Composite tissue allotransplantation in chimeric hosts

Part I. Prevention of graft-versus-host disease

Vijay S. Gorantla, Kaustubha A. Prabhune, Gustavo Perez-Abadia, Suzanne T. Ildstad, Claudio Maldonado, Haldun I. Orhun, Ramsey K. Majzoub, Cedric G. Francois, Thanos P. Kakoulidis, Pascal C R Brouha, Gary L. Anderson, Diane J. Pidwell, Warren C Breidenbach, John H. Barker

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Background. Mixed allogeneic chimerism (MAC) has been shown to induce tolerance to composite tissue allografts (CTA). However, transplantation of unmanipulated donor-specific limbs results in severe graft-versus-host disease (GVHD). This suggests that nontolerant mature donor-derived cells in the CTA may affect the stability of chimerism, potentially resulting in GVHD. The aim of this study was to develop an approach to study and prevent GVHD in a mixed chimeric-rat hind-limb transplantation model. Methods. [ACI→WF] chimeras received a limb from Wistar Furth (WF) (syngeneic), Fisher (third-party), or ACI (irradiated [1,050 cGy] or nonirradiated) rats. In vitro tolerance was assessed using mixed lymphocyte reactivity (MLR) assays at the time the animals were killed. Results. [ACI→WF] chimeras with greater than 85% chimerism exhibited rejection-free survival of donor-specific hind limbs. However, 100% of these animals developed lethal GVHD 22.4±2.8 days after limb transplantation. [ACI→WF] chimeras that underwent transplantation with irradiated ACI or syngeneic WF limbs showed no signs of rejection or GVHD at 5 months. Nonchimeric and third-party controls rejected limbs within 10 days. Conclusions. Conditioning of the host WF rats with 950 cGy of irradiation (sublethal, myeloablative) led to high levels of MAC without GVHD. The mature T-cell content of nonirradiated donor (ACI) limbs was sufficient to induce lethal GVHD in 100% of tolerant mixed chimeric [ACI→WF] hosts. Irradiation of donor limbs before transplantation resulted in long-term donor-specific tolerance and prevented GVHD. These data demonstrate that (1) established chimeras could be susceptible to GVHD caused by immunocompetent donor cells transferred with the hind limb, and (2) inactivating these cells with irradiation prevents GVHD and destabilization of chimerism, and permits rejection-free graft acceptance.

Original languageEnglish (US)
Pages (from-to)922-932
Number of pages11
JournalTransplantation
Volume75
Issue number7
StatePublished - Apr 15 2003
Externally publishedYes

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Vascularized Composite Allotransplantation
Graft vs Host Disease
Extremities
Chimerism
Composite Tissue Allografts
Transplantation
Transplantation Chimera
Inbred WF Rats
Graft Rejection

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Gorantla, V. S., Prabhune, K. A., Perez-Abadia, G., Ildstad, S. T., Maldonado, C., Orhun, H. I., ... Barker, J. H. (2003). Composite tissue allotransplantation in chimeric hosts: Part I. Prevention of graft-versus-host disease. Transplantation, 75(7), 922-932.

Composite tissue allotransplantation in chimeric hosts : Part I. Prevention of graft-versus-host disease. / Gorantla, Vijay S.; Prabhune, Kaustubha A.; Perez-Abadia, Gustavo; Ildstad, Suzanne T.; Maldonado, Claudio; Orhun, Haldun I.; Majzoub, Ramsey K.; Francois, Cedric G.; Kakoulidis, Thanos P.; Brouha, Pascal C R; Anderson, Gary L.; Pidwell, Diane J.; Breidenbach, Warren C; Barker, John H.

In: Transplantation, Vol. 75, No. 7, 15.04.2003, p. 922-932.

