The Effect of Thymectomy on Tolerance Induction and Cardiac Allograft Vasculopathy in a Miniature Swine Heart/Kidney Transplantation Model1,2

Yamada, Kazuhiko; Jk, Choo; Js, Allan; Ae, Erhorn; Mt, Menard; Mawulawde, Kwabena; Jk, Slisz; Ht, Aretz; Shimizu, Akira; Sachs, Daniela; Jc, Madsen

doi:10.1097/00007890-199908270-00007

Cited by 34 publications

(27 citation statements)

References 22 publications

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“…These data, together with our previous studies demonstrating the necessity of the host thymus for induction of tolerance in this model (4), support the hypothesis that radiosensitive cells derived from the kidney traffic to the thymus by way of the peripheral circulation to induce tolerance to donor antigen in the host. Preliminary studies suggest that the unresponsiveness induced in these recipients may ultimately be mediated by CD4 ϩ CD25 ϩ regulatory T cells (22).…”

Section: Infusion Of Leukapheresis Product From a Tolerant Animal Intsupporting

confidence: 87%

“…Subsequent studies have been directed toward elucidating the mechanism by which tolerance is induced in such porcine recipients of heart plus kidney allografts and how this acquired tolerance prevents the development of CAV. These studies have included an assessment of the role of antigen load (3) and the demonstration of an important role for the thymus in permitting tolerance to occur (4). In the present study, we tested the hypothesis that cells found in the kidney but not in the heart may be responsible for facilitating the induction of tolerance.…”

Section: Conclusion Radiosensitive Elements In Kidney Allograft Maymentioning

confidence: 92%

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Induction of tolerance to heart transplants by simultaneous cotransplantation of donor kidneys may depend on a radiation-sensitive renal-cell population

et al. 2003

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Section: Infusion Of Leukapheresis Product From a Tolerant Animal Intsupporting

confidence: 87%

Section: Conclusion Radiosensitive Elements In Kidney Allograft Maymentioning

confidence: 92%

Induction of tolerance to heart transplants by simultaneous cotransplantation of donor kidneys may depend on a radiation-sensitive renal-cell population

et al. 2003

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“…In a large animal model, it has been shown that thymus-dependent mechanisms facilitate the development of allograft tolerance (25)(26)(27). Rodent studies have demonstrated that donor alloantigen administered peripherally can, under some circumstances, enter the recipient thymus (28,29).…”

Section: Discussionmentioning

confidence: 99%

Alloantigen-Induced CD25+CD4+ Regulatory T Cells Can Develop In Vivo from CD25−CD4+ Precursors in a Thymus-Independent Process

Karim

Kingsley

Bushell

et al. 2004

The Journal of Immunology

184

119

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The capacity of naturally occurring autoreactive CD25+CD4+ regulatory T cells (Treg) to control immune responses both in vivo and in vitro is now well established. It has been demonstrated that these cells undergo positive selection within the thymus and appear to enter the periphery as committed CD25+CD4+ Treg. We have shown previously that CD25+CD4+ Treg with the capacity to prevent skin allograft rejection can be generated by pretreatment with donor alloantigen under the cover of anti-CD4 therapy. Here we demonstrate that this process does not require an intact thymus. Furthermore, generation of these Treg is not dependent on the expansion of CD25+CD4+ thymic emigrants, because depletion of CD25+ cells before pretreatment does not prevent Treg development, and Treg can be generated from CD25−CD4+ precursors. Taken together, these results clearly demonstrate that CD25+CD4+ Treg can be generated in the periphery from CD25−CD4+ precursors in a pathway distinct to that by which naturally occurring autoreactive CD25+CD4+ Treg develop. These observations may have important implications for the design of protocols, both experimental and clinical, for the induction of tolerance to autoantigens or alloantigens in adults with limited thymic function.

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“…We have previously demonstrated that the presence of an intact thymus is required for the development of rapid and stable tolerance in miniature swine (8,23,46). Thus, if the recipient thymus was removed 3 wk before a class I-disparate kidney or heart transplant, tolerance was not obtained (8,24). In the present study, thymectomized recipients were used to determine whether a thymic graft is capable of replacing the effect of the host thymus in permitting the induction of tolerance to a class I-mismatched kidney transplant.…”

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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The Effect of Thymectomy on Tolerance Induction and Cardiac Allograft Vasculopathy in a Miniature Swine Heart/Kidney Transplantation Model1,2

Abstract: Thymic-dependent mechanisms are necessary for the induction of acquired tolerance and prevention of CAV in porcine heart/kidney recipients.

Cited by 34 publications

References 22 publications

Induction of tolerance to heart transplants by simultaneous cotransplantation of donor kidneys may depend on a radiation-sensitive renal-cell population

Induction of tolerance to heart transplants by simultaneous cotransplantation of donor kidneys may depend on a radiation-sensitive renal-cell population

Alloantigen-Induced CD25+CD4+ Regulatory T Cells Can Develop In Vivo from CD25−CD4+ Precursors in a Thymus-Independent Process

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

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