T-cell responses during pig-to-primate xenotransplantation

Eduardo Davila, Guerard W. Byrne, Peter T. LaBreche, Hugh C J McGregor, Allison K. Schwab, William R. Davies, Vinay P. Rao, Keiji Oi, Henry D. Tazelaar, John S. Logan, Christopher G A McGregor

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Xenotransplantation using porcine organs may resolve a chronic shortage of donor organs for clinical transplantation if significant immunological barriers can be overcome. To determine the potential role of T lymphocytes in Xenograft (Xg) rejection, we transplanted transgenic hCD46 porcine hearts heterotopically into baboon recipients. Methods: Recipients were treated to deplete anti-Gal antibody with a non-antigenic α-Gal polyethylene glycol polymer (TPC) (n=2), TPC plus rituximab (anti-CD20) (n=1) or were untreated (n=1). None of the recipients received T-cell immunosuppression. Results: All Xgs failed within 7 days and showed evidence of a mixed humoral and cellular rejection process. Cellular infiltration consisting primarily of CD4+ T cells and few CD8+ T cells. Proliferation and cytotoxicity assays showed sensitization of CD4+ and CD8+ T cells that reacted with porcine IFN-γ (pIFN-γ)-stimulated porcine aortic endothelial cells (PAEC). The CD4+ lymphocytes displayed greater cytotoxicity than CD8+ cells. An increased frequency of PAEC-specific interleukin (IL) 2 and IFN-γ-secreting T cells was observed, suggesting a Th1 cytokine bias. An increase in the percentage of circulating CD4+CD28- cells was observed at the time of rejection and over 50% of the CD4+ cells recovered from residual pig tissue at necropsy lacked CD28 expression. Conclusions: These findings show that lymphocytes are efficiently stimulated by PAEC antigens and can mediate direct tissue destruction. These studies (1) provide an insight into the potential of cellular-mediated cardiac Xg rejection, (2) show for the first time the induction of cytotoxic pig-specific CD4+CD28- lymphocytes and (3) provide a rational basis for determining different modes of immunosuppression to treat Xg rejection.

Original languageEnglish (US)
Pages (from-to)31-40
Number of pages10
JournalXenotransplantation
Volume13
Issue number1
DOIs
StatePublished - Jan 2006

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Heterologous Transplantation
Primates
Swine
T-Lymphocytes
Heterografts
Endothelial Cells
Lymphocytes
Immunosuppression
Papio
Organ Transplantation
Interleukin-2
Anti-Idiotypic Antibodies
Polymers
Cytokines
Antigens

Keywords

  • Cell activation
  • Cytotoxicity
  • T cells
  • Transplantation

ASJC Scopus subject areas

  • Immunology

Cite this

Davila, E., Byrne, G. W., LaBreche, P. T., McGregor, H. C. J., Schwab, A. K., Davies, W. R., ... McGregor, C. G. A. (2006). T-cell responses during pig-to-primate xenotransplantation. Xenotransplantation, 13(1), 31-40. https://doi.org/10.1111/j.1399-3089.2005.00258.x

T-cell responses during pig-to-primate xenotransplantation. / Davila, Eduardo; Byrne, Guerard W.; LaBreche, Peter T.; McGregor, Hugh C J; Schwab, Allison K.; Davies, William R.; Rao, Vinay P.; Oi, Keiji; Tazelaar, Henry D.; Logan, John S.; McGregor, Christopher G A.

In: Xenotransplantation, Vol. 13, No. 1, 01.2006, p. 31-40.

Research output: Contribution to journalArticle

Davila, E, Byrne, GW, LaBreche, PT, McGregor, HCJ, Schwab, AK, Davies, WR, Rao, VP, Oi, K, Tazelaar, HD, Logan, JS & McGregor, CGA 2006, 'T-cell responses during pig-to-primate xenotransplantation', Xenotransplantation, vol. 13, no. 1, pp. 31-40. https://doi.org/10.1111/j.1399-3089.2005.00258.x
Davila E, Byrne GW, LaBreche PT, McGregor HCJ, Schwab AK, Davies WR et al. T-cell responses during pig-to-primate xenotransplantation. Xenotransplantation. 2006 Jan;13(1):31-40. https://doi.org/10.1111/j.1399-3089.2005.00258.x
Davila, Eduardo ; Byrne, Guerard W. ; LaBreche, Peter T. ; McGregor, Hugh C J ; Schwab, Allison K. ; Davies, William R. ; Rao, Vinay P. ; Oi, Keiji ; Tazelaar, Henry D. ; Logan, John S. ; McGregor, Christopher G A. / T-cell responses during pig-to-primate xenotransplantation. In: Xenotransplantation. 2006 ; Vol. 13, No. 1. pp. 31-40.
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abstract = "Xenotransplantation using porcine organs may resolve a chronic shortage of donor organs for clinical transplantation if significant immunological barriers can be overcome. To determine the potential role of T lymphocytes in Xenograft (Xg) rejection, we transplanted transgenic hCD46 porcine hearts heterotopically into baboon recipients. Methods: Recipients were treated to deplete anti-Gal antibody with a non-antigenic α-Gal polyethylene glycol polymer (TPC) (n=2), TPC plus rituximab (anti-CD20) (n=1) or were untreated (n=1). None of the recipients received T-cell immunosuppression. Results: All Xgs failed within 7 days and showed evidence of a mixed humoral and cellular rejection process. Cellular infiltration consisting primarily of CD4+ T cells and few CD8+ T cells. Proliferation and cytotoxicity assays showed sensitization of CD4+ and CD8+ T cells that reacted with porcine IFN-γ (pIFN-γ)-stimulated porcine aortic endothelial cells (PAEC). The CD4+ lymphocytes displayed greater cytotoxicity than CD8+ cells. An increased frequency of PAEC-specific interleukin (IL) 2 and IFN-γ-secreting T cells was observed, suggesting a Th1 cytokine bias. An increase in the percentage of circulating CD4+CD28- cells was observed at the time of rejection and over 50{\%} of the CD4+ cells recovered from residual pig tissue at necropsy lacked CD28 expression. Conclusions: These findings show that lymphocytes are efficiently stimulated by PAEC antigens and can mediate direct tissue destruction. These studies (1) provide an insight into the potential of cellular-mediated cardiac Xg rejection, (2) show for the first time the induction of cytotoxic pig-specific CD4+CD28- lymphocytes and (3) provide a rational basis for determining different modes of immunosuppression to treat Xg rejection.",
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