Porcine kidney and heart transplantation in baboons undergoing a tolerance induction regimen and antibody adsorption

Tomasz Kozlowski, Akira Shimizu, Denis Lambrigts, Kazuhiko Yamada, Yasushi Fuchimoto, Roseann Glaser, Rod Monroy, Yuanxin Xu, Michel Awwad, Robert B. Colvin, A. Benedict Cosimi, Simon C. Robson, Jay Fishman, Thomas R. Spitzer, David K C Cooper, David H. Sachs

Research output: Contribution to journalArticle

128 Citations (Scopus)

Abstract

Background. Xenotransplantation would provide a solution to the current shortage of organs for transplantation. Our group has been successful in inducing tolerance in mice and monkey models of allogeneic transplantation. The present study attempts to extend the same tolerance-inducing regimen to a pig-to-baboon organ transplantation model. Methods. Nine baboons underwent a conditioning regimen (consisting of nonmyeloablative or myeloablative whole body and thymic irradiation, splenectomy, anti-thymocyte globulin, pharmacologic immunosuppression and porcine bone marrow transplantation [BMTx]), which has previously been demonstrated to induce donor-specific allograft tolerance in monkeys. In addition, immunoadsorption of anti-αGal antibody (Ab) was performed. Four of the nine baboons received pig kidney transplants (KTx), and one also underwent repeat transplantation with an SLA- matched kidney. Two received heterotopic pig heart transplants (HTx). Three baboons underwent conditioning without organ transplantation for long-term studies of natural Ab kinetics. Results. In the three baboons that received the conditioning regimen without an organ transplant, immunoadsorption reduced Ab by approximately 90%, but recovery of Ab to pretreatment level or higher occurred within 7 days. In contrast, the level of Ab remained low after organ transplant. No Ab to pig antigens other than αGal was detected in any baboon before or after BMTx, KTx, or HTx. No graft succumbed to hyperacute rejection. KTx function began to deteriorate within 3-6 days, with oliguria and hematuria progressing to anuria, and the kidneys were excised after 3, 6, 9, 11, and 14 days, respectively. One HTx ceased functioning at 8 days; the second baboon died with a contracting HTx at 15 days. Features of coagulopathy and thrombocytopenia developed in all six transplanted baboons (high D-dimer, prolonged prothrombin time and partial thromboplastin time, and falling fibrinogen) resulting in serious bleeding complications in two baboons, one of which died on day 9. Donor organs showed progressive acute humoral rejection with deposits of IgM, IgG, and complement; a focal mononuclear cellular infiltrate was also observed. The ureter was the earliest structure of the KTx affected by rejection, with progression to necrosis. Conclusions. This conditioning regimen prevented hyperacute rejection but was ineffective in preventing the return of Ab, which was associated with the development of acute humoral rejection with features of coagulopathy. No baboon developed anti-pig Ab other than αGal Ab. Further modifications of the protocol directed toward suppression of production of Ab are required to successfully induce tolerance to pig organs in baboons.

Original languageEnglish
Pages (from-to)18-30
Number of pages13
JournalTransplantation
Volume67
Issue number1
DOIs
Publication statusPublished - 1999 Jan 15
Externally publishedYes

Fingerprint

Papio
Heart Transplantation
Kidney Transplantation
Adsorption
Swine
Antibodies
Transplants
Organ Transplantation
Kidney
Haplorhini
Anti-Idiotypic Antibodies
Tissue Donors
Oliguria
Transplantation Tolerance
Anuria
Heterologous Transplantation
Antilymphocyte Serum
Partial Thromboplastin Time
Whole-Body Irradiation
Prothrombin Time

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Kozlowski, T., Shimizu, A., Lambrigts, D., Yamada, K., Fuchimoto, Y., Glaser, R., ... Sachs, D. H. (1999). Porcine kidney and heart transplantation in baboons undergoing a tolerance induction regimen and antibody adsorption. Transplantation, 67(1), 18-30. https://doi.org/10.1097/00007890-199901150-00004

Porcine kidney and heart transplantation in baboons undergoing a tolerance induction regimen and antibody adsorption. / Kozlowski, Tomasz; Shimizu, Akira; Lambrigts, Denis; Yamada, Kazuhiko; Fuchimoto, Yasushi; Glaser, Roseann; Monroy, Rod; Xu, Yuanxin; Awwad, Michel; Colvin, Robert B.; Cosimi, A. Benedict; Robson, Simon C.; Fishman, Jay; Spitzer, Thomas R.; Cooper, David K C; Sachs, David H.

In: Transplantation, Vol. 67, No. 1, 15.01.1999, p. 18-30.

