EDWARD C. KEYSTONE, MD,FRCP(C)

Immunopathogenesis of rheumatoid arthritis Professor of Medicine Mount Sinai Hospital 60 Murray Street, Room 2-006, Box 4 Toronto, ON M5T 3L9 Tel: (416) 586-8646 Email: edkeystone@mtsinai.on.ca

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune disorder of unknown etiology characterized by cellular/humoral hyperreactivity in a genetically susceptible host. The precise pathogenetic mechanisms which perpetuate chronic inflammation within the joint, remains unknown.

Our research efforts are focused towards an understanding of the cellular/molecular events contributing to both the early and late phases of RA. We are pursuing several lines of investigation in relation to these goals.

1. Synoviocyte Biology

The synovial lining layer comprises cells of the macrophage and fibroblast lineage. Synovial fibroblast-like cells have been shown to contribute to the inflammatory process by releasing cytokines and metalloproteinases. We are examining the growth and phenotypic properties of synovial tissue fibroblasts from RA patients. Specifically, we are trying to determine the factors leading to a transformed phenotype including both paracrine and autocrine growth regulation and gene expression.

2. Synovial Macrophage/Fibroblast Interaction in RA

We are investigating the in vitro interaction of synovial tissue fibroblasts with synovial macrophages in the process of cartilage degradation. Lysosomal enzyme release and cytokine expression is also being studied. These studies will clarify the role of fibroblast/ macrophage interactions within the synovial membrane as they relate to joint destruction in RA. These studies are being carried out in vitro and in chimeric human RA Nod scid mouse models.

3. Cathepsin L Inhibition in Synoviocytes in RA

We are investigating the ability to inhibit the synthesis of lysosomal enzymes in synovial fibroblasts using in vitro techniques as well as murine models of arthritis.

4. Immunologic Effect of Immunobiologic Agents targetted therapy with the Treatment of RA

We are examining the efficacy and biologic effects of immunobiologic agents in patients with resistant RA. The biologic studies will be performed in vitro as well as with the chimeric RA Nod scid mouse model.