Increased immunosuppression, not anticoagulation, extends cardiac xenograft survival

Guerard W. Byrne, William R. Davies, Keiji Oi, Vinay P. Rao, Sumeet S. Teotia, David Ricci, Henry D. Tazelaar, Randall C. Walker, John S. Logan, Christopher G A McGregor

Research output: Contribution to journalArticle

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Abstract

BACKGROUND. Cardiac xenograft function is lost due to delayed xenograft rejection (DXR) characterized by microvascular thrombosis and myocardial necrosis. The cause of DXR is unknown but may result from thrombosis induced by antibody-mediated activation of endothelial cells and/or by incompatibilities in thromboregulatory interactions. METHODS. To examine these issues, a series (Groups 1-6) of previous transgenic CD46 pig-to-baboon heterotopic cardiac transplants were reanalyzed for baseline immunosuppressive levels, graft survival and infectious complications with and without systemic anticoagulation. Groups 1-4 received low dose tacrolimus and sirolimus maintenance therapy, with splenectomy, anti-CD20 and daily α-Gal polymer. Group 1 recipients received no anticoagulation. Groups 2-4 were anticoagulated with aspirin and Plavix, Lovenox, or Coumadin, respectively. Group 5 was treated with Lovenox and high dose tacrolimus and sirolimus maintenance therapy. Group 6 recipients received no postoperative anticoagulation but the same immunosuppression as group 5. RESULTS. Median survival (15-22 days) within groups 1-4 was not significantly different. At rejection all tissues exhibited microvascular thrombosis, coagulative necrosis and similar levels of platelet and fibrin deposition. Groups 5 and 6 median survival (76 days) was significantly increased compared to groups 1-4. There was no significant difference in median survival between Lovenox treated recipients (68 days) and anticoagulant free recipients (96 days). Rejected tissues showed vascular antibody deposition, microvascular thrombosis, and myocyte necrosis. CONCLUSION. Significant prolongation in xenograft survival is achieved by improved immunosuppression. These results suggest that ongoing immune responses remain the major stimulus for DXR.

Original languageEnglish (US)
Pages (from-to)1787-1791
Number of pages5
JournalTransplantation
Volume82
Issue number12
DOIs
StatePublished - Dec 2006

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Heterografts
Immunosuppression
Enoxaparin
Thrombosis
Necrosis
clopidogrel
Tacrolimus
Sirolimus
Antibodies
Papio
Graft Survival
Splenectomy
Warfarin
Immunosuppressive Agents
Fibrin
Anticoagulants
Muscle Cells
Aspirin
Blood Vessels
Polymers

Keywords

  • Anticoagulation
  • Immunosuppression
  • Xenotransplantation

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Byrne, G. W., Davies, W. R., Oi, K., Rao, V. P., Teotia, S. S., Ricci, D., ... McGregor, C. G. A. (2006). Increased immunosuppression, not anticoagulation, extends cardiac xenograft survival. Transplantation, 82(12), 1787-1791. https://doi.org/10.1097/01.tp.0000251387.40499.0f

Increased immunosuppression, not anticoagulation, extends cardiac xenograft survival. / Byrne, Guerard W.; Davies, William R.; Oi, Keiji; Rao, Vinay P.; Teotia, Sumeet S.; Ricci, David; Tazelaar, Henry D.; Walker, Randall C.; Logan, John S.; McGregor, Christopher G A.

In: Transplantation, Vol. 82, No. 12, 12.2006, p. 1787-1791.

Research output: Contribution to journalArticle

Byrne, GW, Davies, WR, Oi, K, Rao, VP, Teotia, SS, Ricci, D, Tazelaar, HD, Walker, RC, Logan, JS & McGregor, CGA 2006, 'Increased immunosuppression, not anticoagulation, extends cardiac xenograft survival', Transplantation, vol. 82, no. 12, pp. 1787-1791. https://doi.org/10.1097/01.tp.0000251387.40499.0f
Byrne, Guerard W. ; Davies, William R. ; Oi, Keiji ; Rao, Vinay P. ; Teotia, Sumeet S. ; Ricci, David ; Tazelaar, Henry D. ; Walker, Randall C. ; Logan, John S. ; McGregor, Christopher G A. / Increased immunosuppression, not anticoagulation, extends cardiac xenograft survival. In: Transplantation. 2006 ; Vol. 82, No. 12. pp. 1787-1791.
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T1 - Increased immunosuppression, not anticoagulation, extends cardiac xenograft survival

AU - Byrne, Guerard W.

