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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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Anti-non-Gal antibody-mediated cardiac xenograft rejection. This figure shows the immunohistopathology of anti-non-Gal antibody-mediated DXR for Gal-positive CD46 pig heart protected from anti-Gal antibody by continuous infusion of an α-Gal polymer. A. Hematoxylin and eosin stain showing ischemic injury and myocardial coagulative necrosis in a graft with ongoing rejection at 113 days. B. Immunohistochemical staining of the same graft showing positive vascular IgM deposition. The insert shows immunofluorescence staining for fibrin. C. Negative immunohistochemical staining for C5b. The insert shows a low level of positive immunofluorescence staining for CD41 platelet thrombi. All photomicrographs at 200×. (Immunohistochemical staining in panels A–C adapted from: McGregor CGA, et al. Cardiac xenotransplantation: progress toward the clinic. Transplantation. 2004: 78: 1569–1575.)
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fig02: Anti-non-Gal antibody-mediated cardiac xenograft rejection. This figure shows the immunohistopathology of anti-non-Gal antibody-mediated DXR for Gal-positive CD46 pig heart protected from anti-Gal antibody by continuous infusion of an α-Gal polymer. A. Hematoxylin and eosin stain showing ischemic injury and myocardial coagulative necrosis in a graft with ongoing rejection at 113 days. B. Immunohistochemical staining of the same graft showing positive vascular IgM deposition. The insert shows immunofluorescence staining for fibrin. C. Negative immunohistochemical staining for C5b. The insert shows a low level of positive immunofluorescence staining for CD41 platelet thrombi. All photomicrographs at 200×. (Immunohistochemical staining in panels A–C adapted from: McGregor CGA, et al. Cardiac xenotransplantation: progress toward the clinic. Transplantation. 2004: 78: 1569–1575.)

Mentions: Enduring reduction in anti-Gal antibody in vivo was successfully achieved using continuous or intermittent infusion of non-antigenic Gal polymers [1,19,27,31–34]. Of relevance to anti-non-Gal antibody-mediated GTKO pig xenograft rejection, these earlier studies are notable in that, for the first time, transplants using Gal polymers largely blocked the effects of both preformed and post-transplant-induced anti-Gal antibody, leading to a striking change in the histopathology of xenograft rejection [1,33,35]. Whereas anti-Gal-mediated DXR showed prominent interstitial hemorrhage (Fig. 1B), the histopathology of graft failure under conditions that efficiently blocked anti-Gal antibody was largely characterized by microvascular thrombosis with only focal evidence of interstitial hemorrhage (Fig. 1D, Table 1). This thrombotic microangiopathy (TM) was first explicitly noted by Houser using a poly-l-lysine Gal polymer and CD55 (hDAF) transgenic pig hearts [35]. The same histology was also reported using CD46 transgenic donor hearts and a polyethylene glycol Gal polymer [1,33,36,37] and in GTKO cardiac xenografts [3]. In the polymer studies, rejected cardiac xenografts uniformly showed vascular antibody deposition, fibrin, and platelet thrombi, with myocardial coagulative necrosis and ischemia (Fig. 2). Vascular complement deposition, variably measured by detection of C3, C4d, C5b, and C5b-9, was inconsistently observed and may be dependent on donor genetics. Lymphocytic infiltration of the graft was generally minimal or absent.


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)

Anti-non-Gal antibody-mediated cardiac xenograft rejection. This figure shows the immunohistopathology of anti-non-Gal antibody-mediated DXR for Gal-positive CD46 pig heart protected from anti-Gal antibody by continuous infusion of an α-Gal polymer. A. Hematoxylin and eosin stain showing ischemic injury and myocardial coagulative necrosis in a graft with ongoing rejection at 113 days. B. Immunohistochemical staining of the same graft showing positive vascular IgM deposition. The insert shows immunofluorescence staining for fibrin. C. Negative immunohistochemical staining for C5b. The insert shows a low level of positive immunofluorescence staining for CD41 platelet thrombi. All photomicrographs at 200×. (Immunohistochemical staining in panels A–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

License
Show All Figures
getmorefigures.php?uid=PMC4126170&req=5

fig02: Anti-non-Gal antibody-mediated cardiac xenograft rejection. This figure shows the immunohistopathology of anti-non-Gal antibody-mediated DXR for Gal-positive CD46 pig heart protected from anti-Gal antibody by continuous infusion of an α-Gal polymer. A. Hematoxylin and eosin stain showing ischemic injury and myocardial coagulative necrosis in a graft with ongoing rejection at 113 days. B. Immunohistochemical staining of the same graft showing positive vascular IgM deposition. The insert shows immunofluorescence staining for fibrin. C. Negative immunohistochemical staining for C5b. The insert shows a low level of positive immunofluorescence staining for CD41 platelet thrombi. All photomicrographs at 200×. (Immunohistochemical staining in panels A–C adapted from: McGregor CGA, et al. Cardiac xenotransplantation: progress toward the clinic. Transplantation. 2004: 78: 1569–1575.)
Mentions: Enduring reduction in anti-Gal antibody in vivo was successfully achieved using continuous or intermittent infusion of non-antigenic Gal polymers [1,19,27,31–34]. Of relevance to anti-non-Gal antibody-mediated GTKO pig xenograft rejection, these earlier studies are notable in that, for the first time, transplants using Gal polymers largely blocked the effects of both preformed and post-transplant-induced anti-Gal antibody, leading to a striking change in the histopathology of xenograft rejection [1,33,35]. Whereas anti-Gal-mediated DXR showed prominent interstitial hemorrhage (Fig. 1B), the histopathology of graft failure under conditions that efficiently blocked anti-Gal antibody was largely characterized by microvascular thrombosis with only focal evidence of interstitial hemorrhage (Fig. 1D, Table 1). This thrombotic microangiopathy (TM) was first explicitly noted by Houser using a poly-l-lysine Gal polymer and CD55 (hDAF) transgenic pig hearts [35]. The same histology was also reported using CD46 transgenic donor hearts and a polyethylene glycol Gal polymer [1,33,36,37] and in GTKO cardiac xenografts [3]. In the polymer studies, rejected cardiac xenografts uniformly showed vascular antibody deposition, fibrin, and platelet thrombi, with myocardial coagulative necrosis and ischemia (Fig. 2). Vascular complement deposition, variably measured by detection of C3, C4d, C5b, and C5b-9, was inconsistently observed and may be dependent on donor genetics. Lymphocytic infiltration of the graft was generally minimal or absent.

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