Prevention of collagen-induced arthritis by gene delivery of soluble p75 tumour necrosis factor receptor

Collagen type II-induced arthritis (CIA) in DBA/1 mice can be passively tra nsferred to SCID mice with spleen B- and T-lymphocytes. In the present stud y, we show that infection ex vivo of splenocytes from arthritic DBA/1 mice with a retroviral vector, containing cDNA for the soluble form of human p75 receptor of tumour necrosis factor (TNF-R) before transfer, prevents the d evelopment of arthritis, bone erosion and joint inflammation in the SCID re cipients. Assessment of IgG subclass levels and studies of synovial histolo gy suggest that down-regulating the effector functions of T helper-type 1 ( Th1) cells may, at least in part, explain the inhibition of arthritis in th e SCID recipients. In contrast, the transfer of splenocytes infected with m ouse TNF-alpha gene construct resulted in exacerbated arthritis and enhance ment of IgG2a antibody levels. Intriguingly, infection of splenocytes from arthritic DBA/1 mice with a construct for mouse IL-10 had no modulating eff ect on the transfer of arthritis. The data suggest that manipulation of the immune system with cytokines, or cytokine inhibitors using gene transfer p rotocols can be an effective approach to ameliorate arthritis.