title: Novel IL27p28/IL12p40 cytokine suppressed experimental autoimmune uveitis by inhibiting autoreactive Th1/Th17 cells and promoting expansion of regulatory T cells.
abstract: IL-12 family cytokines are important in host immunity. Whereas some members (IL-12, IL-23) play crucial roles in pathogenesis of organ-specific autoimmune diseases by inducing the differentiation of Th1 and Th17 lymphocytes, others (IL-27 and IL-35) suppress inflammatory responses and limit tissue injury induced by these T cell subsets. In this study, we have genetically engineered a novel IL27p28/IL12p40 heterodimeric cytokine (p28/p40) that antagonizes signaling downstream of the gp130 receptor. We investigated whether p28/p40 can be used to ameliorate uveitis, a CNS inflammatory disease. Experimental autoimmune uveitis (EAU) is the mouse model of human uveitis and is mediated by Th1 and Th17 cells. We show here that p28/p40 suppressed EAU by inhibiting the differentiation and inflammatory responses of Th1 and Th17 cells while promoting expansion of IL-10(+)- and Foxp3(+)-expressing regulatory T cells. Lymph node cells from mice treated with p28/p40 blocked adoptive transfer of EAU to naïve syngeneic mice by immunopathogenic T cells and suppressive effects of p28/p40 derived in part from antagonizing STAT1 and STAT3 pathways induced by IL-27 and IL-6. Interestingly, IL27p28 also suppressed EAU, but to a lesser extent than p28/p40. The inhibition of uveitogenic lymphocyte proliferation and suppression of EAU by p28/p40 and IL27p28 establish efficacy of single chain and heterodimeric IL-12 family cytokines in treatment of a CNS autoimmune disease. Creation of the biologically active p28/p40 heterodimeric cytokine represents an important proof-of-concept experiment, suggesting that cytokines comprising unique IL-12 α- and β-subunit pairing may exist in nature and may constitute a new class of therapeutic cytokines.
authors.affiliation: Molecular Immunology Section, Laboratory of Immunology, NEI, National Institutes of Health, Bethesda, Maryland 20892-1857, USA.
authors.forename: Ren-Xi
authors.initials: RX
authors.lastname: Wang
authors.forename: Cheng-Rong
authors.initials: CR
authors.lastname: Yu
authors.forename: Rashid M
authors.initials: RM
authors.lastname: Mahdi
authors.forename: Charles E
authors.initials: CE
authors.lastname: Egwuagu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D014605:Uveitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: C486767:Il27 protein, mouse; C494200:Il6st protein, mouse; D053762:Interleukin-12 Subunit p40; D007378:Interleukins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130