Effect of mixed hematopoietic chimerism on cardiac allograft survival in cynomolgus monkeys

Tatsuo Kawai, A. Benedict Cosimi, Siew Lin Wee, Stuart Houser, David Andrews, Hiroshi Sogawa, Joanne Phelan, Svetlan Boskovic, Ognjenka Nadazdin, Gregory Abrahamian, Robert B. Colvin, David H. Sach, Joren C. Madsen

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Abstract

Background. We have previously reported the successful induction of mixed chimerism and long-term acceptance of renal allografts in MHC-mismatched nonhuman primates after non-myeloablative conditioning and donor bone marrow transplantation. In this study, we extended our regimen to cardiac allotransplantation and compared the immunological responses of heart and kidney allograft recipients. Methods. Five cynomolgus monkeys were conditioned with low-dose total body irradiation (1.5 Gy on days -6 and -5), supplemental thymic irradiation (7 Gy on day -1), antithymocyte globulin (50 mg/kg on days -2, -1, and 0), splenectomy (day 0), donor bone marrow transplantation (day 0), and a 4-week post-transplant course of cyclosporine. Heart allografts from MHC-mismatched donors were transplanted heterotopically on day 0. Results. Two monkeys failed to develop multilineage chimerism and rejected their allografts soon after cyclosporine was stopped (postoperative days [PODs] 43 and 56). Three monkeys developed multi-lineage chimerism, which persisted 20 to 43 days post-transplant by flow cytometric analysis and to POD 124 by polymerase chain reaction analysis. Allograft survival in these recipients was prolonged to 138, 428, and 509 days, and in vitro mixed leukocyte reaction and cell-mediated lympholysis (CML) assays demonstrated donor-specific hypo-responsiveness. However, in contrast to kidney allograft recipients, long-term heart allograft recipients eventually developed humoral and cellular immunity against the donor and rejected the grafts. At the time of rejection, 1.3% to 9.5% of donor coronary arteries exhibited intimal proliferation. Conclusions. The induction of transient mixed hematopoietic chimerism leads to long-term heart allograft survival in MHC disparate monkeys without chronic immunosuppression. However, unlike kidney allografts, full tolerance to cardiac allografts was not achieved. Organ-specific modifications of the preparative regimen may be necessary to prevent the chronic cellular and humoral immune responses elicited by cardiac allografts.

Original languageEnglish
Pages (from-to)1757-1764
Number of pages8
JournalTransplantation
Volume73
Issue number11
StatePublished - Jun 15 2002
Externally publishedYes

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Chimerism
Macaca fascicularis
Allografts
Haplorhini
Kidney
Humoral Immunity
Bone Marrow Transplantation
Transplants
Cellular Immunity
Cyclosporine
Tunica Intima
Transplantation Tolerance
Mixed Lymphocyte Culture Test
Antilymphocyte Serum
Whole-Body Irradiation
Splenectomy
Immunosuppression
Primates
Coronary Vessels
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Kawai, T., Cosimi, A. B., Wee, S. L., Houser, S., Andrews, D., Sogawa, H., ... Madsen, J. C. (2002). Effect of mixed hematopoietic chimerism on cardiac allograft survival in cynomolgus monkeys. Transplantation, 73(11), 1757-1764.

Effect of mixed hematopoietic chimerism on cardiac allograft survival in cynomolgus monkeys. / Kawai, Tatsuo; Cosimi, A. Benedict; Wee, Siew Lin; Houser, Stuart; Andrews, David; Sogawa, Hiroshi; Phelan, Joanne; Boskovic, Svetlan; Nadazdin, Ognjenka; Abrahamian, Gregory; Colvin, Robert B.; Sach, David H.; Madsen, Joren C.

In: Transplantation, Vol. 73, No. 11, 15.06.2002, p. 1757-1764.

