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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.

View Article: PubMed Central - PubMed

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

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Histopathologic features of DXR in the absence of the effects of anti-Gal antibody. Data from three treatment groups are shown. (i) Recipient treated by plasmapheresis (Pheresis) to deplete anti-Gal antibody pre- and post-transplant; (ii) Chronic Gal-polymer-treated recipient to block anti-Gal antibody in vivo; and (iii) Transplantation of a GTKO donor heart. A. Histologic features of DXR in the absence of acute anti-Gal antibody. The intensity of major histopathologic features at explant (mean histology score ± standard error of the mean) are shown. (Abbreviations: CN, coagulative necrosis; MV, myocyte vacuolization; MT, microvascular thrombosis; CON, congestion; HM, hemorrhage.) B–D. Progressive development of DXR (H&E 400×). B. Cardiac biopsy from an apheresis-treated recipient (day 13 of 53) showing early (stage 1) DXR characterized by myocyte vacuolization with minimal microvascular thrombosis or systemic release of cardiac troponin. Insert shows a stage 1 biopsy (day 47 of 71) from a GTKO/CD55 heart (H&E 200×). C. Interim biopsy (day 15 of 21) of a heart from an apheresis-treated recipient showing progressive (stage 2) DXR, characterized by increased levels of microvascular thrombosis (arrows) and developing coagulative necrosis. Insert shows a stage 2 biopsy (day 14 of 26) of a GTKO/CD55 heart (H&E 200×). D. Representative histopathology of grafts at explant in all three groups (Portions of this figure adapted from data in Tazelaar HD, Byrne GW, McGregor CG. Comparison of Gal and non-Gal-mediated cardiac xenograft rejection. Transplantation. 2011: 91: 968–975).
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fig03: Histopathologic features of DXR in the absence of the effects of anti-Gal antibody. Data from three treatment groups are shown. (i) Recipient treated by plasmapheresis (Pheresis) to deplete anti-Gal antibody pre- and post-transplant; (ii) Chronic Gal-polymer-treated recipient to block anti-Gal antibody in vivo; and (iii) Transplantation of a GTKO donor heart. A. Histologic features of DXR in the absence of acute anti-Gal antibody. The intensity of major histopathologic features at explant (mean histology score ± standard error of the mean) are shown. (Abbreviations: CN, coagulative necrosis; MV, myocyte vacuolization; MT, microvascular thrombosis; CON, congestion; HM, hemorrhage.) B–D. Progressive development of DXR (H&E 400×). B. Cardiac biopsy from an apheresis-treated recipient (day 13 of 53) showing early (stage 1) DXR characterized by myocyte vacuolization with minimal microvascular thrombosis or systemic release of cardiac troponin. Insert shows a stage 1 biopsy (day 47 of 71) from a GTKO/CD55 heart (H&E 200×). C. Interim biopsy (day 15 of 21) of a heart from an apheresis-treated recipient showing progressive (stage 2) DXR, characterized by increased levels of microvascular thrombosis (arrows) and developing coagulative necrosis. Insert shows a stage 2 biopsy (day 14 of 26) of a GTKO/CD55 heart (H&E 200×). D. Representative histopathology of grafts at explant in all three groups (Portions of this figure adapted from data in Tazelaar HD, Byrne GW, McGregor CG. Comparison of Gal and non-Gal-mediated cardiac xenograft rejection. Transplantation. 2011: 91: 968–975).

Mentions: This change in histopathology was attributed to sustained depletion of anti-Gal antibody. A recent histopathology comparison of cardiac xenografts under conditions where pre-transplant anti-Gal antibody was uniformly depleted and post-transplant induction of anti-Gal antibody was either partially muted by immunoapheresis, blocked by in vivo Gal polymers, or made irrelevant using GTKO donor hearts supports this conclusion [38]. Under these conditions, the major histopathologic features of developing and terminal xenograft rejection were the same for each group (Fig. 3A). Early evidence of rejection included vascular antibody deposition at 30 min after organ reperfusion and, at later time points, consistent myocyte vacuolization in the absence of appreciable microvascular thrombosis (Fig. 3B). As rejection progressed, based on the systemic release of cardiac troponin, diffuse microvascular thrombosis developed, eventually leading to myocardial coagulative necrosis and ischemic changes (Fig. 3C). At the time of graft failure, all three groups showed prominent microvascular thrombosis and coagulative necrosis with minimal interstitial hemorrhage or lymphocytic infiltration (Fig. 3D). Taken together, these results suggest that muting or elimination of the acute effects of preformed anti-Gal antibody reduced the intensity of humoral rejection, which likely limited the extent of interstitial hemorrhage. Gene expression analysis of these transplants suggested that a chronic state of antibody-mediated EC activation likely contributed to the development of TM [38].


