To the editor
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 Medicine1 and elsewhere2. 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 immunosuppression3,4. 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 ).
CD40 ligand was originally identified on activated CD4+ T cells5, later on stimulated mast cells and basophils6 and most recently on activated platelets in vitro and in vivo on platelets in the process of thrombus formation7. CD40 is constitutively expressed on the vascular endothelium of various organs, and its ligation can upregulate adhesion molecules such as E-selectin, VCAM-1 and ICAM-1. Ligation through CD40 has also been reported to upregulate tissue factor expression on endothelial cells8. CD40 ligand expression has also been seen in vivo on activated platelets by examining fresh thrombi formed during vessel injury. In all fresh thrombi analyzed, CD40 ligand was expressed on a large proportion of platelets in areas in which densely packed platelets had not yet formed an amorphous mass and on platelets directly adhering to the vessel endothelium. These results may be relevant to the mechanism of a possible increased risk factor for thromboembolism induced by monoclonal antibody against CD40 ligand. Our results indicate that the administration of heparin in conjunction with monoclonal antibody against CD40 ligand can reduce the incidence of thromboembolic complications.
References
Kirk, A.D. et al. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nature Med. 5, 686–693 ( 1999).
Kenyon, N.S. et al. Long-term survival and function of intrahepatic islet al lografts in rhesus monkeys treated with humanized anti-CD154. Proc. Natl. Acad. Sci. USA 96, 8132– 8137 (1999).
Kawai, T. et al. Mixed allogeneic chimerism and renal allograft tolerance in cynomolgus monkeys. Transplantation 59, 256- 62 (1995).
Kimikawa, M. et al. Modifications of the conditioning regimen for achieving mixed chimerism and donor-specific tolerance in cynomolgus monkeys. Transplantation 64, 709–716 (1997).
Armitage, R. et al. Molecular and biological characterization of a murine ligand for CD40. Nature 357, 80– 82 (1992).
Gauchat, J.F. et al. Introduction of human IgE synthesis in B cells by mast cells and basophils. Nature 365, 340– 343 (1993).
Henn, V. et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391, 591– 594 (1998).
Slupsky, J.R. et al. Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40. Thromb. Haemost. 80, 1008–1014 ( 1998)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kawai, T., Andrews, D., Colvin, R. et al. Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med 6, 114 (2000). https://doi.org/10.1038/72162
Issue Date:
DOI: https://doi.org/10.1038/72162
This article is cited by
-
Inhibition of platelet activation suppresses reactive enteric glia and mitigates intestinal barrier dysfunction during sepsis
Molecular Medicine (2022)
-
Inhibition of platelet activation suppresses reactive enteric glia and mitigates intestinal barrier dysfunction during sepsis
Molecular Medicine (2022)
-
Evaluation of immunosuppression protocols for MHC-matched allogeneic iPS cell-based transplantation using a mouse skin transplantation model
Inflammation and Regeneration (2022)
-
The immunobiology and clinical use of genetically engineered porcine hearts for cardiac xenotransplantation
Nature Cardiovascular Research (2022)
-
B Cell Aberrance in Lupus: the Ringleader and the Solution
Clinical Reviews in Allergy & Immunology (2022)