Role of the thymus in transplantation tolerance in miniature swine: IV. The thymus is required during the induction phase, but not the maintenance phase, of renal allograft tolerance

Parsia A. Vagefi, Francesco L. Ierino, Pierre R. Gianello, Akira Shimizu, Chisako Kamano, David H. Sachs, Kazuhiko Yamada

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Background. The authors' laboratory previously demonstrated that long-term tolerance to class I-disparate renal allografts in miniature swine can be induced by a short course of cyclosporine A (CsA), and that this stable tolerance is dependent on the presence of an intact thymus. In the present study, the authors have examined the requirement for a thymus during the pretransplant, induction, and maintenance phases of tolerance. Methods. Twenty-two miniature swine underwent class I major histocompatibility complex-mismatched renal transplantation, with a 12-day course of CsA. Thymectomies were performed on days -21, 0, +8, +21, and greater than or equal to +42, in relation to the day of transplantation. Historical controls consisted of euthymic and sham-thymectomized recipients. Results. Euthymic, sham-thymectomized, and day-greater than or equal to +42 thymectomized recipients demonstrated stable renal function and minimal antidonor cytotoxic T-lymphocyte (CTL) responses. In contrast, day -21 and day 0 thymectomized recipients demonstrated allograft dysfunction, marked cellular infiltrates, with severe vasculitis and glomerular changes, and strong anti-donor CTL responses. Animals thymectomized on days +8 and +21 did not undergo severe rejection, but likewise did not demonstrate a stable clinical course. Conclusions. These data indicate that the requirement for thymic function in the induction of rapid and stable tolerance is greatest during the first 8 days and then diminishes over the next 2 weeks posttransplant. Failure of thymectomy to affect the course of tolerance after day +21 suggests that thymic function is not required for the maintenance of tolerance. Understanding the role of the thymus in establishing tolerance may permit the development of tolerance induction strategies, especially for pediatric transplant recipients.

Original languageEnglish (US)
Pages (from-to)979-985
Number of pages7
JournalTransplantation
Volume77
Issue number7
DOIs
StatePublished - Apr 15 2004
Externally publishedYes

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Transplantation Tolerance
Miniature Swine
Thymus Gland
Thymectomy
Maintenance
Cytotoxic T-Lymphocytes
Kidney
Cyclosporine
Allografts
Vasculitis
Major Histocompatibility Complex
Kidney Transplantation
Transplantation
Tissue Donors
Pediatrics

ASJC Scopus subject areas

  • Transplantation

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Role of the thymus in transplantation tolerance in miniature swine : IV. The thymus is required during the induction phase, but not the maintenance phase, of renal allograft tolerance. / Vagefi, Parsia A.; Ierino, Francesco L.; Gianello, Pierre R.; Shimizu, Akira; Kamano, Chisako; Sachs, David H.; Yamada, Kazuhiko.

In: Transplantation, Vol. 77, No. 7, 15.04.2004, p. 979-985.

Research output: Contribution to journalArticle

Vagefi, Parsia A. ; Ierino, Francesco L. ; Gianello, Pierre R. ; Shimizu, Akira ; Kamano, Chisako ; Sachs, David H. ; Yamada, Kazuhiko. / Role of the thymus in transplantation tolerance in miniature swine : IV. The thymus is required during the induction phase, but not the maintenance phase, of renal allograft tolerance. In: Transplantation. 2004 ; Vol. 77, No. 7. pp. 979-985.
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abstract = "Background. The authors' laboratory previously demonstrated that long-term tolerance to class I-disparate renal allografts in miniature swine can be induced by a short course of cyclosporine A (CsA), and that this stable tolerance is dependent on the presence of an intact thymus. In the present study, the authors have examined the requirement for a thymus during the pretransplant, induction, and maintenance phases of tolerance. Methods. Twenty-two miniature swine underwent class I major histocompatibility complex-mismatched renal transplantation, with a 12-day course of CsA. Thymectomies were performed on days -21, 0, +8, +21, and greater than or equal to +42, in relation to the day of transplantation. Historical controls consisted of euthymic and sham-thymectomized recipients. Results. Euthymic, sham-thymectomized, and day-greater than or equal to +42 thymectomized recipients demonstrated stable renal function and minimal antidonor cytotoxic T-lymphocyte (CTL) responses. In contrast, day -21 and day 0 thymectomized recipients demonstrated allograft dysfunction, marked cellular infiltrates, with severe vasculitis and glomerular changes, and strong anti-donor CTL responses. Animals thymectomized on days +8 and +21 did not undergo severe rejection, but likewise did not demonstrate a stable clinical course. Conclusions. These data indicate that the requirement for thymic function in the induction of rapid and stable tolerance is greatest during the first 8 days and then diminishes over the next 2 weeks posttransplant. Failure of thymectomy to affect the course of tolerance after day +21 suggests that thymic function is not required for the maintenance of tolerance. Understanding the role of the thymus in establishing tolerance may permit the development of tolerance induction strategies, especially for pediatric transplant recipients.",
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T1 - Role of the thymus in transplantation tolerance in miniature swine