Research output: Contribution to journalArticle

Gorantla, VS, Prabhune, KA, Perez-Abadia, G, Ildstad, ST, Maldonado, C, Orhun, HI, Majzoub, RK, Francois, CG, Kakoulidis, TP, Brouha, PCR, Anderson, GL, Pidwell, DJ, Breidenbach, WC & Barker, JH 2003, 'Composite tissue allotransplantation in chimeric hosts: Part I. Prevention of graft-versus-host disease', Transplantation, vol. 75, no. 7, pp. 922-932.
Gorantla VS, Prabhune KA, Perez-Abadia G, Ildstad ST, Maldonado C, Orhun HI et al. Composite tissue allotransplantation in chimeric hosts: Part I. Prevention of graft-versus-host disease. Transplantation. 2003 Apr 15;75(7):922-932.
Gorantla, Vijay S. ; Prabhune, Kaustubha A. ; Perez-Abadia, Gustavo ; Ildstad, Suzanne T. ; Maldonado, Claudio ; Orhun, Haldun I. ; Majzoub, Ramsey K. ; Francois, Cedric G. ; Kakoulidis, Thanos P. ; Brouha, Pascal C R ; Anderson, Gary L. ; Pidwell, Diane J. ; Breidenbach, Warren C ; Barker, John H. / Composite tissue allotransplantation in chimeric hosts : Part I. Prevention of graft-versus-host disease. In: Transplantation. 2003 ; Vol. 75, No. 7. pp. 922-932.
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abstract = "Background. Mixed allogeneic chimerism (MAC) has been shown to induce tolerance to composite tissue allografts (CTA). However, transplantation of unmanipulated donor-specific limbs results in severe graft-versus-host disease (GVHD). This suggests that nontolerant mature donor-derived cells in the CTA may affect the stability of chimerism, potentially resulting in GVHD. The aim of this study was to develop an approach to study and prevent GVHD in a mixed chimeric-rat hind-limb transplantation model. Methods. [ACI→WF] chimeras received a limb from Wistar Furth (WF) (syngeneic), Fisher (third-party), or ACI (irradiated [1,050 cGy] or nonirradiated) rats. In vitro tolerance was assessed using mixed lymphocyte reactivity (MLR) assays at the time the animals were killed. Results. [ACI→WF] chimeras with greater than 85{\%} chimerism exhibited rejection-free survival of donor-specific hind limbs. However, 100{\%} of these animals developed lethal GVHD 22.4±2.8 days after limb transplantation. [ACI→WF] chimeras that underwent transplantation with irradiated ACI or syngeneic WF limbs showed no signs of rejection or GVHD at 5 months. Nonchimeric and third-party controls rejected limbs within 10 days. Conclusions. Conditioning of the host WF rats with 950 cGy of irradiation (sublethal, myeloablative) led to high levels of MAC without GVHD. The mature T-cell content of nonirradiated donor (ACI) limbs was sufficient to induce lethal GVHD in 100{\%} of tolerant mixed chimeric [ACI→WF] hosts. Irradiation of donor limbs before transplantation resulted in long-term donor-specific tolerance and prevented GVHD. These data demonstrate that (1) established chimeras could be susceptible to GVHD caused by immunocompetent donor cells transferred with the hind limb, and (2) inactivating these cells with irradiation prevents GVHD and destabilization of chimerism, and permits rejection-free graft acceptance.",
author = "Gorantla, {Vijay S.} and Prabhune, {Kaustubha A.} and Gustavo Perez-Abadia and Ildstad, {Suzanne T.} and Claudio Maldonado and Orhun, {Haldun I.} and Majzoub, {Ramsey K.} and Francois, {Cedric G.} and Kakoulidis, {Thanos P.} and Brouha, {Pascal C R} and Anderson, {Gary L.} and Pidwell, {Diane J.} and Breidenbach, {Warren C} and Barker, {John H.}",
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T1 - Composite tissue allotransplantation in chimeric hosts

T2 - Part I. Prevention of graft-versus-host disease

AU - Gorantla, Vijay S.

AU - Prabhune, Kaustubha A.

AU - Perez-Abadia, Gustavo

AU - Ildstad, Suzanne T.

AU - Maldonado, Claudio

AU - Orhun, Haldun I.

AU - Majzoub, Ramsey K.

AU - Francois, Cedric G.

