Schematic presentation of potential transcriptionally regulated transgene expression constructs for arthritis. Ideally, the expression of the therapeutic gene should follow the intermittent course of the disease in rheumatoid arthritis, and this can be achieved by using disease-regulating promoters (reg. promoter) for upregulation (promoters from interleukin [IL]-6, complement factor 3 [C3], serum amyloid A [SAA], tumour suppressor gene [TSG]6, heat shock protein [HSP]70) or downregulation (promoters from collagen type II, IL-1 receptor antagonist [IL-1Ra], osteocalcin, tumour necrosis factor receptor [TNFR]) of expression. Disease (cytokine balance) will regulate the expression of rtTA and/or tTS that, only in the presence of doxycycline, can regulate the expression of the therapeutic transgene using the drug-regulable expression system (tet-on/tet-off system). Tissue-specific expression elements either in front or downstream of the promoter must restrict the expression of the site of interest. Furthermore, insulator sequences must prevent cis-acting promoter activities and epigenetic interference on the disease-regulating promoter system. The performance of the transcriptionally regulated expression system will also depend on the vector (integrating/episomal), route of delivery (Fig. 2) and transgene (Fig. 2). Because safety is paramount, it must be possible to delete the transduced cells (e.g. by introducing a thymidine kinase gene in case of a worst scenario; not included in the illustration). I, insulator; Enh, enhancer elements; rtTA, reverse tetracycline-modulated transcription factor; tetO, tetracycline repressor-binding sequence; tTS, tetracycline-modulated transcriptional suppressor.