Recent advances in cardiac xenotransplantation using an human anti-human CD154 monoclonal antibody based protocol

Objectives: Natural and elicited anti-pig antibodies (Abs) play a role in the development of acute humoral xenograft rejection (AHXR) which is currently the major immunologic barrier in pig-to-baboon organ transplantation (Tx).

Material and Methods: Ten baboons underwent heterotopic heart Tx from hDAF pigs. Continuous depletion of anti-Galα1,3Gal(Gal) Abs was achieved by the intravenous infusion of a soluble Gal glycoconjugate from day -1. Immunosuppression included induction with anti-thymocyte globulin, thymic irradiation, and cobra venom factor, and maintenance with a human anti-human CD154 mAb, mycophenolate mofetil, and methylprednisolone; heparin and prophylactic ganciclovir were also administered.

Results: Pig heart survival was from 4–139 (mean 37, median 27) days. Three of the 5 that received high-dose heparin functioned for >50 days. Graft failure (n=8) was from classical AHXR (4), thrombotic microangiopathy (3), or intragraft thrombosis (1), with death (2) from pneumonia (1), or possible drug toxicity (with graft thrombotic microangiopathy) (1). Anti-Gal Abs (in �g/mL) were depleted by Gal glycoconjugate infusion before graft implantation from means of 41.3 to 6.3 (IgM) and 12.4 to 4.6 (IgG), respectively. Mean levels of anti-Gal Abs at graft excision were 6.3 and 1.7 �g/mL, respectively. No elicited Abs developed during immunosuppressive treatment. No cellular infiltration was seen in any graft.

Conclusions: The combined administration of a Gal glycoconjugate, an anti-CD154 mAb-based regimen, and heparin was effective in maintaining low anti-Gal Ab levels and in delaying or preventing AHXR for up to 139 days. The combination of costimulatory blockade and heparin with use of a Gal-negative pig organ may prolong graft survival further.