Suppression of Natural and Elicited Antibodies in Pig-to-Baboon Heart Transplantation Using a Human Anti-Human CD154 mAb-Based Regimen

Kenji Kuwaki, Christoph Knosalla, Frank J M F Dor, Bernd Gollackner, Yau Lin Tseng, Stuart Houser, Nicolas Mueller, Derek Prabharasuth, Amy Alt, Kathy Moran, Jane Cheng, Amir Behdad, David H. Sachs, Jay A. Fishman, Henk Jan Schuurman, Michel Awwad, David K C Cooper

Research output: Contribution to journalArticlepeer-review

127 Scopus citations

Abstract

Natural and elicited antipig antibodies (Abs) lead to acute humoral xenograft rejection (AHXR). Ten baboons underwent heterotopic heart transplantation (Tx) from human decay-accelerating factor (hDAF) pigs. Depletion of anti-Galα1, 3Gal (Gal) Abs was achieved by the infusion of a Gal glycoconjugate from day - 1. Immunosuppression included induction of antithymocyte globulin, thymic irradiation, and cobra venom factor, and maintenance with a human antihuman CD154 mAb, mycophenolate mofetil, and methylprednisolone, heparin and prophylactic ganciclovir were also administered. Pig heart survival ranged from 4 to 139 (mean 37, median 27) days, with three functioning for >50 days. Graft failure (n = 8) was from classical AHXR [4], thrombotic microangiopathy [3], or intragraft thrombosis [1], with death (n = 2) from pneumonia [1], or possible drug toxicity (with features of thrombotic microangiopathy) [1]. Anti-Gal Abs (in μg/mL) were depleted by Gal glycoconjugate before graft implantation from means of 41.3 to 6.3 (IgM) and 12.4-4.6 (IgG), respectively, and at graft excision were 6.3 and 1.7 μg/mL, respectively. No elicited Abs developed, and no cellular infiltration was seen. The treatment regimen was effective in maintaining a low anti-Gal Ab levels and in delaying or preventing AHXR. The combination of costimulatory blockade and heparin with Tx of a Gal-negative pig organ may prolong graft survival further.

Original languageEnglish (US)
Pages (from-to)363-372
Number of pages10
JournalAmerican Journal of Transplantation
Volume4
Issue number3
DOIs
StatePublished - Mar 2004

Keywords

  • Anti-CD154 monoclonal antibody
  • Anti-Gal antibody
  • Baboon
  • Costimulatory blockade
  • Heart transplantation
  • Pig
  • Xenotransplantation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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