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Histopathologic insights into the mechanism of anti-non-Gal antibody-mediated pig cardiac xenograft rejection.

Byrne GW, Azimzadeh AM, Ezzelarab M, Tazelaar HD, Ekser B, Pierson RN, Robson SC, Cooper DK, McGregor CG - Xenotransplantation (2013 Sep-Oct)

Bottom Line: The histopathology of cardiac xenograft rejection has evolved over the last 20 yr with the development of new modalities for limiting antibody-mediated injury, advancing regimens for immune suppression, and an ever-widening variety of new donor genetics.These new technologies have helped us progress from what was once an overwhelming anti-Gal-mediated hyperacute rejection to a more protracted anti-Gal-mediated vascular rejection to what is now a more complex manifestation of non-Gal humoral rejection and coagulation dysregulation.This review summarizes the changing histopathology of Gal- and non-Gal-mediated cardiac xenograft rejection and discusses the contributions of immune-mediated injury, species-specific immune-independent factors, transplant and therapeutic procedures, and donor genetics to the overall mechanism(s) of cardiac xenograft rejection.

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Affiliation: Institute of Cardiovascular Science, University College London, London, UK; Department of Surgery, Mayo Clinic, Rochester, MN, USA.

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Histopathology of xenograft rejection. The figure shows a comparison between anti-Gal and non-Gal antibody-mediated cardiac xenograft rejection. All panels show hematoxylin and eosin staining. A. Anti-Gal antibody-induced hyperacute rejection of a Gal-positive heart showing widespread intravascular hemorrhage characteristic of HAR. B. Anti-Gal antibody-mediated delayed xenograft rejection (DXR) of a Gal-positive heart on post-operative day 10. The rejected graft shows vascular injury, hemorrhage, and coagulative necrosis characteristic of anti-Gal-mediated DXR. C. Non-Gal antibody-mediated hyperacute rejection of a GTKO heart 90 min after reperfusion showing intravascular hemorrhage similar to that seen in Gal-mediated HAR (panel A). D. Non-Gal-mediated DXR on post-operative day 92 of a Gal-positive CD46 transgenic heart showing thrombotic microangiopathy. The recipient in panel D received chronic alpha-Gal polymer infusions to block anti-Gal antibody. Original magnification A and C 400×, B and D 200× (Panel C adapted from: McGregor CGA, et al. Cardiac xenotransplantation: progress toward the clinic. Transplantation. 2004: 78: 1569–1575.)
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fig01: Histopathology of xenograft rejection. The figure shows a comparison between anti-Gal and non-Gal antibody-mediated cardiac xenograft rejection. All panels show hematoxylin and eosin staining. A. Anti-Gal antibody-induced hyperacute rejection of a Gal-positive heart showing widespread intravascular hemorrhage characteristic of HAR. B. Anti-Gal antibody-mediated delayed xenograft rejection (DXR) of a Gal-positive heart on post-operative day 10. The rejected graft shows vascular injury, hemorrhage, and coagulative necrosis characteristic of anti-Gal-mediated DXR. C. Non-Gal antibody-mediated hyperacute rejection of a GTKO heart 90 min after reperfusion showing intravascular hemorrhage similar to that seen in Gal-mediated HAR (panel A). D. Non-Gal-mediated DXR on post-operative day 92 of a Gal-positive CD46 transgenic heart showing thrombotic microangiopathy. The recipient in panel D received chronic alpha-Gal polymer infusions to block anti-Gal antibody. Original magnification A and C 400×, B and D 200× (Panel C adapted from: McGregor CGA, et al. Cardiac xenotransplantation: progress toward the clinic. Transplantation. 2004: 78: 1569–1575.)

Mentions: The initial barrier to xenotransplantation was hyperacute rejection (HAR) caused by complement-mediated endothelial cell (EC) destruction directed by preformed anti-Gal antibody. The histopathology of HAR is predominantly characterized by rapid graft failure and widespread intravascular hemorrhage (Fig. 1A,C, Table 1). This is accompanied by vascular antibody, complement, and fibrin deposition with the formation of platelet-rich thrombi (not shown) [23–27]. Improved xenograft survival was not reliably achieved until methods were developed to block the effects of complement and anti-Gal antibody. Early attempts depleted anti-Gal antibody through pig-specific organ perfusion [10,23,24], plasmapheresis, or affinity immunoadsorption [11–14,28,29]. These studies demonstrated the dominant role of anti-Gal antibody in graft rejection [14,28–30], but provided only temporary antibody reduction. An induced anti-Gal antibody response led to delayed xenograft rejection (DXR) also characterized by interstitial hemorrhage, vascular antibody and complement deposition with diffuse platelet-rich fibrin thrombosis (Fig. 1B, Table 1). Unlike HAR, DXR occurs over the course of days to weeks, and vascular antibody and complement deposition, nearly universal in HAR, is more variable in DXR. This is due in part to the efficacy of different modalities (hCRP transgenic organs, cobra venom factor, plasmapheresis, or soluble complement inhibitors) used to limit antibody-dependent complement-mediated injury.