AU - Davies, William R.

AU - Oi, Keiji

AU - Rao, Vinay P.

AU - Teotia, Sumeet S.

AU - Ricci, David

AU - Tazelaar, Henry D.

AU - Walker, Randall C.

AU - Logan, John S.

AU - McGregor, Christopher G A

PY - 2006/12

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N2 - BACKGROUND. Cardiac xenograft function is lost due to delayed xenograft rejection (DXR) characterized by microvascular thrombosis and myocardial necrosis. The cause of DXR is unknown but may result from thrombosis induced by antibody-mediated activation of endothelial cells and/or by incompatibilities in thromboregulatory interactions. METHODS. To examine these issues, a series (Groups 1-6) of previous transgenic CD46 pig-to-baboon heterotopic cardiac transplants were reanalyzed for baseline immunosuppressive levels, graft survival and infectious complications with and without systemic anticoagulation. Groups 1-4 received low dose tacrolimus and sirolimus maintenance therapy, with splenectomy, anti-CD20 and daily α-Gal polymer. Group 1 recipients received no anticoagulation. Groups 2-4 were anticoagulated with aspirin and Plavix, Lovenox, or Coumadin, respectively. Group 5 was treated with Lovenox and high dose tacrolimus and sirolimus maintenance therapy. Group 6 recipients received no postoperative anticoagulation but the same immunosuppression as group 5. RESULTS. Median survival (15-22 days) within groups 1-4 was not significantly different. At rejection all tissues exhibited microvascular thrombosis, coagulative necrosis and similar levels of platelet and fibrin deposition. Groups 5 and 6 median survival (76 days) was significantly increased compared to groups 1-4. There was no significant difference in median survival between Lovenox treated recipients (68 days) and anticoagulant free recipients (96 days). Rejected tissues showed vascular antibody deposition, microvascular thrombosis, and myocyte necrosis. CONCLUSION. Significant prolongation in xenograft survival is achieved by improved immunosuppression. These results suggest that ongoing immune responses remain the major stimulus for DXR.

AB - BACKGROUND. Cardiac xenograft function is lost due to delayed xenograft rejection (DXR) characterized by microvascular thrombosis and myocardial necrosis. The cause of DXR is unknown but may result from thrombosis induced by antibody-mediated activation of endothelial cells and/or by incompatibilities in thromboregulatory interactions. METHODS. To examine these issues, a series (Groups 1-6) of previous transgenic CD46 pig-to-baboon heterotopic cardiac transplants were reanalyzed for baseline immunosuppressive levels, graft survival and infectious complications with and without systemic anticoagulation. Groups 1-4 received low dose tacrolimus and sirolimus maintenance therapy, with splenectomy, anti-CD20 and daily α-Gal polymer. Group 1 recipients received no anticoagulation. Groups 2-4 were anticoagulated with aspirin and Plavix, Lovenox, or Coumadin, respectively. Group 5 was treated with Lovenox and high dose tacrolimus and sirolimus maintenance therapy. Group 6 recipients received no postoperative anticoagulation but the same immunosuppression as group 5. RESULTS. Median survival (15-22 days) within groups 1-4 was not significantly different. At rejection all tissues exhibited microvascular thrombosis, coagulative necrosis and similar levels of platelet and fibrin deposition. Groups 5 and 6 median survival (76 days) was significantly increased compared to groups 1-4. There was no significant difference in median survival between Lovenox treated recipients (68 days) and anticoagulant free recipients (96 days). Rejected tissues showed vascular antibody deposition, microvascular thrombosis, and myocyte necrosis. CONCLUSION. Significant prolongation in xenograft survival is achieved by improved immunosuppression. These results suggest that ongoing immune responses remain the major stimulus for DXR.

KW - Anticoagulation

KW - Immunosuppression

KW - Xenotransplantation

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