A novel IL233 fusion cytokine in a therapeutic approach for acute kidney injury (CAM1P.155)

Abstract Since we found that interleukin (IL)-2 upregulated IL-33 receptor-ST2 on CD4+ T-cells, we hypothesized that IL-2 and IL-33 may cooperate to expand endogenous Tregs. Indeed Tregs expressed ST2 and IL-33 contributed to increase Treg-expansion. We designed a fusion cytokine (IL233) containing the activities of IL-2 and IL-33 for better targeting of Tregs. We expressed the cytokines in E.coli, purified them to homogeneity and tested them in mouse model of ischemia reperfusion injury (IRI). C57BL/6 male mice were pretreated (ip) with different doses of cytokines prior to 26 min of bilateral ischemia and 24 hours of reperfusion and kidneys were characterized for function (plasma creatinine) and acute tubular necrosis. IL-2 and IL-33 in combination or as IL233 fusion cytokine, but not alone protected mice from IRI, with IL233 being more efficient than the combination. Our data suggests that the IL233 treatment first increases splenic levels of Tregs followed by their mobilization. Since both IL-2 and IL-33 also promote T-helper (Th)-2 response, an increase in IL-4 and IL-5, and a decrease in inflammatory cytokines IFN-γ and TNF-α were observed, indicating a shift towards a protective Th2 response. Adoptive transfer studies revealed higher degree of protection in mice injected with Tregs obtained from mice pretreated with IL233. Thus, IL233 fusion cytokine attenuates kidney inflammation to protect from IRI and bears strong potential to be a therapeutic agent for acute kidney injury.