AU - Kakoulidis, Thanos P.

AU - Brouha, Pascal C R

AU - Anderson, Gary L.

AU - Pidwell, Diane J.

AU - Breidenbach, Warren C

AU - Barker, John H.

PY - 2003/4/15

Y1 - 2003/4/15

N2 - Background. Mixed allogeneic chimerism (MAC) has been shown to induce tolerance to composite tissue allografts (CTA). However, transplantation of unmanipulated donor-specific limbs results in severe graft-versus-host disease (GVHD). This suggests that nontolerant mature donor-derived cells in the CTA may affect the stability of chimerism, potentially resulting in GVHD. The aim of this study was to develop an approach to study and prevent GVHD in a mixed chimeric-rat hind-limb transplantation model. Methods. [ACI→WF] chimeras received a limb from Wistar Furth (WF) (syngeneic), Fisher (third-party), or ACI (irradiated [1,050 cGy] or nonirradiated) rats. In vitro tolerance was assessed using mixed lymphocyte reactivity (MLR) assays at the time the animals were killed. Results. [ACI→WF] chimeras with greater than 85% chimerism exhibited rejection-free survival of donor-specific hind limbs. However, 100% of these animals developed lethal GVHD 22.4±2.8 days after limb transplantation. [ACI→WF] chimeras that underwent transplantation with irradiated ACI or syngeneic WF limbs showed no signs of rejection or GVHD at 5 months. Nonchimeric and third-party controls rejected limbs within 10 days. Conclusions. Conditioning of the host WF rats with 950 cGy of irradiation (sublethal, myeloablative) led to high levels of MAC without GVHD. The mature T-cell content of nonirradiated donor (ACI) limbs was sufficient to induce lethal GVHD in 100% of tolerant mixed chimeric [ACI→WF] hosts. Irradiation of donor limbs before transplantation resulted in long-term donor-specific tolerance and prevented GVHD. These data demonstrate that (1) established chimeras could be susceptible to GVHD caused by immunocompetent donor cells transferred with the hind limb, and (2) inactivating these cells with irradiation prevents GVHD and destabilization of chimerism, and permits rejection-free graft acceptance.

AB - Background. Mixed allogeneic chimerism (MAC) has been shown to induce tolerance to composite tissue allografts (CTA). However, transplantation of unmanipulated donor-specific limbs results in severe graft-versus-host disease (GVHD). This suggests that nontolerant mature donor-derived cells in the CTA may affect the stability of chimerism, potentially resulting in GVHD. The aim of this study was to develop an approach to study and prevent GVHD in a mixed chimeric-rat hind-limb transplantation model. Methods. [ACI→WF] chimeras received a limb from Wistar Furth (WF) (syngeneic), Fisher (third-party), or ACI (irradiated [1,050 cGy] or nonirradiated) rats. In vitro tolerance was assessed using mixed lymphocyte reactivity (MLR) assays at the time the animals were killed. Results. [ACI→WF] chimeras with greater than 85% chimerism exhibited rejection-free survival of donor-specific hind limbs. However, 100% of these animals developed lethal GVHD 22.4±2.8 days after limb transplantation. [ACI→WF] chimeras that underwent transplantation with irradiated ACI or syngeneic WF limbs showed no signs of rejection or GVHD at 5 months. Nonchimeric and third-party controls rejected limbs within 10 days. Conclusions. Conditioning of the host WF rats with 950 cGy of irradiation (sublethal, myeloablative) led to high levels of MAC without GVHD. The mature T-cell content of nonirradiated donor (ACI) limbs was sufficient to induce lethal GVHD in 100% of tolerant mixed chimeric [ACI→WF] hosts. Irradiation of donor limbs before transplantation resulted in long-term donor-specific tolerance and prevented GVHD. These data demonstrate that (1) established chimeras could be susceptible to GVHD caused by immunocompetent donor cells transferred with the hind limb, and (2) inactivating these cells with irradiation prevents GVHD and destabilization of chimerism, and permits rejection-free graft acceptance.

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