Schematic presentation of the various gene transfer methods that are used in experimental models of rheumatoid arthritis. Central to gene therapy is the transfer of therapeutic genes to the site of inflammation. In the 'ex vivo' method autologous or allogeneic fibroblasts that are retrovirally transduced to express therapeutic genes are transplanted into inflamed joint. In 'adoptive cellular gene therapy', the transduced cells are either antigen-presenting cells (dendritic cells, macrophages, or B cells) or T cells (primary or hybridoma cells) that have the capacity to home to the site of inflammation. In the direct or in vivo method the therapeutic gene constructs (viral or nonviral) are directly transferred to the animal either locally (intra-articular, periarticular) or systemically (intramuscular, intravenous). All of these routes of gene delivery have been successful in gene therapy for experimental arthritis, and some of them also exhibited a 'contralateral' effect (i.e. protection of remote untreated joints). The numbers in brackets indicate reference numbers. AAV, adeno-associated virus; DC, dendritic cell; HSV, herpes simplex virus; Mφ, macrophage.