Purchase this article with an account.
Jin Kyeong Choi, Venkat Mohanram, Chengrong Yu, Anita Uche, Daniel Gebreselassie, Hyunsu lee, Charles Egwuagu; IL-12p35 induces expansion of IL-10- and IL-35-expressing regulatory B cells (Bregs) and ameliorates autoimmune disease. Invest. Ophthalmol. Vis. Sci. 2017;58(8):543.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Interleukin 35, a heterodimeric cytokine composed of IL-12p35 and Ebi3 subunits, suppresses autoimmune diseases, prevents sterilizing immunity to pathogens and limits anti-tumor immunity by inducing IL-35-producing regulatory B (i35-Breg) and T cells (iTR35). Thus far, biologically active, native or recombinant heterodimeric IL-35 is not commercially available due to technical challenges. Despite sharing IL-12p35 subunit, IL-12 (IL-12p35/IL-12p40) promotes inflammatory responses that mediate autoimmune diseases while IL-35 (IL-12p35/Ebi3) induces regulatory responses that maintain self-tolerance and suppresses chronic inflammatory diseases, suggesting that IL-12p35 may possess unknown intrinsic immune-regulatory functions regulated, in part, by its heterodimeric partner.
Using experimental autoimmune uveitis (EAU), an animal model of Uveitis, we have produced mouse recombinant IL-12p35 (rIL-12p35) and rEbi3 and examined whether either protein can recapitulate the inhibitory activities of IL-35 in uveitis.
We demonstrate that the IL-12p35 subunit exhibits immunoregulatory functions hitherto attributed to IL-35: It suppresses lymphocyte proliferation, induces expansion of IL-10- and IL-35-expressing regulatory B-cells (Bregs) and suppresses CNS autoimmune disease by antagonizing pathogenic Th17 responses. The demonstration that IL-12p35 can recapitulate essential immunosuppressive activities of IL-35 offers tremendous promise for therapeutic use of IL-12p35, particularly for in vivo expansion of Breg cells and autologous Breg immunotherapy.
Our data showing that IL-12p35 might be an effective drug for the treatment of autoimmune uveitis further suggest that intrinsic immune-regulatory activities of other single-chain IL-12 family proteins can also be exploited therapeutically in other autoimmune or infectious diseases.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
This PDF is available to Subscribers Only