Anti-Cd154 Monoclonal Antibody and Thromboembolism

Dear Sir, Therapy with anti-CD154 monoclonal antibody (mAb) would seem to have considerable potential in preventing rejection of organ allografts (1). The association of anti-CD154 mAb therapy with thromboembolic complications in humans and nonhuman primates has provoked discussion and concern (2, 3). Our own experiences of the use of this agent in the transplantation of pig hematopoietic cells and kidneys in baboons may be of interest. In an attempt to induce mixed hematopoietic chimerism in the pig-to-baboon model, we have infused large numbers of porcine hematopoietic cells into baboons following a preparative regimen that includes splenectomy, whole body irradiation (300 cGy), antithymocyte globulin, thymic irradiation, extracorporeal immunoadsorption of anti-Galα1-3Gal antibodies, cobra venom factor, mycophenolate mofetil, and an anti-CD154 mAb (at 20 mg/kg, beginning before hematopoietic cell or organ transplantation on day 0, and continued on alternate days for 14 or 28 days). In some cases of hematopoietic cell transplantation (but not of kidney transplantation), cyclosporine has also been administered. Pig cells were infused on days 0, 1, and 2, or kidney transplantation was carried out on day 0. Therapy with a prostaglandin (PGI2), low-dose heparin, and corticosteroids was initiated immediately before infusion of the hematopoietic cells. PGI2 and corticosteroid therapy was also initiated before reperfusion of the pig kidney, although heparin infusion was delayed for 1 to 2 days. We have now carried out 10 hematopoietic cell transplants and 8 kidney transplants using anti-CD154 mAb and have seen no thromboembolic complications, with follow-up in some cases extending for more than a year. After hematopoietic cell transplantation, we routinely see a thrombotic microangiography that occurs immediately after the first pig cell infusion, but this occurs even in the absence of anti-CD154 mAb therapy (4). We have investigated the effect of anti-CD154 mAb on platelet aggregation (Appel JZ, et al., unpublished). Anti-CD154 mAb was administered intravenously to two baboons at 40 mg/kg. Blood was withdrawn and platelet aggregation measured by light aggregometry in vitro using four agonists known to induce platelet aggregation. Anti-CD154 mAb was not associated with any modification in the response of the baboon’s platelets to any of the agonists. Furthermore, in an in vitro model in which baboon platelets were stimulated by porcine leukocytes, anti-CD154 mAb modestly inhibited platelet aggregation (Alwayn IPJ, et al., unpublished). Our colleagues recently reported their experience in a cynomolgus monkey renal allograft model (2). They reported four thromboembolic occurrences in nine cynomolgus monkeys receiving anti-CD154 mAb. When a single dose of heparin was given immediately before the mAb, however, the incidence of thromboembolism was reduced to 2 of 10 monkeys, and when heparin was given on days 0–3, no thromboembolism was seen in 5 monkeys. Furthermore, thromboembolism in the allografted monkeys seems to have been prevented by concomitant prostaglandin (PGE1) infusion (Kawai T, et al., Massachusetts General Hospital, personal communication, 2000), and it may be that, because prostaglandin (and heparin) therapy has been included in all of our xenograft experiments, it is for this reason that we have not experienced thromboembolism. Our experience would suggest that anti-CD154 mAb can be administered safely to nonhuman primates without thromboembolic complications if appropriate prophylactic treatments are used . In view of the excellent results obtained in nonhuman primate allograft models using anti-CD154 mAb (1), and because it is the only agent we have tested to date that consistently prevents an induced antibody response to transplanted porcine hematopoietic cells (5) or kidneys, we hope that its development for clinical use will continue. Leo Buhler1 Ian P. J. Alwayn1 James Z. Appel III1 Simon C. Robson2 David K. C. Cooper1