Role of IL-12 family cytokines in human autoimmune Uveitis

Egwuagu, Charles E.

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 (human &mouse);(i) Recombinant heterodimeric IL-27 (human &mouse);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 investigated 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. Taken together these important proof-of-concept studies, suggest that cytokines comprising of unique IL-12 αand βsubunits pairing may exist in nature and may constitute a new class of therapeutic cytokines.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Eye Institute (NEI)
• Type: Investigator-Initiated Intramural Research Projects (ZIA)
• Project #: 1ZIAEY000262-18
• Application #: 8737609
• Support Year: 18
• Fiscal Year: 2013
• Total Cost: $260,031

Institution

• Name: U.S. National Eye Institute

Publications

Yu, Cheng-Rong; Choi, Jin Kyeong; Uche, Anita N et al. (2018) Production of IL-35 by Bregs is mediated through binding of BATF-IRF-4-IRF-8 complex to il12a and ebi3 promoter elements. J Leukoc Biol 104:1147-1157

Choi, Jin Kyeong; Dambuza, Ivy M; He, Chang et al. (2017) IL-12p35 Inhibits Neuroinflammation and Ameliorates Autoimmune Encephalomyelitis. Front Immunol 8:1258

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

Sun, Lin; He, Chang; Nair, Lekha et al. (2015) Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease. Cytokine 75:249-55

Egwuagu, C E; Sun, L; Kim, S-H et al. (2015) Ocular Inflammatory Diseases: Molecular Pathogenesis and Immunotherapy. Curr Mol Med 15:517-28

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

Wang, Ren-Xi; Yu, Cheng-Rong; Dambuza, Ivy M et al. (2014) Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med 20:633-41

Amadi-Obi, Ahjoku; Yu, Cheng-Rong; Dambuza, Ivy et al. (2012) Interleukin 27 induces the expression of complement factor H (CFH) in the retina. PLoS One 7:e45801