of relapsing remitting multiplesclerosis(MS).BasedonourpreliminaryresultsontheincreasedIL-11serum andcerebrospinalfluidlevelsinpatientswiththeearliestclinicalpresentationofMS,and causalroleofIL-11inexacerbatingexperimentalautoimmuneencephalomyelitis(EAE), ourstudieswillcharacterizethecapacityofIL-11toinduceencephalitogenicCD4+cells. IL-11+CD4+ cells are enriched in the cerebrospinal fluid and MS brain lesions. We will characterizetheirtranscriptomeandTCRVb?repertoire.Therapeuticpotentialofanti-IL- 11RmAbwillbetestedinpreclinicalEAEmodel.
