The IL-12 family cytokines have emerged as an important group of cytokines that regulate many critical aspects of host immunity, including antigen presentation, T cell lineage commitment and cytokine signaling. IL-12 family cytokines are comprised of heterodimeric protein subunits. Unique combinations of subunits can form through covalent and non-covalent binding and these include IL-12 (IL12p40 &IL12p35), IL-23 (IL12p40 and IL23p19), IL-27 (IL27p28 &EBI3 and a novel pairing between IL12p35 and EBI3 now constitutes the newly described member, IL-35. Individual subunits (e.g. IL27p28) have also been shown to have intrinsic biological activities. Our research goal has been to generate various combinations of IL-12 cytokine family subunit chains as basis for a new class of therapeutic cytokines. In this regard we have genetically engineered novel IL-12-like cytokines by pairing IL12p40 to IL27p28 and EBI3 to IL23p19 and are now defining their potential biological activities on lymphocytes and ocular cells. Specifically, we intend to use these reagents to test each subunit and various subunit combination in T cell assays to determine if they exhibit any useful biological activities and eventually, to explore their use in treating ocular diseases. We show for the first time that IL-35 induces Bregs in vivo and promotes the conversion of Bregs to a unique Breg subset that produces IL-35 (i35-Breg). Treatment of mice with IL-35 conferred protection from autoimmune uveitis and mice that lack IL-35 or are defective in IL-35-signaling developed severe uveitis because they produced less Bregs. Ex-vivo generated Bregs also suppressed uveitis by inhibiting pathogenic Th17/Th1 cells while promoting Tregs expansion. IL-35 also induced the conversion of human B-cells into Bregs, suggesting that this function of IL-35 is evolutionarily conserved between humans and mice. We further show that IL-35 induced Bregs/i35-Bregs and suppressed uveitis by activating STAT1 and STAT3 through IL-35-Receptor comprising IL-12Rβ2/IL-27Rαsubunits. Our discovery that IL-35 induces conversion of both human and mouse 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.

National Institute of Health (NIH)
National Eye Institute (NEI)
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U.S. National Eye Institute
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Dambuza, Ivy M; He, Chang; Choi, Jin Kyeong et al. (2017) IL-12p35 induces expansion of IL-10 and IL-35-expressing regulatory B cells and ameliorates autoimmune disease. Nat Commun 8:719
Choi, Jin Kyeong; Dambuza, Ivy M; He, Chang et al. (2017) IL-12p35 Inhibits Neuroinflammation and Ameliorates Autoimmune Encephalomyelitis. Front Immunol 8:1258
He, Chang; Yu, Cheng-Rong; Mattapallil, Mary J et al. (2016) SOCS1 Mimetic Peptide Suppresses Chronic Intraocular Inflammatory Disease (Uveitis). Mediators Inflamm 2016:2939370
Wang, Xiaoqian; Wei, Yinxiang; Xiao, He et al. (2016) Pre-existing CD19-independent GL7(-) Breg cells are expanded during inflammation and in mice with lupus-like disease. Mol Immunol 71:54-63
Wang, Xiaoqian; Wei, Yinxiang; Xiao, He et al. (2016) A novel IL-23p19/Ebi3 (IL-39) cytokine mediates inflammation in Lupus-like mice. Eur J Immunol 46:1343-50
Egwuagu, C E; Sun, L; Kim, S-H et al. (2015) Ocular Inflammatory Diseases: Molecular Pathogenesis and Immunotherapy. Curr Mol Med 15:517-28
He, Chang; Yu, Cheng-Rong; Sun, Lin et al. (2015) Topical administration of a suppressor of cytokine signaling-1 (SOCS1) mimetic peptide inhibits ocular inflammation and mitigates ocular pathology during mouse uveitis. J Autoimmun 62:31-8
Yu, Cheng-Rong; Hayashi, Kozaburo; Lee, Yun Sang et al. (2015) Suppressor of cytokine signaling 1 (SOCS1) mitigates anterior uveitis and confers protection against ocular HSV-1 infection. Inflammation 38:555-65
Egwuagu, Charles E; Yu, Cheng-Rong; Sun, Lin et al. (2015) Interleukin 35: Critical regulator of immunity and lymphocyte-mediated diseases. Cytokine Growth Factor Rev 26:587-93
Egwuagu, Charles E; Yu, Cheng-Rong (2015) Interleukin 35-Producing B Cells (i35-Breg): A New Mediator of Regulatory B-Cell Functions in CNS Autoimmune Diseases. Crit Rev Immunol 35:49-57

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