This application requests funding to help defray the costs of conducting the first human trial in which a potentially therapeutic agent will be transferred to a joint. The protocol was approved by the Recombinant DNA Advisory Committee (RAC) of the NIH in June, 1994; a pre-IND meeting with the FDA was held in 10/94 and the IND itself is in the process of being filed. The applicants propose to use a replication-defective retrovirus (MFG) carrying a cDNA encoding the human interleukin-1 receptor antagonist protein (IRAP) to transduce autologous human synovial cells grown ex vivo, and then to reinject the cells into metacarpaphalageal joints (MCP) in 6 post-menopausal patients with chronic rheumatoid arthritis rheumatoid arthritis (RA). The Specific Aims are to: 1) establish synovial cell cultures from biopsies from MCP joints from 6 patients with RA and transduce the cells with a replication-defective retrovirus (MFG) carrying a cDNA encoding the human IRAP; 2) transfer the autologous transduced synoviocytes to MCP joints of patients 1 week before MCP arthroplasty; and 3) after 1 week, at the time of joint replacement surgery, lavages will be performed and periarticular tissues recovered to determine whether the IRAP gene has been successfully transferred to the synovium and expressed intrarticularly, and whether a local biological response to the transgene product has occurred based on evaluation of the expression pattern of cytokines and inflammatory markers, and whether there has been changes in articular cartilage glycosaminoglycan (GAG) synthesis. The IRAP was selected because it is a naturally occurring antagonist of IL-1alpha and IL-1beta, cytokines that play a role in a variety of immune and inflammatory diosorders. IRAP competes for binding to the IL-1 receptor but fails to transduce biological responses. The applicants suggest that the proposed human studies should advance the development of gene treatments for arthritis and other diseases of bones and joints.