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Jin Kyeong Choi, Chengrong Yu, Anita Uche, Mary J Mattapallil, Favour Oladipupop, Minkyung Kang, Rachel R Caspi, Charles E Egwuagu; Therapeutic potential of IL-12p35 Subunit for treatment of uveitis and multiple sclerosis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2550.
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The heterodimeric Interleukin 35 (IL-35) cytokine suppresses autoimmune diseases by inducing the development/expansion of regulatory B cells (Bregs). Non-covalent binding of its 2 subunits, p35 and Ebi3, is thought to be required to exert its immune suppressive functions. However, technical challenges of producing sufficient quantities of IL-35 are a major impediment to its therapeutic use. Because the association of the p35 and Ebi3 subunits is weak, they readily dissociate, making it difficult to ascertain the effective dose of bioactive p35/Ebi3 heterodimer administered or required to ameliorate disease. In this study, we have investigated whether each individual subunit possesses intrinsic biological activities that can be exploited to treat EAU or EAE, mouse models of Uveitis or multiple sclerosis, respectively.
We induced EAU or EAE and treated the mice with 100 ng p35, every other day until day 12 after disease initiation[RC1] . EAU development and severity were established by fundoscopy, OCT, ERG and histology. Clinical EAE and EAU were scored according to established criteria. Immune responses during EAU or EAE were analyzed by FACS, intracellular cytokine assay, PCR, Western blotting and ELISA. Cell proliferation was assessed by Thymidine incorporation.
We show that the IL-12p35 subunit possesses anti-inflammatory properties. It induced expansion of Breg cells and was effective in treating EAU and EAE. In immunized but untreated mice, inflammatory immune cells penetrated the retina, brain or spinal cord, causing characteristic features of EAU or EAE, which were markedly reduced in the treated mice.
We recapitulated the activities of the heterodimer cytokine by using the IL-12p35 subunit alone. In addition to IL-12p35, our previous data indicate that the IL-27p28 subunit alone is also effective in suppressing EAU or EAE. In the aggregate, these data suggest that IL-12 family single-chain proteins may constitute a new generation of therapeutic cytokines that can be used to treat autoimmune diseases of the CNS.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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