Adoptive cellular gene therapy for the treatment of experimental autoimmune polychondritis ear disease (THER2P.966)

Abstract

Abstract Clinical therapy of autoimmune diseases used to be limited to non-specific immune-suppressive agents and was, for the most part, based on chance observations. Currently, gene therapy research aims at achieving higher specificity and thus less adverse side effects. This concept comprises the adoptive transfer of autologous T-cells that have been retrovirally transduced ex vivo to express and deliver immune-regulatory gene products to sites of autoimmune inflammation. In the animal model of collagen-induced autoimmune polychondritis ear disease (CIAPED), the adoptive transfer of IL-12p40 expressing collagen type II (CII)-specific CD4+ T-cell hybridomas resulted in a significantly lower disease incidence and severity compared with untreated or vector-only treated animals. In vivo cell detection using bioluminescent labels showed that transferred CII-reactive T-cell hybridomas accumulated in inflamed ear lobes in mice with CIAPED. In vitro analysis demonstrated that IL-12p40-transduced T-cells did not affect the antigen-specific T-cell activation or systemic anti-CII antibody responses. However, IL-12p40-transduced T-cells suppressed IFN-γ and augmented IL-4 production, indicating its potential to act therapeutically by interrupting Th1-mediated inflammatory responses via augmenting Th2 responses. These results indicate that the local delivery of IL-12p40 by T-cells could inhibit CIAPED by suppressing autoimmune responses at the site of inflammation.