Exciting results reporting that blockade of the CD40/CD40 ligand pathway by monoclonal antibody against CD40 ligand led to long-term acceptance of renal allografts in monkeys were recently reported in Nature Medicine 1 and elsewhere 2. Our own group has previously reported that mixed chimerism and renal allograft tolerance are achieved in monkeys conditioned with a multi-modality peritransplant regimen and without long-term maintenance immunosuppression 3, 4. In an effort to simplify this therapeutic regimen, we tested a monoclonal antibody against CD40 ligand (American Type Culture Collection catalog number 5C8. 33) in this protocol. In the first animals treated, we encountered an unusually high incidence of thromboembolic complications, which we thought worthy of reporting.

Using our standard regimen (non-myeloablative total body irradiation, thymic irradiation, anti-thymocyte globulin, donor bone marrow infusion and a 1-month course of cyclosporine), we found no thromboembolic complications in more than 50 animals. In contrast, after adding 20 mg/kg of monoclonal antibody against CD40 ligand to the regimen on days 0 and 2, we observed four thromboembolic complications in nine recipients. These included two renal artery thromboses, one renal vein thrombosis and one superior mesenteric artery thrombosis. In subsequent animals, the addition of 100 units/kg heparin immediately before the antibody (days 0 and 2) reduced the incidence of thrombotic complications to just two (one renal artery, one renal vein) in ten recipients. We then tried additional heparin treatments (100 units/kg, days 0, 1, 2, 3) preceded by vigorous postoperative hydration. None of the five animals tested after this change have developed thrombotic complications. These observations may be relevant to ongoing clinical trials of monoclonal antibody against CD40 ligand (humanized version of 5C8) in which some thromboembolic complications have been reported (Vincent, J. Biogen News http://www. prnewswire. com, 11/2/99).