Research output: Contribution to journalArticle

Kawai, T, Cosimi, AB, Wee, SL, Houser, S, Andrews, D, Sogawa, H, Phelan, J, Boskovic, S, Nadazdin, O, Abrahamian, G, Colvin, RB, Sach, DH & Madsen, JC 2002, 'Effect of mixed hematopoietic chimerism on cardiac allograft survival in cynomolgus monkeys', Transplantation, vol. 73, no. 11, pp. 1757-1764.
Kawai T, Cosimi AB, Wee SL, Houser S, Andrews D, Sogawa H et al. Effect of mixed hematopoietic chimerism on cardiac allograft survival in cynomolgus monkeys. Transplantation. 2002 Jun 15;73(11):1757-1764.
Kawai, Tatsuo ; Cosimi, A. Benedict ; Wee, Siew Lin ; Houser, Stuart ; Andrews, David ; Sogawa, Hiroshi ; Phelan, Joanne ; Boskovic, Svetlan ; Nadazdin, Ognjenka ; Abrahamian, Gregory ; Colvin, Robert B. ; Sach, David H. ; Madsen, Joren C. / Effect of mixed hematopoietic chimerism on cardiac allograft survival in cynomolgus monkeys. In: Transplantation. 2002 ; Vol. 73, No. 11. pp. 1757-1764.
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abstract = "Background. We have previously reported the successful induction of mixed chimerism and long-term acceptance of renal allografts in MHC-mismatched nonhuman primates after non-myeloablative conditioning and donor bone marrow transplantation. In this study, we extended our regimen to cardiac allotransplantation and compared the immunological responses of heart and kidney allograft recipients. Methods. Five cynomolgus monkeys were conditioned with low-dose total body irradiation (1.5 Gy on days -6 and -5), supplemental thymic irradiation (7 Gy on day -1), antithymocyte globulin (50 mg/kg on days -2, -1, and 0), splenectomy (day 0), donor bone marrow transplantation (day 0), and a 4-week post-transplant course of cyclosporine. Heart allografts from MHC-mismatched donors were transplanted heterotopically on day 0. Results. Two monkeys failed to develop multilineage chimerism and rejected their allografts soon after cyclosporine was stopped (postoperative days [PODs] 43 and 56). Three monkeys developed multi-lineage chimerism, which persisted 20 to 43 days post-transplant by flow cytometric analysis and to POD 124 by polymerase chain reaction analysis. Allograft survival in these recipients was prolonged to 138, 428, and 509 days, and in vitro mixed leukocyte reaction and cell-mediated lympholysis (CML) assays demonstrated donor-specific hypo-responsiveness. However, in contrast to kidney allograft recipients, long-term heart allograft recipients eventually developed humoral and cellular immunity against the donor and rejected the grafts. At the time of rejection, 1.3{\%} to 9.5{\%} of donor coronary arteries exhibited intimal proliferation. Conclusions. The induction of transient mixed hematopoietic chimerism leads to long-term heart allograft survival in MHC disparate monkeys without chronic immunosuppression. However, unlike kidney allografts, full tolerance to cardiac allografts was not achieved. Organ-specific modifications of the preparative regimen may be necessary to prevent the chronic cellular and humoral immune responses elicited by cardiac allografts.",
author = "Tatsuo Kawai and Cosimi, {A. Benedict} and Wee, {Siew Lin} and Stuart Houser and David Andrews and Hiroshi Sogawa and Joanne Phelan and Svetlan Boskovic and Ognjenka Nadazdin and Gregory Abrahamian and Colvin, {Robert B.} and Sach, {David H.} and Madsen, {Joren C.}",
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T1 - Effect of mixed hematopoietic chimerism on cardiac allograft survival in cynomolgus monkeys

AU - Kawai, Tatsuo

AU - Cosimi, A. Benedict

AU - Wee, Siew Lin

AU - Houser, Stuart

AU - Andrews, David

AU - Sogawa, Hiroshi

AU - Phelan, Joanne

AU - Boskovic, Svetlan

AU - Nadazdin, Ognjenka

AU - Abrahamian, Gregory

AU - Colvin, Robert B.

