Histopathology of cardiac xenograft rejection in the pig-to-baboon model

Goddard, Martin; Dunning, John; Horsley, Jo; Atkinson, Carl; Pino-Chavez, Gilda; Wallwork, J.

doi:10.1016/s1053-2498(01)00402-8

Cited by 39 publications

(27 citation statements)

References 37 publications

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“…21,22 The distribution of macrophages in intimate contact with the graft and of T cells in more peripheral regions is concordant with what one would expect with live xenograft tissue cellular rejection. 23 Because these xenografts do not have allogenic or syngeneic HLA antigens, macrophages attack the graft first (because they do not require specific antigen recognition) and then, through the release of cytokines and other chemoattractants, T cells are recruited for further attack. In the grafts, we also observed small thrombi more often in the xenograft group than in the syngeneic group.…”

Section: Discussionmentioning

confidence: 99%

Glutaraldehyde-Fixed Bioprosthetic Heart Valve Conduits Calcify and Fail From Xenograft Rejection

et al. 2006

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Background— Glutaraldehyde fixation (G-F) decreases but likely does not eliminate the antigenicity of bioprosthetic heart valves. Rejection (with secondary dystrophic calcification) may be why G-F xenograft valves fail, especially in young patients, who are more immunocompetent than the elderly. Therefore, we sought to determine whether rejection of G-F xenograft occurs and to correlate this with graft calcification. Methods and Results— Ascending aortas/valves (from rats [syngeneic] or guinea pigs [xenogeneic]) were transplanted (fresh or after 48 hour of G-F) into the infrarenal aortas of young rat recipients for 20 days. A xenogeneic group was also treated with steroids until graft harvest. The valves and media/adventitia were scored blindly for inflammation (0 to 4). Percent graft infiltration by T cells/macrophages was determined (immunohistochemistry), and rat IgG ELISAs were performed. There was >3 times more valve inflammation, >10 times more valve T-cell/macrophage infiltrate, and >3 times antibody rise in the G-F xenogeneic groups compared with the fresh syngeneic or the G-F syngeneic groups ( P <0.05). There was >2 times more adventitial inflammation and T-cell/macrophage infiltrate in the xenogeneic groups ( P <0.05). Steroid treatment decreased inflammation and antibody rise in the xenogeneic groups ( P <0.05). Correlation analysis revealed media/adventitia inflammation ( P =0.02) and percent macrophage ( P =0.01) infiltration to be predictors of calcification. Conclusions— G-F xenografts have cellular/humoral rejection and calcify secondarily.

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Section: Discussionmentioning

confidence: 99%

Glutaraldehyde-Fixed Bioprosthetic Heart Valve Conduits Calcify and Fail From Xenograft Rejection

et al. 2006

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“…3,4 AVR, which occurs days to weeks after transplantation in nonhuman primates, is characterized by endothelial cell (EC) activation, intravascular thrombosis, and fibrin deposition. [5][6][7] Other investigators have shown that activation of graft EC during AVR leads to a loss of thromboregulatory molecules, including thrombomodulin, heparan sulfate, and CD39, and an increase in expression of tissue factor (TF). 8,9 We recently reported that porcine kidney xenografts undergoing AVR showed induction of a novel procoagulant Fgl-2 on graft vascular EC.…”

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confidence: 99%

Targeted Deletion of Fgl-2/Fibroleukin in the Donor Modulates Immunologic Response and Acute Vascular Rejection in Cardiac Xenografts

et al. 2005

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Background— Xenografts ultimately fail as a result of acute vascular rejection (AVR), a process characterized by intravascular thrombosis, fibrin deposition, and endothelial cell activation. Methods and Results— We studied whether targeted deletion of Fgl-2, an inducible endothelial cell procoagulant, (Fgl-2 −/− ) in the donor prevents AVR in a mouse-to-rat cardiac xenotransplantation model. By 3 days after transplant, Fgl-2 +/+ grafts developed typical features of AVR associated with increased levels of donor Fgl-2 mRNA. Grafts from Fgl-2 −/− mice had reduced fibrin deposition but developed cellular rejection. Treatment with a short course of cobra venom factor and maintenance cyclosporine resulted in long-term acceptance of both Fgl-2 +/+ and Fgl-2 −/− grafts. On withdrawal of cyclosporine, Fgl-2 +/+ grafts developed features of AVR; in contrast, Fgl-2 −/− grafts again developed acute cellular rejection. Rejecting Fgl-2 +/+ hearts stained positively for IgG, IgM, C3, and C5b-9, whereas rejecting Fgl-2 −/− hearts had minimal Ig and complement deposition despite xenoantibodies in the serum. Furthermore, serum containing xenoantibodies failed to stain Fgl-2 −/− long-term treated hearts but did stain wild-type heart tissues. Treatment of Fgl-2 −/− xenografts with mycophenolate mofetil and tacrolimus, a clinically relevant immune suppression protocol, led to long-term graft acceptance. Conclusions— Deletion of Fgl-2 ameliorates AVR by downregulation of xenoantigens and may facilitate successful clinical heart xenotransplantation.

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“…For this reason others have suggested that the use of EmBx as a monitoring tool in the setting of xenotransplantation may not be appropriate. 15, 16 We observed diffuse microvascular thrombosis and coagulative necrosis without any predilection for the specific zones within the myocardium. The disparity between the observations may be explained by differences in procedure since Rose et al used pig-to-baboon heterotransplants in the neck, while ours were all abdominal transplants.…”

Section: Discussionmentioning

confidence: 70%

The Utility of Right Ventricular Endomyocardial Biopsy for the Diagnosis of Xenograft Rejection After CD46 Pig-to-Baboon Cardiac Transplantation

Ricci

Tazelaar

Miyagi

et al. 2007

The Journal of Heart and Lung Transplantation

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Introduction-Endomyocardial biopsy (EmBx) is the standard means of establishing cardiac allograft rejection diagnosis. The efficacy of this procedure in xenotransplantation has not been determined. In this study we compare the histology of right ventricular EmBx specimens with the corresponding full cross sections of explanted right ventricle (RV). We also compare RV with the related left ventricle (LV) cross sections.

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Histopathology of cardiac xenograft rejection in the pig-to-baboon model

Cited by 39 publications

References 37 publications

Glutaraldehyde-Fixed Bioprosthetic Heart Valve Conduits Calcify and Fail From Xenograft Rejection

Glutaraldehyde-Fixed Bioprosthetic Heart Valve Conduits Calcify and Fail From Xenograft Rejection

Targeted Deletion of Fgl-2/Fibroleukin in the Donor Modulates Immunologic Response and Acute Vascular Rejection in Cardiac Xenografts

The Utility of Right Ventricular Endomyocardial Biopsy for the Diagnosis of Xenograft Rejection After CD46 Pig-to-Baboon Cardiac Transplantation

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