Abstract
CD154 is the ligand for the receptor CD40. This ligand–receptor pair mediates endothelial and antigen-presenting cell activation, and facilitates the interaction of these cells with T cells and platelets. We demonstrate here that administration of a CD154-specific monoclonal antibody (hu5C8) allows for renal allotransplantation in outbred, MHC-mismatched rhesus monkeys without acute rejection. The effect persisted for more than 10 months after therapy termination, and no additional drug was required to achieve extended graft survival. Indeed, the use of tacrolimus or chronic steroids seemed to antagonize the anti-rejection effect. Monkeys treated with antibody against CD154 remained healthy during and after therapy. The mechanism of action does not require global depletion of T or B cells. Long-term survivors lost their mixed lymphocyte reactivity in a donor-specific manner, but still formed donor-specific antibody and generated T cells that infiltrated the grafted organ without any obvious effect on graft function. Thus, therapy with antibody against CD154 is a promising agent for clinical use in human allotransplantation.
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Acknowledgements
The authors acknowledge the technical assistance of D.L. Doctor, G. Garth and J. Hyde, the photographic assistance of L. Duckett and the veterinary care provided by M. Chartier and P.J. Rico. This work was supported by Naval Medical Research and Development Command Grant EW.0095.003.1412, Office of Naval Research Grant N00014-96-1-1282, and Biogen. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Navy, the Department of Defense nor the United States Government.
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Kirk, A., Burkly, L., Batty, D. et al. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med 5, 686–693 (1999). https://doi.org/10.1038/9536
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DOI: https://doi.org/10.1038/9536