AU - Sach, David H.

AU - Madsen, Joren C.

PY - 2002/6/15

Y1 - 2002/6/15

N2 - Background. We have previously reported the successful induction of mixed chimerism and long-term acceptance of renal allografts in MHC-mismatched nonhuman primates after non-myeloablative conditioning and donor bone marrow transplantation. In this study, we extended our regimen to cardiac allotransplantation and compared the immunological responses of heart and kidney allograft recipients. Methods. Five cynomolgus monkeys were conditioned with low-dose total body irradiation (1.5 Gy on days -6 and -5), supplemental thymic irradiation (7 Gy on day -1), antithymocyte globulin (50 mg/kg on days -2, -1, and 0), splenectomy (day 0), donor bone marrow transplantation (day 0), and a 4-week post-transplant course of cyclosporine. Heart allografts from MHC-mismatched donors were transplanted heterotopically on day 0. Results. Two monkeys failed to develop multilineage chimerism and rejected their allografts soon after cyclosporine was stopped (postoperative days [PODs] 43 and 56). Three monkeys developed multi-lineage chimerism, which persisted 20 to 43 days post-transplant by flow cytometric analysis and to POD 124 by polymerase chain reaction analysis. Allograft survival in these recipients was prolonged to 138, 428, and 509 days, and in vitro mixed leukocyte reaction and cell-mediated lympholysis (CML) assays demonstrated donor-specific hypo-responsiveness. However, in contrast to kidney allograft recipients, long-term heart allograft recipients eventually developed humoral and cellular immunity against the donor and rejected the grafts. At the time of rejection, 1.3% to 9.5% of donor coronary arteries exhibited intimal proliferation. Conclusions. The induction of transient mixed hematopoietic chimerism leads to long-term heart allograft survival in MHC disparate monkeys without chronic immunosuppression. However, unlike kidney allografts, full tolerance to cardiac allografts was not achieved. Organ-specific modifications of the preparative regimen may be necessary to prevent the chronic cellular and humoral immune responses elicited by cardiac allografts.

AB - Background. We have previously reported the successful induction of mixed chimerism and long-term acceptance of renal allografts in MHC-mismatched nonhuman primates after non-myeloablative conditioning and donor bone marrow transplantation. In this study, we extended our regimen to cardiac allotransplantation and compared the immunological responses of heart and kidney allograft recipients. Methods. Five cynomolgus monkeys were conditioned with low-dose total body irradiation (1.5 Gy on days -6 and -5), supplemental thymic irradiation (7 Gy on day -1), antithymocyte globulin (50 mg/kg on days -2, -1, and 0), splenectomy (day 0), donor bone marrow transplantation (day 0), and a 4-week post-transplant course of cyclosporine. Heart allografts from MHC-mismatched donors were transplanted heterotopically on day 0. Results. Two monkeys failed to develop multilineage chimerism and rejected their allografts soon after cyclosporine was stopped (postoperative days [PODs] 43 and 56). Three monkeys developed multi-lineage chimerism, which persisted 20 to 43 days post-transplant by flow cytometric analysis and to POD 124 by polymerase chain reaction analysis. Allograft survival in these recipients was prolonged to 138, 428, and 509 days, and in vitro mixed leukocyte reaction and cell-mediated lympholysis (CML) assays demonstrated donor-specific hypo-responsiveness. However, in contrast to kidney allograft recipients, long-term heart allograft recipients eventually developed humoral and cellular immunity against the donor and rejected the grafts. At the time of rejection, 1.3% to 9.5% of donor coronary arteries exhibited intimal proliferation. Conclusions. The induction of transient mixed hematopoietic chimerism leads to long-term heart allograft survival in MHC disparate monkeys without chronic immunosuppression. However, unlike kidney allografts, full tolerance to cardiac allografts was not achieved. Organ-specific modifications of the preparative regimen may be necessary to prevent the chronic cellular and humoral immune responses elicited by cardiac allografts.

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