Composite tissue allotransplantation in chimeric hosts part II. A clinically relevant protocol to induce tolerance in a rat model

Kaustubha A. Prabhune, Vijay S. Gorantla, Gustavo Perez-Abadia, Cedric G. Francois, Marieke Vossen, Luis A. Laurentin-Perez, Warren C Breidenbach, Gordon G. Wang, Gary L. Anderson, Diane J. Pidwell, John H. Barker, Claudio Maldonado

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Background. We and others have shown that mixed allogeneic chimerism induces donor-specific tolerance to composite tissue allografts across major histocompatibility complex barriers without the need for immunosuppression. However, a delay period between bone marrow transplantation and limb allotransplantation is required, making such protocols impractical for clinical application. This study eliminates this delay period in a rat hind limb allotransplantation model by performing mixed allogeneic chimerism induction and transplantation "simultaneously." Methods. Group 1 included controls in which naïve Wistar Furth (WF) hosts received ACI hind limbs. Group 2 included (ACI→WF chimeras that received limbs from third-party donors (Fisher), and group 3 included chimeras that received irradiated (1,050 cGy) ACI limbs. In group 4, WF hosts conditioned with 950 cGy received irradiated (1,050 cGy) ACI limbs followed by infusion of 100×10 6 ACI T-cell-depleted bone marrow cells and immunotherapy (tacrolimus and mycophenolate mofetil) for 28 days. Group 5 animals received the same treatment as group 4 animals without immunotherapy. Results. The rats in groups 1 and 2 rejected their limbs within 10 days. Only one rat in group 4 survived to the end of the study. Groups 3 and 5 demonstrated long-term limb survival without rejection or graft-versus-host disease. High levels of donor chimerism (<80%) were achieved and maintained throughout the study. Mixed lymphocyte reaction assays in both groups revealed donor-specific hyporesponsiveness with vigorous third-party reactivity. Conclusions. This study demonstrated that infusion of donor bone marrow cells into conditioned hosts immediately after limb transplantation results in stable mixed chimerism, robust tolerance, and reliable limb allograft survival.

Original languageEnglish (US)
Pages (from-to)1548-1555
Number of pages8
JournalTransplantation
Volume76
Issue number11
DOIs
StatePublished - Dec 15 2003
Externally publishedYes

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Vascularized Composite Allotransplantation
Extremities
Chimerism
Bone Marrow Cells
Immunotherapy
Composite Tissue Allografts
Transplantation
Mycophenolic Acid
Mixed Lymphocyte Culture Test
Tacrolimus
Graft vs Host Disease
Clinical Protocols
Major Histocompatibility Complex
Bone Marrow Transplantation
Immunosuppression
Allografts

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Prabhune, K. A., Gorantla, V. S., Perez-Abadia, G., Francois, C. G., Vossen, M., Laurentin-Perez, L. A., ... Maldonado, C. (2003). Composite tissue allotransplantation in chimeric hosts part II. A clinically relevant protocol to induce tolerance in a rat model. Transplantation, 76(11), 1548-1555. https://doi.org/10.1097/01.TP.0000085288.12571.65

Composite tissue allotransplantation in chimeric hosts part II. A clinically relevant protocol to induce tolerance in a rat model. / Prabhune, Kaustubha A.; Gorantla, Vijay S.; Perez-Abadia, Gustavo; Francois, Cedric G.; Vossen, Marieke; Laurentin-Perez, Luis A.; Breidenbach, Warren C; Wang, Gordon G.; Anderson, Gary L.; Pidwell, Diane J.; Barker, John H.; Maldonado, Claudio.

In: Transplantation, Vol. 76, No. 11, 15.12.2003, p. 1548-1555.

Research output: Contribution to journalArticle

Prabhune, KA, Gorantla, VS, Perez-Abadia, G, Francois, CG, Vossen, M, Laurentin-Perez, LA, Breidenbach, WC, Wang, GG, Anderson, GL, Pidwell, DJ, Barker, JH & Maldonado, C 2003, 'Composite tissue allotransplantation in chimeric hosts part II. A clinically relevant protocol to induce tolerance in a rat model', Transplantation, vol. 76, no. 11, pp. 1548-1555. https://doi.org/10.1097/01.TP.0000085288.12571.65
Prabhune, Kaustubha A. ; Gorantla, Vijay S. ; Perez-Abadia, Gustavo ; Francois, Cedric G. ; Vossen, Marieke ; Laurentin-Perez, Luis A. ; Breidenbach, Warren C ; Wang, Gordon G. ; Anderson, Gary L. ; Pidwell, Diane J. ; Barker, John H. ; Maldonado, Claudio. / Composite tissue allotransplantation in chimeric hosts part II. A clinically relevant protocol to induce tolerance in a rat model. In: Transplantation. 2003 ; Vol. 76, No. 11. pp. 1548-1555.
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AU - Gorantla, Vijay S.

AU - Perez-Abadia, Gustavo

AU - Francois, Cedric G.

AU - Vossen, Marieke

AU - Laurentin-Perez, Luis A.

AU - Breidenbach, Warren C

AU - Wang, Gordon G.

AU - Anderson, Gary L.

AU - Pidwell, Diane J.

AU - Barker, John H.

AU - Maldonado, Claudio

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N2 - Background. We and others have shown that mixed allogeneic chimerism induces donor-specific tolerance to composite tissue allografts across major histocompatibility complex barriers without the need for immunosuppression. However, a delay period between bone marrow transplantation and limb allotransplantation is required, making such protocols impractical for clinical application. This study eliminates this delay period in a rat hind limb allotransplantation model by performing mixed allogeneic chimerism induction and transplantation "simultaneously." Methods. Group 1 included controls in which naïve Wistar Furth (WF) hosts received ACI hind limbs. Group 2 included (ACI→WF chimeras that received limbs from third-party donors (Fisher), and group 3 included chimeras that received irradiated (1,050 cGy) ACI limbs. In group 4, WF hosts conditioned with 950 cGy received irradiated (1,050 cGy) ACI limbs followed by infusion of 100×10 6 ACI T-cell-depleted bone marrow cells and immunotherapy (tacrolimus and mycophenolate mofetil) for 28 days. Group 5 animals received the same treatment as group 4 animals without immunotherapy. Results. The rats in groups 1 and 2 rejected their limbs within 10 days. Only one rat in group 4 survived to the end of the study. Groups 3 and 5 demonstrated long-term limb survival without rejection or graft-versus-host disease. High levels of donor chimerism (<80%) were achieved and maintained throughout the study. Mixed lymphocyte reaction assays in both groups revealed donor-specific hyporesponsiveness with vigorous third-party reactivity. Conclusions. This study demonstrated that infusion of donor bone marrow cells into conditioned hosts immediately after limb transplantation results in stable mixed chimerism, robust tolerance, and reliable limb allograft survival.

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