Role of IL-12 family cytokines in human autoimmune Uveitis

National Eye Institute

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Abstract

IL-12 family cytokines are important in host immunity. 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, while 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: (i) Recombinant heterodimeric IL-35; (i) Recombinant heterodimeric IL-27; Novel recombinant IL27p28/IL12p40 heterodimeric cytokine (p28/p40); (i) Recombinant single chain mouse IL12p35; (i) Recombinant single chain mouse IL12p40; (i) Recombinant single chain mouse IL27p28; (i) Recombinant single chain mouse Ebi3. We continue to investigate whether each of these recombinant heterodimeric or single chain cytokines can be used to treat uveitis, a CNS inflammatory disease. Thus, far we have shown that IL-35, IL-27 and IL27p28/IL12p40 are effective in ameliorating EAU while p35, Ebi3 were found to inhibit lymphocyte proliferation. We have identified a unique regulatory B cell (Breg) population that secretes IL-10 and IL-35. These Breg cells called i35-Bregs play critical roles in regulating immunity during autoimmune and infectious diseases. We have shown that IL-35 induces Bregs in vivo and promotes the conversion of activated B cells to i35-Bregs. Treatment of mice with IL-35 conferred protection from autoimmune uveitis and mice that lack i35-Bregs or defective in IL-35-signaling pathway developed severe uveitis. Ex-vivo generated i35-Bregs suppressed uveitis by inhibiting pathogenic Th17/Th1 cells while promoting Tregs expansion. Our discovery that IL-35 induces conversion of B-cells into Bregs, allows ex-vivo production of autologous Bregs for immunotherapy and investigating the roles of Bregs/i35-Bregs in autoimmune diseases and cancer.