Interleukin-1[beta]-Targeted Vaccine Improves Glucose Control and [beta]-Cell Function in a Diabetic KK-A.sup.y Mouse Model

Interleukin-1[beta] (IL-1[beta]) has been implicated as a key proinflammatory cytokine involved in the pancreatic islet inflammation of type 2 diabetes mellitus (T2DM). Excess IL-1[beta] impairs islet function by inducing insulin resistance and [beta]-cell apoptosis. Therefore, specifically reducing IL-1[beta] activity provides a therapeutic improvement for T2DM by sustaining the inhibition of IL-1[beta]-mediated islet inflammation. In this study, we developed an IL-1[beta]-targeted epitope peptide vaccine adjuvanted with polylactic acid microparticles (1[beta]EPP) and applied it to a diabetic KK-A.sup.y mouse model. Results showed that the 1[beta]EPP elicited high antibody responses, which neutralized the biological activity of IL-1[beta], and induced barely detectable inflammatory activity. 1[beta]EPP immunization reduced body weight gain, protected KK-A.sup.y mice from hyperglycemia, improved glucose tolerance and insulin sensitivity, and decreased the serum levels of free fatty acids, total cholesterol and triglyceride. Moreover, 1[beta]EPP restored [beta]-cell mass; inhibited [beta]-cell apoptosis; decreased the expression of IL-1[beta]; and interrupted NF-[kappa]B activation by reducing IKK[beta] and pRelA levels. These studies indicated that the IL-1[beta]-targeted vaccine may be a promising immunotherapeutic for T2DM treatment.