Liposome-mediated transfer of IL-1 receptor antagonist gene to dispersed islet cells does not prevent recurrence of disease in syngeneically transplanted NOD mice

IL-1 beta is cytotoxic to pancreatic beta-cells in vitro but its role in th e vicinity of beta-cells in vivo is unknown, We explored whether liposome-m ediated transfer of the interleukin 1 receptor antagonist (IL-1ra) gene to islet cells might prevent recurrence of disease in syngeneically transplant ed non-obese diabetic (NOD) mice. NOD mouse islet cells were transfected us ing liposome-mediated gene transfer with a human IL-1ra cDNA construct and transplanted two days later to prediabetic NOD mice, Graft infiltration and destruction were monitored three, five and eight days posttransplantation by histology and determination of insulin and cytokine content. IL-1ra gene transfer resulted in transient expression of IL-1ra protein in islet cells in vitro as assessed by ELISA and of IL-1ra mRNA in transplanted islets as revealed by RT-PCR, However, both control and IL-1ra transfected NOD graft s exhibited massive infiltration and loss of insulin-positive cells, parall eled by a decreased insulin content. Increased IL-1ra expression did not cl early affect other cytokine profiles (IL-1 beta, IFN-gamma, IL-2), except f or an increase of IL-10 on day eight. In conclusion, liposome-mediated IL-1 ra gene transfer to mouse islet cells results in transient expression of IL -1ra which is, however, insufficient to confer resistance to destruction of grafted insulin-producing cells in the NOD mouse. (C) 2000 Academic Press.