Long-term acceptance of renal allografts following prenatal inoculation with adult bone marrow

David W. Mathes, Mario G. Solari, Mark A. Randolph, G. Scott Gazelle, Kazuhiko Yamada, Christene A. Huang, David H. Sachs, W P Andrew Lee

Research output: Contribution to journalArticle

Abstract

Background. The aim was to investigate if intravascular in utero injection of adult bone marrow into swine fetuses could lead to macrochimerism and tolerance to the donor. Methods. Outbred Yorkshire sows and boars screening negative for MHC allele SLAc of MGH miniature swine were bred. A laparotomy was performed on the sows at 50 days gestation to expose the uterus. Bone marrow harvested from SLACC miniature swine was T-cell depleted and injected intravascularly into seventeen fetuses. Flow cytometry was performed to detect donor cells (chimerism) in the peripheral blood after birth. Mixed lymphocyte reactions (MLR) and cell-mediated lympholysis (CML) assays were used to assess the response to donor MHC. Previously frozen skin grafts from the bone marrow donor were placed on the offspring from the first litter. Donor-matched renal transplant from SLAcc donors were performed on chimeric swine, with and without a short 12-day course of cyclosporine, and one nonchimeric littermate. Results. Nine inoculated offspring demonstrated donor cell chimerism in the peripheral blood and lymphohematopoietic tissues. All animals with detectable chimerism within the first three weeks were consistently nonreactive to donor MHC in vitro. Animals challenged with donor skin grafts displayed prolonged graft survival without producing antidonor antibodies. All chimeric animals accepted donor-matched kidney allografts, even one without cyclosporine. The kidney in the nonchimeric littermate rejected by day 21. Conclusions. Transplantation of allogeneic adult bone marrow into immunocompetent fetal recipients resulted in chimerism. In utero inoculation led to operational tolerance to the donor's major histocompatibility antigens and long-term acceptance to organ allografts.

Original languageEnglish (US)
Pages (from-to)1300-1308
Number of pages9
JournalTransplantation
Volume80
Issue number9
DOIs
StatePublished - Nov 2005
Externally publishedYes

Fingerprint

Chimerism
Allografts
Bone Marrow
Kidney
Miniature Swine
Transplants
Cyclosporine
Fetus
Swine
Skin
Mixed Lymphocyte Culture Test
Histocompatibility Antigens
Homologous Transplantation
Graft Survival
Laparotomy
Uterus
Flow Cytometry
Alleles
Parturition
T-Lymphocytes

Keywords

  • Blood transfusion
  • Bone marrow infusion
  • Chimerism and microchimerism
  • Experimental transplantation

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Mathes, D. W., Solari, M. G., Randolph, M. A., Gazelle, G. S., Yamada, K., Huang, C. A., ... Lee, W. P. A. (2005). Long-term acceptance of renal allografts following prenatal inoculation with adult bone marrow. Transplantation, 80(9), 1300-1308. https://doi.org/10.1097/01.tp.0000178933.31987.11

Long-term acceptance of renal allografts following prenatal inoculation with adult bone marrow. / Mathes, David W.; Solari, Mario G.; Randolph, Mark A.; Gazelle, G. Scott; Yamada, Kazuhiko; Huang, Christene A.; Sachs, David H.; Lee, W P Andrew.

In: Transplantation, Vol. 80, No. 9, 11.2005, p. 1300-1308.

Research output: Contribution to journalArticle

Mathes, DW, Solari, MG, Randolph, MA, Gazelle, GS, Yamada, K, Huang, CA, Sachs, DH & Lee, WPA 2005, 'Long-term acceptance of renal allografts following prenatal inoculation with adult bone marrow', Transplantation, vol. 80, no. 9, pp. 1300-1308. https://doi.org/10.1097/01.tp.0000178933.31987.11
Mathes, David W. ; Solari, Mario G. ; Randolph, Mark A. ; Gazelle, G. Scott ; Yamada, Kazuhiko ; Huang, Christene A. ; Sachs, David H. ; Lee, W P Andrew. / Long-term acceptance of renal allografts following prenatal inoculation with adult bone marrow. In: Transplantation. 2005 ; Vol. 80, No. 9. pp. 1300-1308.
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abstract = "Background. The aim was to investigate if intravascular in utero injection of adult bone marrow into swine fetuses could lead to macrochimerism and tolerance to the donor. Methods. Outbred Yorkshire sows and boars screening negative for MHC allele SLAc of MGH miniature swine were bred. A laparotomy was performed on the sows at 50 days gestation to expose the uterus. Bone marrow harvested from SLACC miniature swine was T-cell depleted and injected intravascularly into seventeen fetuses. Flow cytometry was performed to detect donor cells (chimerism) in the peripheral blood after birth. Mixed lymphocyte reactions (MLR) and cell-mediated lympholysis (CML) assays were used to assess the response to donor MHC. Previously frozen skin grafts from the bone marrow donor were placed on the offspring from the first litter. Donor-matched renal transplant from SLAcc donors were performed on chimeric swine, with and without a short 12-day course of cyclosporine, and one nonchimeric littermate. Results. Nine inoculated offspring demonstrated donor cell chimerism in the peripheral blood and lymphohematopoietic tissues. All animals with detectable chimerism within the first three weeks were consistently nonreactive to donor MHC in vitro. Animals challenged with donor skin grafts displayed prolonged graft survival without producing antidonor antibodies. All chimeric animals accepted donor-matched kidney allografts, even one without cyclosporine. The kidney in the nonchimeric littermate rejected by day 21. Conclusions. Transplantation of allogeneic adult bone marrow into immunocompetent fetal recipients resulted in chimerism. In utero inoculation led to operational tolerance to the donor's major histocompatibility antigens and long-term acceptance to organ allografts.",
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AU - Mathes, David W.