T2 - IV. The thymus is required during the induction phase, but not the maintenance phase, of renal allograft tolerance

AU - Vagefi, Parsia A.

AU - Ierino, Francesco L.

AU - Gianello, Pierre R.

AU - Shimizu, Akira

AU - Kamano, Chisako

AU - Sachs, David H.

AU - Yamada, Kazuhiko

PY - 2004/4/15

Y1 - 2004/4/15

N2 - Background. The authors' laboratory previously demonstrated that long-term tolerance to class I-disparate renal allografts in miniature swine can be induced by a short course of cyclosporine A (CsA), and that this stable tolerance is dependent on the presence of an intact thymus. In the present study, the authors have examined the requirement for a thymus during the pretransplant, induction, and maintenance phases of tolerance. Methods. Twenty-two miniature swine underwent class I major histocompatibility complex-mismatched renal transplantation, with a 12-day course of CsA. Thymectomies were performed on days -21, 0, +8, +21, and greater than or equal to +42, in relation to the day of transplantation. Historical controls consisted of euthymic and sham-thymectomized recipients. Results. Euthymic, sham-thymectomized, and day-greater than or equal to +42 thymectomized recipients demonstrated stable renal function and minimal antidonor cytotoxic T-lymphocyte (CTL) responses. In contrast, day -21 and day 0 thymectomized recipients demonstrated allograft dysfunction, marked cellular infiltrates, with severe vasculitis and glomerular changes, and strong anti-donor CTL responses. Animals thymectomized on days +8 and +21 did not undergo severe rejection, but likewise did not demonstrate a stable clinical course. Conclusions. These data indicate that the requirement for thymic function in the induction of rapid and stable tolerance is greatest during the first 8 days and then diminishes over the next 2 weeks posttransplant. Failure of thymectomy to affect the course of tolerance after day +21 suggests that thymic function is not required for the maintenance of tolerance. Understanding the role of the thymus in establishing tolerance may permit the development of tolerance induction strategies, especially for pediatric transplant recipients.

AB - Background. The authors' laboratory previously demonstrated that long-term tolerance to class I-disparate renal allografts in miniature swine can be induced by a short course of cyclosporine A (CsA), and that this stable tolerance is dependent on the presence of an intact thymus. In the present study, the authors have examined the requirement for a thymus during the pretransplant, induction, and maintenance phases of tolerance. Methods. Twenty-two miniature swine underwent class I major histocompatibility complex-mismatched renal transplantation, with a 12-day course of CsA. Thymectomies were performed on days -21, 0, +8, +21, and greater than or equal to +42, in relation to the day of transplantation. Historical controls consisted of euthymic and sham-thymectomized recipients. Results. Euthymic, sham-thymectomized, and day-greater than or equal to +42 thymectomized recipients demonstrated stable renal function and minimal antidonor cytotoxic T-lymphocyte (CTL) responses. In contrast, day -21 and day 0 thymectomized recipients demonstrated allograft dysfunction, marked cellular infiltrates, with severe vasculitis and glomerular changes, and strong anti-donor CTL responses. Animals thymectomized on days +8 and +21 did not undergo severe rejection, but likewise did not demonstrate a stable clinical course. Conclusions. These data indicate that the requirement for thymic function in the induction of rapid and stable tolerance is greatest during the first 8 days and then diminishes over the next 2 weeks posttransplant. Failure of thymectomy to affect the course of tolerance after day +21 suggests that thymic function is not required for the maintenance of tolerance. Understanding the role of the thymus in establishing tolerance may permit the development of tolerance induction strategies, especially for pediatric transplant recipients.

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