Human CD55 expression blocks hyperacute rejection and restricts complement activation in gal knockout cardiac xenografts

Christopher G A McGregor, Davide Ricci, Naoto Miyagi, Paul G. Stalboerger, Zeji Du, Elise A. Oehler, Henry D. Tazelaar, Guerard W. Byrne

Research output: Contribution to journalArticle

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Abstract

Background. Transgenic expression of human complement regulatory proteins reduces the frequency of hyperacute rejection (HAR) in Gal-positive cardiac xenotransplantation. In this study, we examined the impact of human CD55 (hCD55) expression on a Gal knockout (GTKO) background using pig-to-primate heterotopic cardiac xenotransplantation. Methods. Cardiac xenotransplantation was performed with GTKO (group 1; n=6) and GTKO.hCD55 (group 2; n=5) donor pigs using similar immunosuppression. Cardiac biopsies were obtained 30 min after organ reperfusion. Rejection was characterized by histology and immunohistology. Intragraft gene expression, serum non-Gal antibody, and antibody recovered from rejected hearts were analyzed. Results. HAR of a GTKO heart was observed. Remaining grafts developed delayed xenograft rejection. Median survival was 21 and 28 days for groups 1 and 2, respectively. Vascular antibody deposition was uniformly detected 30 min after organ reperfusion and at explant. A higher frequency of vascular C5b deposition was seen in GTKO organs at explant. Serum non-Gal antibody, antibody recovered from the graft, and intragraft gene expression were similar between the groups. Conclusion. HAR of GTKO hearts without hCD55 may occur. Expression of hCD55 seemed to restrict local complement activation but did not improve graft survival. Chronic vascular antibody deposition with evidence of protracted endothelial cell activation was seen. These observations suggest that non-Gal antibody-induced chronic endothelial cell activation coupled to possible hemostatic incompatibilities may be the primary stimulus for delayed xenograft rejection of GTKO hearts. To avoid possible HAR, future clinical studies should use donors expressing human complement regulatory proteins in the GTKO background.

Original languageEnglish (US)
Pages (from-to)686-692
Number of pages7
JournalTransplantation
Volume93
Issue number7
DOIs
StatePublished - Apr 15 2012

Fingerprint

Complement Activation
Heterografts
Antibodies
Heterologous Transplantation
Blood Vessels
Reperfusion
Complement System Proteins
Swine
Endothelial Cells
Transplants
Gene Expression
Graft Survival
Hemostatics
Serum
Immunosuppression
Primates
Histology
Biopsy
Survival

Keywords

  • Antibody-mediated rejection
  • Cardiac xenotransplantation
  • Complement regulation
  • Endothelial cell activation
  • Xenotransplantation

ASJC Scopus subject areas

  • Transplantation

Cite this

McGregor, C. G. A., Ricci, D., Miyagi, N., Stalboerger, P. G., Du, Z., Oehler, E. A., ... Byrne, G. W. (2012). Human CD55 expression blocks hyperacute rejection and restricts complement activation in gal knockout cardiac xenografts. Transplantation, 93(7), 686-692. https://doi.org/10.1097/TP.0b013e3182472850

Human CD55 expression blocks hyperacute rejection and restricts complement activation in gal knockout cardiac xenografts. / McGregor, Christopher G A; Ricci, Davide; Miyagi, Naoto; Stalboerger, Paul G.; Du, Zeji; Oehler, Elise A.; Tazelaar, Henry D.; Byrne, Guerard W.

In: Transplantation, Vol. 93, No. 7, 15.04.2012, p. 686-692.

Research output: Contribution to journalArticle

McGregor, CGA, Ricci, D, Miyagi, N, Stalboerger, PG, Du, Z, Oehler, EA, Tazelaar, HD & Byrne, GW 2012, 'Human CD55 expression blocks hyperacute rejection and restricts complement activation in gal knockout cardiac xenografts', Transplantation, vol. 93, no. 7, pp. 686-692. https://doi.org/10.1097/TP.0b013e3182472850
McGregor, Christopher G A ; Ricci, Davide ; Miyagi, Naoto ; Stalboerger, Paul G. ; Du, Zeji ; Oehler, Elise A. ; Tazelaar, Henry D. ; Byrne, Guerard W. / Human CD55 expression blocks hyperacute rejection and restricts complement activation in gal knockout cardiac xenografts. In: Transplantation. 2012 ; Vol. 93, No. 7. pp. 686-692.
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AU - McGregor, Christopher G A

AU - Ricci, Davide

AU - Miyagi, Naoto

AU - Stalboerger, Paul G.

