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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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Expression of recipient TF in cardiac xenotransplantation. Immunohistochemical staining for recipient baboon tissue factor (bTF) expression in rejected cardiac xenografts. A. Staining for bTF in pig heart grafts that rejected at day 12. B. bTF expression at 8 weeks. Both photomicrographs in A and B show strong TF staining in thrombosed vessels and less staining in the interstitium (arrows) (×600). C and D. Colocalization of bTF (red stain) and macrophages (stained for CD68, brown) in heart grafts excised on day 12 (C) and at 8 weeks (D) is indicated by arrows (×600) (Reproduced with permission from Ezzelarab M, et al. Transplantation 2009; 87: 805–812).
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fig04: Expression of recipient TF in cardiac xenotransplantation. Immunohistochemical staining for recipient baboon tissue factor (bTF) expression in rejected cardiac xenografts. A. Staining for bTF in pig heart grafts that rejected at day 12. B. bTF expression at 8 weeks. Both photomicrographs in A and B show strong TF staining in thrombosed vessels and less staining in the interstitium (arrows) (×600). C and D. Colocalization of bTF (red stain) and macrophages (stained for CD68, brown) in heart grafts excised on day 12 (C) and at 8 weeks (D) is indicated by arrows (×600) (Reproduced with permission from Ezzelarab M, et al. Transplantation 2009; 87: 805–812).

Mentions: α1,3-galactosyltransferase gene knockout pigs heart xenografts have also been reported to undergo early immune injury from preformed anti-non-Gal antibody, which did not result in HAR [34,41]. In these studies, GTKO graft survival was <1 day in the absence of immune suppression, but was extended to 2 to 12 days with “partial” immune suppression and up to 8 weeks with a “full” regimen. Xenograft rejection was complex, as the grafts, regardless of the efficiency of immune suppression, showed evidence of both humoral rejection, in the form of vascular antibody and complement deposition, and recipient innate immune cell activation. The innate cell activation was manifested as CC (defined by thrombocytopenia, low fibrinogen levels, prolongation of prothrombin and activated partial thromboplastin times, bleeding) and as a significantly increased level of intragraft neutrophil infiltration with a marked increase in recipient baboon tissue factor (bTF) expression from intragraft and graft adherent intravascular monocytes and macrophages (Fig. 4A–D, Table 1). Activation of recipient innate immune cells and induction of bTF expression have also been reported in kidney xenograft recipients subject to CC [42].


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)

Expression of recipient TF in cardiac xenotransplantation. Immunohistochemical staining for recipient baboon tissue factor (bTF) expression in rejected cardiac xenografts. A. Staining for bTF in pig heart grafts that rejected at day 12. B. bTF expression at 8 weeks. Both photomicrographs in A and B show strong TF staining in thrombosed vessels and less staining in the interstitium (arrows) (×600). C and D. Colocalization of bTF (red stain) and macrophages (stained for CD68, brown) in heart grafts excised on day 12 (C) and at 8 weeks (D) is indicated by arrows (×600) (Reproduced with permission from Ezzelarab M, et al. Transplantation 2009; 87: 805–812).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4126170&req=5

fig04: Expression of recipient TF in cardiac xenotransplantation. Immunohistochemical staining for recipient baboon tissue factor (bTF) expression in rejected cardiac xenografts. A. Staining for bTF in pig heart grafts that rejected at day 12. B. bTF expression at 8 weeks. Both photomicrographs in A and B show strong TF staining in thrombosed vessels and less staining in the interstitium (arrows) (×600). C and D. Colocalization of bTF (red stain) and macrophages (stained for CD68, brown) in heart grafts excised on day 12 (C) and at 8 weeks (D) is indicated by arrows (×600) (Reproduced with permission from Ezzelarab M, et al. Transplantation 2009; 87: 805–812).
Mentions: α1,3-galactosyltransferase gene knockout pigs heart xenografts have also been reported to undergo early immune injury from preformed anti-non-Gal antibody, which did not result in HAR [34,41]. In these studies, GTKO graft survival was <1 day in the absence of immune suppression, but was extended to 2 to 12 days with “partial” immune suppression and up to 8 weeks with a “full” regimen. Xenograft rejection was complex, as the grafts, regardless of the efficiency of immune suppression, showed evidence of both humoral rejection, in the form of vascular antibody and complement deposition, and recipient innate immune cell activation. The innate cell activation was manifested as CC (defined by thrombocytopenia, low fibrinogen levels, prolongation of prothrombin and activated partial thromboplastin times, bleeding) and as a significantly increased level of intragraft neutrophil infiltration with a marked increase in recipient baboon tissue factor (bTF) expression from intragraft and graft adherent intravascular monocytes and macrophages (Fig. 4A–D, Table 1). Activation of recipient innate immune cells and induction of bTF expression have also been reported in kidney xenograft recipients subject to CC [42].

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