Histopathologic insights into the mechanism of anti-non-Gal antibody-mediated pig cardiac xenograft rejection.

Byrne GW, Azimzadeh AM, Ezzelarab M, Tazelaar HD, Ekser B, Pierson RN, Robson SC, Cooper DK, McGregor CG - Xenotransplantation (2013 Sep-Oct)

Histopathology of xenograft rejection. The figure shows a comparison between anti-Gal and non-Gal antibody-mediated cardiac xenograft rejection. All panels show hematoxylin and eosin staining. A. Anti-Gal antibody-induced hyperacute rejection of a Gal-positive heart showing widespread intravascular hemorrhage characteristic of HAR. B. Anti-Gal antibody-mediated delayed xenograft rejection (DXR) of a Gal-positive heart on post-operative day 10. The rejected graft shows vascular injury, hemorrhage, and coagulative necrosis characteristic of anti-Gal-mediated DXR. C. Non-Gal antibody-mediated hyperacute rejection of a GTKO heart 90 min after reperfusion showing intravascular hemorrhage similar to that seen in Gal-mediated HAR (panel A). D. Non-Gal-mediated DXR on post-operative day 92 of a Gal-positive CD46 transgenic heart showing thrombotic microangiopathy. The recipient in panel D received chronic alpha-Gal polymer infusions to block anti-Gal antibody. Original magnification A and C 400×, B and D 200× (Panel C adapted from: McGregor CGA, et al. Cardiac xenotransplantation: progress toward the clinic. Transplantation. 2004: 78: 1569–1575.)
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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fig01: Histopathology of xenograft rejection. The figure shows a comparison between anti-Gal and non-Gal antibody-mediated cardiac xenograft rejection. All panels show hematoxylin and eosin staining. A. Anti-Gal antibody-induced hyperacute rejection of a Gal-positive heart showing widespread intravascular hemorrhage characteristic of HAR. B. Anti-Gal antibody-mediated delayed xenograft rejection (DXR) of a Gal-positive heart on post-operative day 10. The rejected graft shows vascular injury, hemorrhage, and coagulative necrosis characteristic of anti-Gal-mediated DXR. C. Non-Gal antibody-mediated hyperacute rejection of a GTKO heart 90 min after reperfusion showing intravascular hemorrhage similar to that seen in Gal-mediated HAR (panel A). D. Non-Gal-mediated DXR on post-operative day 92 of a Gal-positive CD46 transgenic heart showing thrombotic microangiopathy. The recipient in panel D received chronic alpha-Gal polymer infusions to block anti-Gal antibody. Original magnification A and C 400×, B and D 200× (Panel C adapted from: McGregor CGA, et al. Cardiac xenotransplantation: progress toward the clinic. Transplantation. 2004: 78: 1569–1575.)
Mentions: The initial barrier to xenotransplantation was hyperacute rejection (HAR) caused by complement-mediated endothelial cell (EC) destruction directed by preformed anti-Gal antibody. The histopathology of HAR is predominantly characterized by rapid graft failure and widespread intravascular hemorrhage (Fig. 1A,C, Table 1). This is accompanied by vascular antibody, complement, and fibrin deposition with the formation of platelet-rich thrombi (not shown) [23–27]. Improved xenograft survival was not reliably achieved until methods were developed to block the effects of complement and anti-Gal antibody. Early attempts depleted anti-Gal antibody through pig-specific organ perfusion [10,23,24], plasmapheresis, or affinity immunoadsorption [11–14,28,29]. These studies demonstrated the dominant role of anti-Gal antibody in graft rejection [14,28–30], but provided only temporary antibody reduction. An induced anti-Gal antibody response led to delayed xenograft rejection (DXR) also characterized by interstitial hemorrhage, vascular antibody and complement deposition with diffuse platelet-rich fibrin thrombosis (Fig. 1B, Table 1). Unlike HAR, DXR occurs over the course of days to weeks, and vascular antibody and complement deposition, nearly universal in HAR, is more variable in DXR. This is due in part to the efficacy of different modalities (hCRP transgenic organs, cobra venom factor, plasmapheresis, or soluble complement inhibitors) used to limit antibody-dependent complement-mediated injury.

Bottom Line: The histopathology of cardiac xenograft rejection has evolved over the last 20 yr with the development of new modalities for limiting antibody-mediated injury, advancing regimens for immune suppression, and an ever-widening variety of new donor genetics.These new technologies have helped us progress from what was once an overwhelming anti-Gal-mediated hyperacute rejection to a more protracted anti-Gal-mediated vascular rejection to what is now a more complex manifestation of non-Gal humoral rejection and coagulation dysregulation.This review summarizes the changing histopathology of Gal- and non-Gal-mediated cardiac xenograft rejection and discusses the contributions of immune-mediated injury, species-specific immune-independent factors, transplant and therapeutic procedures, and donor genetics to the overall mechanism(s) of cardiac xenograft rejection.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cardiovascular Science, University College London, London, UK; Department of Surgery, Mayo Clinic, Rochester, MN, USA.

Show MeSH
Related in: MedlinePlus