TRANSFORMING GROWTH FACTOR-BETAS AS AGENTS FOR THE TREATMENTOF ARTHRITIS

TWO HOMOLOGOUS PROTEINS, ISOLATED FROM DEMINERALIZED BOVINE BONE AND OPERATIONALLY REFERRED TO AS CARTILAGE-INDUCING FACTORS-A AND -B(CIF-A AND CIF-B), HAVE BEEN FOUND TO BE POTENT INHIBITORS OF LYMPHOCYTE FUNCTION AND TO HAVE ANTI-INFLAMMATORY ACTIVITY. THESE FACTORS HAVE THE SAME BIOLOGICAL ACTIVITIES AS THE HUMAN TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA). CIF-A AND TGF-BETA APPEAR TO BE THESAME MOLECULE (CIF-A/TGF-BETA), WHILE CIF-B HAS 63 PERCENT SEQUENCE HOMOLOGY. THE FOLLOWING OBSERVATIONS SUGGEST THESE ARE NATURALLY OCCURRING IMMUNOREGULATOR MOLECULES: (1) THESE FACTORS ARE ANTAGONISTS OF INTERLEUKIN-1 (THYMOCYTE PROLIFERATION ASSAY). (2) THESE FACTORS INHIBIT MITOGEN-INDUCED T-CELL AND B-CELL PROLIFERATION. (3) THESE FACTORS ARE POTENT INHIBITORS OF IGM AND IGG PRODUCTION BY PLASMA CELLS. (4) THESE FACTORS ARE ACTIVE AT <1.0NG/ML IN CULTURE. (5) CIF-A/TGF-BETA MRNA IS DETECTED IN MITOGEN-ACTIVATED LYMPHOCYTES AND IS SECRETED BY THESE CELLS. (6) EXOGENOUS FACTOR DOWN-REGULATES THE INTERLEUKIN-2 RECEPTOR. (7) THESEFACTORS EXHIBIT ANTI-INFLAMMATORY ACTIVITY IN VIVO. IN PHASE I OF THIS PROPOSAL, COLLAGEN CORPORATION WILL EVALUATE THE THERAPEUTIC USE OF THESE FACTORS FOR THE TREATMENT OF AUTOIMMUNE DISEASES. POLYARTHRITIS WILL BE INDUCED IN RATS BY IMMUNIZING WITH TYPE II COLLAGEN. THE ARTHRITIS WILL BE TREATED BY INJECTING THESE IMMUNOSUPPRESSIVE FACTORS INTO THE INFLAMED JOINTS. THE EFFICACY OF TREATMENT WILL BE DETERMINED BY CLINICAL, IMMUNOLOGIC, HISTOPATHOLOGIC, AND RADIOGRAPHIC METHODS. IN PHASE II, RHEUMATOID ARTHRITIS PATIENTS WILL BE TREATED WITHTHERAPEUTICALLY EFFECTIVE AMOUNTS OF THESE FACTORS.