This research proposal concerns the therapeutic use of anti-CD-44 monoclonal for the treatment of experimental inflammatory and human rheumatoid arthritic (RA). This is a basic research approach to a comprehensive study on the effects of anti-CD44 treatment upon joint inflammation. In the near future at Rush Medical Center, in collaboration with the Section of Rheumatology (Department of Internal Medicine) and our research groups (Departments of Biochemistry and Orthopedic Surgery), we are planning to introduce anti-CD44 immunotherapy to patients with rheumatoid arthritis. The protocol of treatment and the evaluation of clinical efficacy will be largely based upon the information obtained from this study. Recently we have reported that the interaction of CD44 with hyaluronic acid (HA) plays a major role in maintaining tissue swelling as well as in directing the traffic of inflammatory leukocytes to the site of inflammation in mice with experimental arthritis (Nature Med. 1:558-563, 1995). We demonstrated that the injection of monoclonal antibody IM7.8.1 (mAb IM7), directed to CD44, eliminates joint swelling and leukocyte infiltration in the synovial tissue of mice with joint inflammation. This antibody induces the loss (shedding of the CD44 receptor from the surface of both leukocytes and synovial cells. The loss of CD44, along with receptor-bound HA and associated water from the synovium, results in a decrease of tissue swelling, and CD44-deficient leukocytes will no longer be able to recognize HA and migrate into the HA-rich extracellular compartment of the inflamed synovium. Our preliminary results show that antibody IM7 cross-reacts with human CD44 and induces the loss of CD44 from human leukocytes and synovial cells in vitro as it has been similarly shown in the murine system. This antibody has a potential, therefore, to be introduced as a therapeutic agent for the treatment of human RA. Our pioneer study on animal models of inflammatory arthritis has revealed the basic mechanism of anti-CD44 treatment, however, many other aspects of this immunotherapy should be explored before human application. We will identify CD44 isoforms which play dominant roles in the maintenance of joint inflammation and design a narrow-range immunotherapy targeted to cells involved in inflammatory processes. We will study the regulatory mechanisms, linked to anti-CD44 treatment, in animal models in vivo and on human cells in vitro. Finally, we will investigate the effects of anti-CD44 therapy on the functions of the immune, hemopoietic and reproductive systems in vivo. We believe that these studies will contribute to the understanding of the role of CD44 in inflammation and increase the clinical safety and efficacy of anti-CD44 immunotherapy in RA.
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