B-cell depletion extends the survival of GTKO.hCD46Tg pig heart xenografts in baboons for up to 8 months

M. M. Mohiuddin, P. C. Corcoran, A. K. Singh, A. Azimzadeh, R. F. Hoyt, M. L. Thomas, M. A. Eckhaus, C. Seavey, D. Ayares, R. N. Pierson, K. A. Horvath

Research output: Contribution to journalArticlepeer-review

Abstract

Xenotransplantation of genetically modified pig organs offers great potential to address the shortage of human organs for allotransplantation. Rejection in Gal knockout (GTKO) pigs due to elicited non-Gal antibody response required further genetic modifications of donor pigs and better control of the B-cell response to xenoantigens. We report significant prolongation of heterotopic alpha Galactosyl transferase "knock-out" and human CD46 transgenic (GTKO.hCD46Tg) pig cardiac xenografts survival in specific pathogen free baboons. Peritransplant B-cell depletion using 4 weekly doses of anti-CD20 antibody in the context of an established ATG, anti-CD154 and MMF-based immunosuppressive regimen prolonged GTKO.hCD46Tg graft survival for up to 236 days (n = 9, median survival 71 days and mean survival 94 days). B-cell depletion persisted for over 2 months, and elicited anti-non-Gal antibody production remained suppressed for the duration of graft follow-up. This result identifies a critical role for B cells in the mechanisms of elicited anti-non-Gal antibody and delayed xenograft rejection. Model-related morbidity due to variety of causes was seen in these experiments, suggesting that further therapeutic interventions, including candidate genetic modifications of donor pigs, may be necessary to reduce late morbidity in this model to a clinically manageable level. The authors describe the use of recipient B cell depletion and genetically modified donor pigs in a series of heterotopic pig to baboon cardiac xenografts with survival up to 8 months.

Original languageEnglish (US)
Pages (from-to)763-771
Number of pages9
JournalAmerican Journal of Transplantation
Volume12
Issue number3
DOIs
StatePublished - Mar 2012

Keywords

  • B-cell depletion
  • CD46 transgenic
  • Gal knockout pigs
  • Xenograft
  • anti-CD20
  • complement
  • xenoantibody

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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