Transplantation Tolerance Prevents Cardiac Allograft Vasculopathy in Major Histocompatibility Complex Class I-Disparate Miniature Swine1

Madsen, Joren C.; Yamada, Kazuhiko; Allan, James S.; Choo, Joseph K.; Erhorn, Angelique E.; Pins, Michael; Vesga, Liana; Slisz, Joanna; Sachs, David H.

doi:10.1097/00007890-199802150-00002

Cited by 86 publications

(94 citation statements)

References 34 publications

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“…Thus, vascularized grafts are relatively tolerogenic (21,25,26), whereas skin and tissue grafts are relatively immunogenic, probably because they release cells or Ags from cells into the lymphatic system where they sensitize the host (27). Even in the case of autografts, direct thymic grafts require a revascularization period after transplantation.…”

Section: Discussionmentioning

confidence: 99%

Thymic Transplantation in Miniature Swine. II. Induction of Tolerance by Transplantation of Composite Thymokidneys to Thymectomized Recipients

Yamada¹,

Shimizu

Utsugi³

et al. 2000

The Journal of Immunology

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110

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Previous studies in our laboratory have demonstrated that the presence of the thymus is essential for rapid and stable tolerance induction in allotransplant models. We now report an attempt to induce tolerance to kidney allografts by transplanting donor thymic grafts simultaneously with the kidney in thymectomized recipients. Recipients were thymectomized 3 wk before receiving an organ and/or tissues from a class I-mismatched donor. Recipients received 1) a kidney allograft alone, 2) a composite allogeneic thymokidney (kidney with vascularized autologous thymic tissue under its capsule), or 3) separate kidney and thymic grafts from the same donor. All recipients received a 12-day course of cyclosporine. Thymectomized animals receiving a kidney allograft alone or receiving separate thymic and kidney grafts had unstable renal function due to severe rejection with the persistence of anti-donor cytotoxic T cell reactivity. In contrast, recipients of composite thymokidney grafts had stable renal function with no evidence of rejection histologically and donor-specific unresponsiveness. By postoperative day 14, the thymic tissue in the thymokidney contained recipient-type dendritic cells. By postoperative day 60, recipient-type class I positive thymocytes appeared in the thymic medulla, indicating thymopoiesis. T cells were both recipient and donor MHC-restricted. These data demonstrate that the presence of vascularized-donor thymic tissue induces rapid and stable tolerance to class I-disparate kidney allografts in thymectomized recipients. To our knowledge, this is the first evidence of functional vascularized thymic grafts permitting transplantation tolerance to be induced in a large animal model.

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Section: Discussionmentioning

confidence: 99%

Thymic Transplantation in Miniature Swine. II. Induction of Tolerance by Transplantation of Composite Thymokidneys to Thymectomized Recipients

Yamada¹,

Shimizu

Utsugi³

et al. 2000

The Journal of Immunology

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110

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“…Given the rapid rejection of near-syngeneic grafts we were surprised that no rejection occurred in IFN-γ perfused, MHC class I mismatched heart grafts of heart-kidney recipients. According to historical experiments, transplantation of a MHC class I disparate kidney combined with a 12-day course of high-dose CyA induces stable tolerance not only to the kidney but also to the cotransplanted heart (6). Studies investigating the mechanism of tolerance in this model revealed regulatory T cells (8) and upregulation of interleukin (IL) 10 (9) in tolerant heart-kidney recipients.…”

Section: Discussionmentioning

confidence: 99%

“…In Group 2 transplants were performed between highly inbred animals (G8; co-ancestry > 0.92) (5) referred to as nearsyngeneic. Group 3 recipients were cotransplanted with a MHC class I disparate heart and kidney, which uniformly induces tolerance to both grafts (6). An additional group of animals received intracoronary IFN-γ infusion into their native hearts.…”

Section: Methodsmentioning

confidence: 99%

Effects of Tolerance Induction on the Actions of Interferon-γ on Porcine Cardiac Allografts

Hoerbelt

Benjamin

Tanaka

et al. 2006

Transplantation Proceedings

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It is well known that Interferon-γ (IFN-γ) not only plays a critical role in antigen-dependent but in antigen-independent tissue injury, but it is not clear how tolerance induction affects the actions of IFN-γ in the transplant setting. To address this question, we compared the effects of IFN-γ on porcine recipients of syngeneic, rejecting and tolerant heart transplants. IFN-γ was perfused continuously into the left anterior descending artery of hearts transplanted into three groups of MHC inbred miniature swine, each treated with a 12-day course of CyA. Group 1 recipients received a class I disparate heart, Group 2 recipients received a near syngeneic heart and Group 3 recipients were cotransplanted with a class I disparate heart and kidney, which uniformly induces tolerance to both grafts. An additional, group of animals were not transplanted but received intracoronary IFN-γ infusion into their native hearts. IFN-perfusion not only accelerated the acute rejection of class I disparate hearts (mean survival time = 19±7.21 vs. 38±8.19, p=0.025) but caused near syngeneic, heart transplants, which otherwise survive indefinitely, to reject within 35 days (n=3). In contrast, IFN-γ perfusion had no demonstrable effects on either interstitial rejection, the development of vascular lesions or graft survival in tolerant heart plus kidney allograft recipients (n=4) or in autologous hearts (n=2). These results suggest that tolerance induction mitigates the damaging effects of IFN-γ itself and that the beneficial effects of tolerance induction on acute and chronic rejection may extend to antigen-independent factors like ischemia/reperfusion injury.

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“…More recently, it was shown, in different experimental models, that specific tolerance can be induced following the reconstitution of the host bone marrow with genetically modified host hematopoietic cells engineered to express donor MHC genes. 83,84 Another interesting approach to induce donor-specific tolerance has been attempted by intrathymic injection of autologous cells engineered to express donor MHC. Knechtle et al 85 reported donor-specific unresponsiveness to MHC-disparate liver and cardiac transplants when autologous myoblasts and myotubes were engineered to express donor class I MHC.…”

Section: Inhibition Of Leukocyte-mediated Rejectionmentioning

confidence: 99%

Gene therapy in transplantation

1999

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Transplantation Tolerance Prevents Cardiac Allograft Vasculopathy in Major Histocompatibility Complex Class I-Disparate Miniature Swine1

Abstract: These findings in a preclinical system establish the significance of antigen-dependent mechanisms in the pathogenesis of CAV and underscore the importance of achieving tolerance in clinical transplantation.

Cited by 86 publications

References 34 publications

Thymic Transplantation in Miniature Swine. II. Induction of Tolerance by Transplantation of Composite Thymokidneys to Thymectomized Recipients

Thymic Transplantation in Miniature Swine. II. Induction of Tolerance by Transplantation of Composite Thymokidneys to Thymectomized Recipients

Effects of Tolerance Induction on the Actions of Interferon-γ on Porcine Cardiac Allografts

Gene therapy in transplantation

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