AU - Du, Zeji

AU - Oehler, Elise A.

AU - Tazelaar, Henry D.

AU - Byrne, Guerard W.

PY - 2012/4/15

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N2 - Background. Transgenic expression of human complement regulatory proteins reduces the frequency of hyperacute rejection (HAR) in Gal-positive cardiac xenotransplantation. In this study, we examined the impact of human CD55 (hCD55) expression on a Gal knockout (GTKO) background using pig-to-primate heterotopic cardiac xenotransplantation. Methods. Cardiac xenotransplantation was performed with GTKO (group 1; n=6) and GTKO.hCD55 (group 2; n=5) donor pigs using similar immunosuppression. Cardiac biopsies were obtained 30 min after organ reperfusion. Rejection was characterized by histology and immunohistology. Intragraft gene expression, serum non-Gal antibody, and antibody recovered from rejected hearts were analyzed. Results. HAR of a GTKO heart was observed. Remaining grafts developed delayed xenograft rejection. Median survival was 21 and 28 days for groups 1 and 2, respectively. Vascular antibody deposition was uniformly detected 30 min after organ reperfusion and at explant. A higher frequency of vascular C5b deposition was seen in GTKO organs at explant. Serum non-Gal antibody, antibody recovered from the graft, and intragraft gene expression were similar between the groups. Conclusion. HAR of GTKO hearts without hCD55 may occur. Expression of hCD55 seemed to restrict local complement activation but did not improve graft survival. Chronic vascular antibody deposition with evidence of protracted endothelial cell activation was seen. These observations suggest that non-Gal antibody-induced chronic endothelial cell activation coupled to possible hemostatic incompatibilities may be the primary stimulus for delayed xenograft rejection of GTKO hearts. To avoid possible HAR, future clinical studies should use donors expressing human complement regulatory proteins in the GTKO background.

AB - Background. Transgenic expression of human complement regulatory proteins reduces the frequency of hyperacute rejection (HAR) in Gal-positive cardiac xenotransplantation. In this study, we examined the impact of human CD55 (hCD55) expression on a Gal knockout (GTKO) background using pig-to-primate heterotopic cardiac xenotransplantation. Methods. Cardiac xenotransplantation was performed with GTKO (group 1; n=6) and GTKO.hCD55 (group 2; n=5) donor pigs using similar immunosuppression. Cardiac biopsies were obtained 30 min after organ reperfusion. Rejection was characterized by histology and immunohistology. Intragraft gene expression, serum non-Gal antibody, and antibody recovered from rejected hearts were analyzed. Results. HAR of a GTKO heart was observed. Remaining grafts developed delayed xenograft rejection. Median survival was 21 and 28 days for groups 1 and 2, respectively. Vascular antibody deposition was uniformly detected 30 min after organ reperfusion and at explant. A higher frequency of vascular C5b deposition was seen in GTKO organs at explant. Serum non-Gal antibody, antibody recovered from the graft, and intragraft gene expression were similar between the groups. Conclusion. HAR of GTKO hearts without hCD55 may occur. Expression of hCD55 seemed to restrict local complement activation but did not improve graft survival. Chronic vascular antibody deposition with evidence of protracted endothelial cell activation was seen. These observations suggest that non-Gal antibody-induced chronic endothelial cell activation coupled to possible hemostatic incompatibilities may be the primary stimulus for delayed xenograft rejection of GTKO hearts. To avoid possible HAR, future clinical studies should use donors expressing human complement regulatory proteins in the GTKO background.

KW - Antibody-mediated rejection

KW - Cardiac xenotransplantation

KW - Complement regulation

KW - Endothelial cell activation

KW - Xenotransplantation

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