Application of cellular gene therapy for rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by persistent inflammation of joints resulting in progressive destruction of cartilage and bone. Recently, biological agents that suppress the activities of proinflammatory cytokines have shown efficacy as antirheumatic drugs, but require frequent administration, and often result in systemic immune suppression. Thus, gene transfer approaches are being developed as an alternative approach for targeted, more efficient, and sustained delivery of inhibitors of inflammatory cytokines as well as other therapeutic agents. Several gene therapy approaches have been established in preclinical animal models. In these models, autoantigen-specific T cells have been demonstrated to be ideal gene delivery vehicles for the local delivery of "immunoregulatory molecules" because these cells have tissue-specific homing and retention properties. Indeed, bioluminescence studies in an animal model of inflammatory arthritis revealed that these cells accumulated in and remained in inflamed joints. Transfer of genetically modified dendritic cells (DCs) may also have interesting effects. We conclude that modifying antigen-specific T cells or autologous DCs by retroviral transduction for local expression of regulatory proteins is a promising therapeutic strategy for the treatment of RA.

Fig. 1

Approaches and vectors used for local gene transfer to joints. IL, interleukin; HSV, herpes simplex virus; AAV, adeno-associated virus

Fig. 2

Visualization of lymphocyte trafficking in vivo. CII-immunized DBA/1 LacJ mice received CII-specific CD4⁺ T-cell hybridomas expressing a GFP-luciferase reporter gene (1 × 10⁶/mouse) intravenously. The images were obtained on day 14 after the cell transfer