INDUCTION OF TOLERANCE TO EXPERIMENTAL ANTIPHOSPHOLIPID SYNDROME (APS) BY SYNGENEIC BONE-MARROW CELL TRANSPLANTATION

Previously, we have shown the ability to induce experimental autoimmune conditions (e.g. SLE, APLS, Wegener's granulomatosis) following active immunization with the pathogenic autoantibody emulsified in adjuvant. The mice first develop anti-autoantibodies (Ab(2): anti-id) and eventually generate anti-anti-autoantibodies (Ab(3): anti-anti-id) which carry the same antigen binding characteristic as the autoantibody (Ab(1)). The appearance of the specific autoantibodies in mice sera was associated with the emergence of the compatible laboratory and with the clinical findings characteristic to the respective autoimmune disease. The effects of syngeneic bone marrow transplantation (BMT) on experimental anti-phospholipid syndrome (APS) were investigated. BALB/c mice were immunized with anticardiolipin monoclonal antibody (MoAb) named CAM and developed elevated serum titres of antiphospholipid Abs accompanied by prolonged activated partial thromboplastin time, thrombocytopenia and a high percentage of fetal resorptions. These mice were then lethally irradiated and transfused with bone marrow (BM) cells (T cell depleted) from syngeneic naive mice. The titres of antiphospholipid antibodies were reduced in the recipients. The decrease in titre of autoantibodies was found to be related to depletion of antibody forming cells in vivo, associated with reduced proliferative response of lymph node cells to anti-cardiolipin MoAbs. The recipients showed improvement in clinical parameters following syngeneic BMT. The same recipients developed specific unresponsiveness to a second challenge with the anticardiolipin MoAb (CAM), but developed experimental systemic lupus erythematosus upon immunization with a monoclonal anti-DNA antibody. We conclude that acute myeloablative immunosuppression combined with syngeneic bone marrow transplantation may induce a state of tolerance to the pathogenic autoantibodies in mice with experimental APLS. Our results suggest that a similar approach may be useful in treating life-threatening autoimmune syndromes (e.g. catastrophic APLS) in clinical practice.