Tumor necrosis factor receptor gene therapy influences humoral and cellular immune responses in collagen induced arthritis

Therapeutic strategies to block tumor necrosis factor (TNF) activity in both experimental autoimmune arthritis models and rheumatoid arthritis (RA) have proven highly successful. Since pathogenesis of collagen induced arthritis (CIA) is characterized by a synergy between an altered cellular and humoral immune response, we evaluated whether retrovirus mediated anti-inflammatory tumor necrosis factor receptor (TNF-R) gene therapy could: (1) affect the reactivity of autoimmune lymphocytes in CIA, (2) alter CII peptide epitope specificity and (3) influence Vβ gene usage in this disease. Single peri-articular injections of retroviral vectors encoding for TNF-R into arthritic paws of DBA/1 mice resulted in a significant decrease in the severity of CIA compared with controls. Histological analysis revealed a marked reduction of synovial inflammation and bone damage in injected as well as uninjected arthritic contralateral and ipsilateral paws of TNF-R treated animals. A shift in anti-collagen IgG2a: IgG1 ratio towards Th2 driven IgG1 occurred due to significant reduction in Th1 driven IgG2a antibody. TNF-R treated animals also demonstrated a specificity shift from the dominant arthritogenic CII peptide 245–270 towards the non-arthritogenic sub-dominant CII peptide 334–360, and suppression of the predominant T cell receptor (TCR) Vβ8.2 gene usage. Overall, the results indicate that retroviral-mediated local TNF-R gene therapy exerts systemic effects that block progression of inflammation to uninjected arthritic joints leading to overall disease amelioration by downregulation of the Th1 driven anti-CII IgG2a response, diversification of the T cell response towards the non-arthitogenic CII 334–360 peptide epitopes and skewing of the predominantly used TCR Vβ8.2 subset towards Vβ8.3. Therefore, these results demonstrate that peri-articular delivery of retrovirus mediated TNF-R gene therapy has an excellent therapeutic potential in treatment of RA.