Allosensitization Does Not Increase the Risk of Xenoreactivity to ??1,3-Galactosyltransferase Gene-Knockout Miniature Swine in Patients on Transplantation Waiting Lists

Wong, Banny S.; Yamada, Kazuhiko; Okumi, Masayoshi; Weiner, Joshua; O'Malley, Patricia E.; Tseng, Yau‐Lin; Dor, Frank J. M. F.; Cooper, David K. C.; Saidman, Susan L.; Griesemer, Adam; Sachs, David H.

doi:10.1097/01.tp.0000228907.12073.0b

Cited by 73 publications

(56 citation statements)

References 29 publications

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“…36,37 Previous studies have also reported the presence of variable amounts of preformed anti-nonGal antibodies in humans. 38 Additional induction therapy to reduce the levels of preformed anti-nonGal antibodies and to prevent initial graft injury associated with preformed anti-nonGal antibodies may be required to ensure long-term xenograft survival. Transgenic modification of swine to allow overexpression of human anticoagulant and thromboregulatory factors such as CD39 may be also further required for long-term xenograft survival.…”

Section: Discussionmentioning

confidence: 99%

Pathologic Characteristics of Transplanted Kidney Xenografts

Shimizu

Yamada²,

Robson

et al. 2012

Journal of the American Society of Nephrology

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For xenotransplantation to become a clinical reality, we need to better understand the mechanisms of graft rejection or acceptance. We examined pathologic changes in a1,3-galactosyltransferase geneknockout pig kidneys transplanted into baboons that were treated with a protocol designed to induce immunotolerance through thymic transplantation (n=4) or were treated with long-term immunosuppressants (n=3). Hyperacute rejection did not occur in a1,3-galactosyltransferase gene-knockout kidney xenografts. By 34 days, acute humoral rejection led to xenograft loss in all three xenografts in the long-term immunosuppression group. The failing grafts exhibited thrombotic microangiopathic glomerulopathy with multiple platelet-fibrin microthrombi, focal interstitial hemorrhage, and acute cellular xenograft rejection. Damaged glomeruli showed IgM, IgG, C4d, and C5b-9 deposition. They also demonstrated endothelial cell death, diffuse endothelial procoagulant activation with high expression of tissue factor and vWF, and low expression of the ectonucleotidase CD39. In contrast, in the immunotolerance group, two of four grafts had normal graft function and no pathologic findings of acute or chronic rejection at 56 and 83 days. One of the remaining kidneys had mild but transient graft dysfunction with reversible, mild microangiopathic glomerulopathy, probably associated with preformed antibodies. The other kidney in the immunotolerance group developed unstable graft function at 81 days and developed chronic xenograft glomerulopathy. In summary, the success of pig-to-primate xenotransplantation may necessitate immune tolerance to inhibit acute humoral and cellular xenograft rejection.

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Section: Discussionmentioning

confidence: 99%

Pathologic Characteristics of Transplanted Kidney Xenografts

Shimizu

Yamada²,

Robson

et al. 2012

Journal of the American Society of Nephrology

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“…In addition, infection of the human host by porcine endogenous retroviruses poses a major problem [27] . It was reported that infection can be avoided by breeding GalT KO swines that show no infectivity for human cells in vitro [28,29] . Thus, porcine organs may be used for xenotransplantation in donors with no alternative.…”

Section: Discussionmentioning

confidence: 99%

Hepatic reconstruction from fetal porcine liver cells using a radial flow bioreactor

Ishii¹,

Saito²,

Marushima³

et al. 2008

WJG

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“…The antibody response to DD-SC and DD-STSG was evaluated by flow cytometry using serum obtained before and at different time points after grafting. The presence of anti-donor alloantibody was assessed by flow cytometry-based binding and complement-dependent cytotoxicity assays(11,23,24). Peripheral Blood Mononuclear Cells (PBMC) were prepared by Ficoll gradient centrifugation(23).…”

Section: Methodsmentioning

confidence: 99%

Survival of Allogeneic Self-Assembled Cultured Skin

Climov¹,

Matar

Farkash

et al. 2016

Transplantation

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Background Deficiency of autologous skin for reconstruction of severe wounds is a major problem in plastic surgery. Autologous substitutes can provide additional coverage, but due to the duration of production, treatment is significantly delayed. The allogeneic approach offers a potential of having an off-the-shelf solution for the immediate application. Methods In this study, we assess the engraftment and immunogenicity of allogeneic bilayered bioengineered skin prepared by a self-assembly method. Bioengineered skin has the potential immunological advantage of lacking passenger leukocytes including antigen presenting cells. The skin constructs were transplanted across MHC barriers in a porcine animal model. Animals received a second grafting of the same skin construct 7 weeks following the first set of grafts together with MHC-matched constructs to assess for clinical sensitization. Results All allo-constructs successfully engrafted with histologic evidence of neovascularization by day 4. Complete cellular rejection and tissue loss occurred by day 8 for most grafts. Following the second application, accelerated rejection (<4 days) took place with the development of swine MHC-specific cytotoxic alloantibody. Conclusions These data demonstrate preclinically that self-assembled allogeneic constructs engraft and reject similar to allogeneic skin despite the absence of professional donor antigen-presenting cells.

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Allosensitization Does Not Increase the Risk of Xenoreactivity to ??1,3-Galactosyltransferase Gene-Knockout Miniature Swine in Patients on Transplantation Waiting Lists

Abstract: Highly allosensitized patients awaiting renal transplants appear to be at no increased risk of xenosensitization over their non-sensitized cohorts, and could therefore be candidates for xenotransplantation using GalT-KO swine donors.

Cited by 73 publications

References 29 publications

Pathologic Characteristics of Transplanted Kidney Xenografts

Pathologic Characteristics of Transplanted Kidney Xenografts

Hepatic reconstruction from fetal porcine liver cells using a radial flow bioreactor

Survival of Allogeneic Self-Assembled Cultured Skin

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