Research output: Contribution to journalArticle

Kozlowski, T, Shimizu, A, Lambrigts, D, Yamada, K, Fuchimoto, Y, Glaser, R, Monroy, R, Xu, Y, Awwad, M, Colvin, RB, Cosimi, AB, Robson, SC, Fishman, J, Spitzer, TR, Cooper, DKC & Sachs, DH 1999, 'Porcine kidney and heart transplantation in baboons undergoing a tolerance induction regimen and antibody adsorption', Transplantation, vol. 67, no. 1, pp. 18-30. https://doi.org/10.1097/00007890-199901150-00004
Kozlowski, Tomasz ; Shimizu, Akira ; Lambrigts, Denis ; Yamada, Kazuhiko ; Fuchimoto, Yasushi ; Glaser, Roseann ; Monroy, Rod ; Xu, Yuanxin ; Awwad, Michel ; Colvin, Robert B. ; Cosimi, A. Benedict ; Robson, Simon C. ; Fishman, Jay ; Spitzer, Thomas R. ; Cooper, David K C ; Sachs, David H. / Porcine kidney and heart transplantation in baboons undergoing a tolerance induction regimen and antibody adsorption. In: Transplantation. 1999 ; Vol. 67, No. 1. pp. 18-30.
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abstract = "Background. Xenotransplantation would provide a solution to the current shortage of organs for transplantation. Our group has been successful in inducing tolerance in mice and monkey models of allogeneic transplantation. The present study attempts to extend the same tolerance-inducing regimen to a pig-to-baboon organ transplantation model. Methods. Nine baboons underwent a conditioning regimen (consisting of nonmyeloablative or myeloablative whole body and thymic irradiation, splenectomy, anti-thymocyte globulin, pharmacologic immunosuppression and porcine bone marrow transplantation [BMTx]), which has previously been demonstrated to induce donor-specific allograft tolerance in monkeys. In addition, immunoadsorption of anti-αGal antibody (Ab) was performed. Four of the nine baboons received pig kidney transplants (KTx), and one also underwent repeat transplantation with an SLA- matched kidney. Two received heterotopic pig heart transplants (HTx). Three baboons underwent conditioning without organ transplantation for long-term studies of natural Ab kinetics. Results. In the three baboons that received the conditioning regimen without an organ transplant, immunoadsorption reduced Ab by approximately 90{\%}, but recovery of Ab to pretreatment level or higher occurred within 7 days. In contrast, the level of Ab remained low after organ transplant. No Ab to pig antigens other than αGal was detected in any baboon before or after BMTx, KTx, or HTx. No graft succumbed to hyperacute rejection. KTx function began to deteriorate within 3-6 days, with oliguria and hematuria progressing to anuria, and the kidneys were excised after 3, 6, 9, 11, and 14 days, respectively. One HTx ceased functioning at 8 days; the second baboon died with a contracting HTx at 15 days. Features of coagulopathy and thrombocytopenia developed in all six transplanted baboons (high D-dimer, prolonged prothrombin time and partial thromboplastin time, and falling fibrinogen) resulting in serious bleeding complications in two baboons, one of which died on day 9. Donor organs showed progressive acute humoral rejection with deposits of IgM, IgG, and complement; a focal mononuclear cellular infiltrate was also observed. The ureter was the earliest structure of the KTx affected by rejection, with progression to necrosis. Conclusions. This conditioning regimen prevented hyperacute rejection but was ineffective in preventing the return of Ab, which was associated with the development of acute humoral rejection with features of coagulopathy. No baboon developed anti-pig Ab other than αGal Ab. Further modifications of the protocol directed toward suppression of production of Ab are required to successfully induce tolerance to pig organs in baboons.",
author = "Tomasz Kozlowski and Akira Shimizu and Denis Lambrigts and Kazuhiko Yamada and Yasushi Fuchimoto and Roseann Glaser and Rod Monroy and Yuanxin Xu and Michel Awwad and Colvin, {Robert B.} and Cosimi, {A. Benedict} and Robson, {Simon C.} and Jay Fishman and Spitzer, {Thomas R.} and Cooper, {David K C} and Sachs, {David H.}",
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T1 - Porcine kidney and heart transplantation in baboons undergoing a tolerance induction regimen and antibody adsorption

AU - Kozlowski, Tomasz

AU - Shimizu, Akira

AU - Lambrigts, Denis

AU - Yamada, Kazuhiko

AU - Fuchimoto, Yasushi

AU - Glaser, Roseann

AU - Monroy, Rod

AU - Xu, Yuanxin

AU - Awwad, Michel

AU - Colvin, Robert B.

AU - Cosimi, A. Benedict

AU - Robson, Simon C.

AU - Fishman, Jay

AU - Spitzer, Thomas R.

AU - Cooper, David K C

AU - Sachs, David H.