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)

Histopathologic features of DXR in the absence of the effects of anti-Gal antibody. Data from three treatment groups are shown. (i) Recipient treated by plasmapheresis (Pheresis) to deplete anti-Gal antibody pre- and post-transplant; (ii) Chronic Gal-polymer-treated recipient to block anti-Gal antibody in vivo; and (iii) Transplantation of a GTKO donor heart. A. Histologic features of DXR in the absence of acute anti-Gal antibody. The intensity of major histopathologic features at explant (mean histology score ± standard error of the mean) are shown. (Abbreviations: CN, coagulative necrosis; MV, myocyte vacuolization; MT, microvascular thrombosis; CON, congestion; HM, hemorrhage.) B–D. Progressive development of DXR (H&E 400×). B. Cardiac biopsy from an apheresis-treated recipient (day 13 of 53) showing early (stage 1) DXR characterized by myocyte vacuolization with minimal microvascular thrombosis or systemic release of cardiac troponin. Insert shows a stage 1 biopsy (day 47 of 71) from a GTKO/CD55 heart (H&E 200×). C. Interim biopsy (day 15 of 21) of a heart from an apheresis-treated recipient showing progressive (stage 2) DXR, characterized by increased levels of microvascular thrombosis (arrows) and developing coagulative necrosis. Insert shows a stage 2 biopsy (day 14 of 26) of a GTKO/CD55 heart (H&E 200×). D. Representative histopathology of grafts at explant in all three groups (Portions of this figure adapted from data in Tazelaar HD, Byrne GW, McGregor CG. Comparison of Gal and non-Gal-mediated cardiac xenograft rejection. Transplantation. 2011: 91: 968–975).
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fig03: Histopathologic features of DXR in the absence of the effects of anti-Gal antibody. Data from three treatment groups are shown. (i) Recipient treated by plasmapheresis (Pheresis) to deplete anti-Gal antibody pre- and post-transplant; (ii) Chronic Gal-polymer-treated recipient to block anti-Gal antibody in vivo; and (iii) Transplantation of a GTKO donor heart. A. Histologic features of DXR in the absence of acute anti-Gal antibody. The intensity of major histopathologic features at explant (mean histology score ± standard error of the mean) are shown. (Abbreviations: CN, coagulative necrosis; MV, myocyte vacuolization; MT, microvascular thrombosis; CON, congestion; HM, hemorrhage.) B–D. Progressive development of DXR (H&E 400×). B. Cardiac biopsy from an apheresis-treated recipient (day 13 of 53) showing early (stage 1) DXR characterized by myocyte vacuolization with minimal microvascular thrombosis or systemic release of cardiac troponin. Insert shows a stage 1 biopsy (day 47 of 71) from a GTKO/CD55 heart (H&E 200×). C. Interim biopsy (day 15 of 21) of a heart from an apheresis-treated recipient showing progressive (stage 2) DXR, characterized by increased levels of microvascular thrombosis (arrows) and developing coagulative necrosis. Insert shows a stage 2 biopsy (day 14 of 26) of a GTKO/CD55 heart (H&E 200×). D. Representative histopathology of grafts at explant in all three groups (Portions of this figure adapted from data in Tazelaar HD, Byrne GW, McGregor CG. Comparison of Gal and non-Gal-mediated cardiac xenograft rejection. Transplantation. 2011: 91: 968–975).
Mentions: This change in histopathology was attributed to sustained depletion of anti-Gal antibody. A recent histopathology comparison of cardiac xenografts under conditions where pre-transplant anti-Gal antibody was uniformly depleted and post-transplant induction of anti-Gal antibody was either partially muted by immunoapheresis, blocked by in vivo Gal polymers, or made irrelevant using GTKO donor hearts supports this conclusion [38]. Under these conditions, the major histopathologic features of developing and terminal xenograft rejection were the same for each group (Fig. 3A). Early evidence of rejection included vascular antibody deposition at 30 min after organ reperfusion and, at later time points, consistent myocyte vacuolization in the absence of appreciable microvascular thrombosis (Fig. 3B). As rejection progressed, based on the systemic release of cardiac troponin, diffuse microvascular thrombosis developed, eventually leading to myocardial coagulative necrosis and ischemic changes (Fig. 3C). At the time of graft failure, all three groups showed prominent microvascular thrombosis and coagulative necrosis with minimal interstitial hemorrhage or lymphocytic infiltration (Fig. 3D). Taken together, these results suggest that muting or elimination of the acute effects of preformed anti-Gal antibody reduced the intensity of humoral rejection, which likely limited the extent of interstitial hemorrhage. Gene expression analysis of these transplants suggested that a chronic state of antibody-mediated EC activation likely contributed to the development of TM [38].

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