AU - Solari, Mario G.

AU - Randolph, Mark A.

AU - Gazelle, G. Scott

AU - Yamada, Kazuhiko

AU - Huang, Christene A.

AU - Sachs, David H.

AU - Lee, W P Andrew

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N2 - Background. The aim was to investigate if intravascular in utero injection of adult bone marrow into swine fetuses could lead to macrochimerism and tolerance to the donor. Methods. Outbred Yorkshire sows and boars screening negative for MHC allele SLAc of MGH miniature swine were bred. A laparotomy was performed on the sows at 50 days gestation to expose the uterus. Bone marrow harvested from SLACC miniature swine was T-cell depleted and injected intravascularly into seventeen fetuses. Flow cytometry was performed to detect donor cells (chimerism) in the peripheral blood after birth. Mixed lymphocyte reactions (MLR) and cell-mediated lympholysis (CML) assays were used to assess the response to donor MHC. Previously frozen skin grafts from the bone marrow donor were placed on the offspring from the first litter. Donor-matched renal transplant from SLAcc donors were performed on chimeric swine, with and without a short 12-day course of cyclosporine, and one nonchimeric littermate. Results. Nine inoculated offspring demonstrated donor cell chimerism in the peripheral blood and lymphohematopoietic tissues. All animals with detectable chimerism within the first three weeks were consistently nonreactive to donor MHC in vitro. Animals challenged with donor skin grafts displayed prolonged graft survival without producing antidonor antibodies. All chimeric animals accepted donor-matched kidney allografts, even one without cyclosporine. The kidney in the nonchimeric littermate rejected by day 21. Conclusions. Transplantation of allogeneic adult bone marrow into immunocompetent fetal recipients resulted in chimerism. In utero inoculation led to operational tolerance to the donor's major histocompatibility antigens and long-term acceptance to organ allografts.

AB - Background. The aim was to investigate if intravascular in utero injection of adult bone marrow into swine fetuses could lead to macrochimerism and tolerance to the donor. Methods. Outbred Yorkshire sows and boars screening negative for MHC allele SLAc of MGH miniature swine were bred. A laparotomy was performed on the sows at 50 days gestation to expose the uterus. Bone marrow harvested from SLACC miniature swine was T-cell depleted and injected intravascularly into seventeen fetuses. Flow cytometry was performed to detect donor cells (chimerism) in the peripheral blood after birth. Mixed lymphocyte reactions (MLR) and cell-mediated lympholysis (CML) assays were used to assess the response to donor MHC. Previously frozen skin grafts from the bone marrow donor were placed on the offspring from the first litter. Donor-matched renal transplant from SLAcc donors were performed on chimeric swine, with and without a short 12-day course of cyclosporine, and one nonchimeric littermate. Results. Nine inoculated offspring demonstrated donor cell chimerism in the peripheral blood and lymphohematopoietic tissues. All animals with detectable chimerism within the first three weeks were consistently nonreactive to donor MHC in vitro. Animals challenged with donor skin grafts displayed prolonged graft survival without producing antidonor antibodies. All chimeric animals accepted donor-matched kidney allografts, even one without cyclosporine. The kidney in the nonchimeric littermate rejected by day 21. Conclusions. Transplantation of allogeneic adult bone marrow into immunocompetent fetal recipients resulted in chimerism. In utero inoculation led to operational tolerance to the donor's major histocompatibility antigens and long-term acceptance to organ allografts.

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