Co-stimulation blockade targeting CD154 and CD28/B7 modulates the induced antibody response after a pig-to-baboon cardiac xenograft

Guosheng Wu, Steffen Pfeiffer, Carsten Schröder, Tianshu Zhang, Bao N. Nguyen, William Lea, Sean Kelishadi, James B. Atkinson, Henk Jan Schuurman, David J.G. White, Agnes M. Azimzadeh, Richard N. Pierson

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30 Scopus citations

Abstract

Background: The induced antibodies against Galα1,3Gal (Gal) and non-Gal epitopes may contribute to delayed xenograft rejection (DXR). We asked whether blockade of the CD40/CD154 and CD28/B7 co-stimulatory pathways modulates the baboon elicited antibody response to pig Gal and non-Gal antigens. Methods: Eighteen baboons received heterotopic heart transplants from pigs transgenic for human decay-accelerating factor (n = 13) or membrane cofactor protein (n = 5). Ten reference "conventional therapy" animals received cyclosporin A, cyclophosphamide and mycophenolate mofetil, with (n = 4) or without (n = 6) anti-CD20. Eight "co-stimulation blockade" animals received anti-CD154 mAb (IDEC-131) and anti-thymocyte globulin, with (n = 4) or without (n = 4) anti-CD20; two of these animals also received CTLA4-Fc. Anti-αGal IgG and IgM, anti-non-Gal antibodies and graft histology were assessed serially. Results: Excluding two early graft failures, median graft survival with conventional therapy was 15 days (range 6 to 36 days, n = 8). Anti-Gal IgG antibody remained low through day 6 to 10, only one graft failure was accompanied by significant rise in anti-Gal IgG, and the anti-non-Gal response was weak (n = 2) or absent (n = 7). However many recipients succumbed with infection (n = 4) or coagulopathy (n = 2); DXR and ICOS + T cells were prevalent in long-surviving grafts. With co-stimulation blockade, excluding three early graft failures, median graft survival was 7 days (range 6 to 11 days, n = 5). This regimen was very well tolerated, but increased anti-Gal antibody titer within 14 days was associated with graft failure in four of six animals. Although an anti-non-Gal response was present in three of six animals during IDEC-131 monotherapy (one strong, two weak), it was absent in both cases with additional CTLA4-Fc treatment. Conclusions: As used here, CD154 blockade alone does not completely prevent induction of Gal and non-Gal anti-pig antibodies. Our preliminary data suggest that other co-stimulation pathways, including CD28/B7 and ICOS, are sufficient to mediate high-titer anti-non-Gal antibody to porcine antigens in baboons, and contribute significantly to the pathogenesis of DXR.

Original languageEnglish (US)
Pages (from-to)197-208
Number of pages12
JournalXenotransplantation
Volume12
Issue number3
DOIs
StatePublished - May 1 2005

Keywords

  • B7
  • CD154
  • CD28
  • CD40
  • CTLA4
  • Co-stimulation
  • Delayed xenograft rejection
  • ICOS
  • MCP transgenic organs
  • Nonhuman primates
  • T-cell activation
  • Xenoantigen
  • Xenoreactive antibody
  • Xenotransplantation
  • hDAF transgenic organs

ASJC Scopus subject areas

  • Immunology
  • Transplantation

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    Wu, G., Pfeiffer, S., Schröder, C., Zhang, T., Nguyen, B. N., Lea, W., Kelishadi, S., Atkinson, J. B., Schuurman, H. J., White, D. J. G., Azimzadeh, A. M., & Pierson, R. N. (2005). Co-stimulation blockade targeting CD154 and CD28/B7 modulates the induced antibody response after a pig-to-baboon cardiac xenograft. Xenotransplantation, 12(3), 197-208. https://doi.org/10.1111/j.1399-3089.2005.00221.x