PY - 1999/1/15

Y1 - 1999/1/15

N2 - Background. Xenotransplantation would provide a solution to the current shortage of organs for transplantation. Our group has been successful in inducing tolerance in mice and monkey models of allogeneic transplantation. The present study attempts to extend the same tolerance-inducing regimen to a pig-to-baboon organ transplantation model. Methods. Nine baboons underwent a conditioning regimen (consisting of nonmyeloablative or myeloablative whole body and thymic irradiation, splenectomy, anti-thymocyte globulin, pharmacologic immunosuppression and porcine bone marrow transplantation [BMTx]), which has previously been demonstrated to induce donor-specific allograft tolerance in monkeys. In addition, immunoadsorption of anti-αGal antibody (Ab) was performed. Four of the nine baboons received pig kidney transplants (KTx), and one also underwent repeat transplantation with an SLA- matched kidney. Two received heterotopic pig heart transplants (HTx). Three baboons underwent conditioning without organ transplantation for long-term studies of natural Ab kinetics. Results. In the three baboons that received the conditioning regimen without an organ transplant, immunoadsorption reduced Ab by approximately 90%, but recovery of Ab to pretreatment level or higher occurred within 7 days. In contrast, the level of Ab remained low after organ transplant. No Ab to pig antigens other than αGal was detected in any baboon before or after BMTx, KTx, or HTx. No graft succumbed to hyperacute rejection. KTx function began to deteriorate within 3-6 days, with oliguria and hematuria progressing to anuria, and the kidneys were excised after 3, 6, 9, 11, and 14 days, respectively. One HTx ceased functioning at 8 days; the second baboon died with a contracting HTx at 15 days. Features of coagulopathy and thrombocytopenia developed in all six transplanted baboons (high D-dimer, prolonged prothrombin time and partial thromboplastin time, and falling fibrinogen) resulting in serious bleeding complications in two baboons, one of which died on day 9. Donor organs showed progressive acute humoral rejection with deposits of IgM, IgG, and complement; a focal mononuclear cellular infiltrate was also observed. The ureter was the earliest structure of the KTx affected by rejection, with progression to necrosis. Conclusions. This conditioning regimen prevented hyperacute rejection but was ineffective in preventing the return of Ab, which was associated with the development of acute humoral rejection with features of coagulopathy. No baboon developed anti-pig Ab other than αGal Ab. Further modifications of the protocol directed toward suppression of production of Ab are required to successfully induce tolerance to pig organs in baboons.

AB - Background. Xenotransplantation would provide a solution to the current shortage of organs for transplantation. Our group has been successful in inducing tolerance in mice and monkey models of allogeneic transplantation. The present study attempts to extend the same tolerance-inducing regimen to a pig-to-baboon organ transplantation model. Methods. Nine baboons underwent a conditioning regimen (consisting of nonmyeloablative or myeloablative whole body and thymic irradiation, splenectomy, anti-thymocyte globulin, pharmacologic immunosuppression and porcine bone marrow transplantation [BMTx]), which has previously been demonstrated to induce donor-specific allograft tolerance in monkeys. In addition, immunoadsorption of anti-αGal antibody (Ab) was performed. Four of the nine baboons received pig kidney transplants (KTx), and one also underwent repeat transplantation with an SLA- matched kidney. Two received heterotopic pig heart transplants (HTx). Three baboons underwent conditioning without organ transplantation for long-term studies of natural Ab kinetics. Results. In the three baboons that received the conditioning regimen without an organ transplant, immunoadsorption reduced Ab by approximately 90%, but recovery of Ab to pretreatment level or higher occurred within 7 days. In contrast, the level of Ab remained low after organ transplant. No Ab to pig antigens other than αGal was detected in any baboon before or after BMTx, KTx, or HTx. No graft succumbed to hyperacute rejection. KTx function began to deteriorate within 3-6 days, with oliguria and hematuria progressing to anuria, and the kidneys were excised after 3, 6, 9, 11, and 14 days, respectively. One HTx ceased functioning at 8 days; the second baboon died with a contracting HTx at 15 days. Features of coagulopathy and thrombocytopenia developed in all six transplanted baboons (high D-dimer, prolonged prothrombin time and partial thromboplastin time, and falling fibrinogen) resulting in serious bleeding complications in two baboons, one of which died on day 9. Donor organs showed progressive acute humoral rejection with deposits of IgM, IgG, and complement; a focal mononuclear cellular infiltrate was also observed. The ureter was the earliest structure of the KTx affected by rejection, with progression to necrosis. Conclusions. This conditioning regimen prevented hyperacute rejection but was ineffective in preventing the return of Ab, which was associated with the development of acute humoral rejection with features of coagulopathy. No baboon developed anti-pig Ab other than αGal Ab. Further modifications of the protocol directed toward suppression of production of Ab are required to successfully induce tolerance to pig organs in baboons.

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