Gene Modified Cell Therapy Ameliorates Rheumatoid Arthritis In Animal Model

NEW YORK (Reuters Health) - Dendritic cells that express an apoptosis-inducing protein and that target antigen-specific T cells inhibit the development of disease in an animal model of rheumatoid arthritis, researchers at The University of Alabama at Birmingham report.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) inhibits autoimmune inflammation by inducing apoptosis in autoreactive T cells. In the Journal of Clinical Investigation for November, Dr. John D. Mountz and his colleagues describe research using murine dendritic cells transfected with an adenovirus engineered to express TRAIL. The vector also contained a doxycycline-inducible promoter gene in order to control levels of TRAIL expression.

Dr. Mountz's team treated mice with bovine collagen type II to induce arthritis and 2 weeks later injected the transfected cells. Doxycycline was added to the animals' drinking water.

The incidence of arthritis was significantly reduced compared with control animals, and onset was significantly delayed. The investigators found that T cell infiltration into the joints had decreased.

Dendritic cells that were primed with bovine collagen II prior to transfection were even more effective than the nonprimed cells, the report indicates. After treatment with primed cells, plasma levels of anti-collagen IgG antibodies were decreased and interferon-gamma levels declined. Almost no T cells remained in the joints.

This experimental approach may be safer than current anti-TNF therapies for rheumatoid arthritis "because we can control what time, when and for how long" TRAIL is delivered, and does not cause generalized immunosuppression, co-investigator Dr. Hui-Chen Hsu told Reuters Health.

The prospect of treating humans was illuminated when a similar construct was applied to human T cells in vitro, she added. There, too, it appeared that TRAIL expression led to cell death.

But before this strategy can be effective in patients with rheumatoid arthritis, "we have to find out what auto-antigen causes the disease," she added, in order to enhance tissue specificity.

The ability of dendritic cells to reverse the process of autoimmune diseases has been studied extensively, Maryland scientists note in an accompanying editorial.

"These results suggest that gene-modified cell therapy represents a therapeutic option for systemic rheumatic diseases," write Dr. George C. Tsokos, with the Water Reed army Institute of Research, and Dr. Maria Tsokos, affiliated with the National Cancer Institute.

Source: J Clin Invest 2003. [ Google search on this article ]

MeSH Headings: Biological Therapy : Genetic Engineering : Genetic Techniques : Investigative Techniques : Therapeutics : Gene Therapy : Analytical, Diagnostic and Therapeutic Techniques and Equipment