Targeting IL-12 and/or IL-23 by employing peptide-based vaccines in the amelioration of murine colitis
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Overexpression of IL-12 and IL-23 has been implicated in the pathogenesis of Crohn’s disease. Targeting these cytokines with monoclonal antibodies has emerged as an effective therapy, but one with adverse reactions. In this study, we sought to develop peptide-based virus-like particle vaccines specific to p40 unit (shared by IL-12 and IL-23) or IL-12 (p35) or IL-23 (p19) and evaluate the effects of the vaccine in 2,4,6-trinitrobenzene sulphonic acid (TNBS)- and dextran sodium sulfate (DSS)-induced acute and chronic murine colitis. Three vaccines against p40 induced high-titered and long-lasting antibodies to IL-12, IL-23 and p40 without the use of adjuvants. Vaccine-induced antibodies could block IL-12- and IL-23-induced biological functions in vitro dose-dependently. One of the three p40 vaccines was selected for further evaluation in acute and chronic colitis. Administration of the vaccine before or after the commencement of TNBS or DSS delivery, significantly improved body weight loss and decreased inflammatory scores, collagen deposition, and the expression of p40, IL-12, IL-23, IL-17 and TNF in colon tissues, compared with mice receiving carrier protein (HBcAg) or saline. Moreover, in mesenteric lymph nodes, vaccinated mice exhibited a trend to lower percentages of Th1 cells in acute colitis and of Th17 cells in chronic colitis compared to carrier and saline controls. Vaccinated mice also had higher ratios of Treg/Th1 and Treg/Th17 and higher percentages of apoptosis in Th1 and Th17 cells than controls. Vaccine treatment decreased the infiltration of CD11c+ cells into the gut, but promoted the production of IL-10 from these cells. Safety evaluation indicated that vaccine immunization did not increase the susceptibility to the infection of chlamydia muridarum. Two vaccines specific to IL-12 (against p35) and one vaccine to IL-23 (against p19) were also developed. They induced specific antibodies against IL-12 and IL-23, respectively. IL-23p19 vaccine immunization, not IL-12p23 vaccine, ameliorated TNBS-induced chronic colitis. In summary, IL-12/IL-23p40 vaccine treatment ameliorated murine colitis through rebalancing Th1/Th17/Treg responses, promoting Th1 and Th17 apoptosis, and promoting IL-10 production, and did not increase the severity of chlamydia muridarum infection. This vaccine strategy may provide a novel long-term treatment for Crohn’s disease.