Desensitization and prevention of antibody-mediated rejection in vascularized composite allotransplantation by syngeneic hematopoietic stem cell transplantation

Howard D. Wang; Samuel A.J. Fidder; Devin T. Miller; Georg J. Furtmüller; Ali R. Ahmadi; Felix Nägele; Joseph Lopez; Amy Quan; Joshua Budihardjo; Denver M. Lough; Burcu Akpinarli; Joanna W. Etra; Dalibor Vasilic; Giorgio Raimondi; W. P.Andrew Lee; Robert A. Montgomery; Zhaoli Sun; Gerald Brandacher

doi:10.1097/TP.0000000000002070

Desensitization and prevention of antibody-mediated rejection in vascularized composite allotransplantation by syngeneic hematopoietic stem cell transplantation

Howard D. Wang, Samuel A.J. Fidder, Devin T. Miller, Georg J. Furtmüller, Ali R. Ahmadi, Felix Nägele, Joseph Lopez, Amy Quan, Joshua Budihardjo, Denver M. Lough, Burcu Akpinarli, Joanna W. Etra, Dalibor Vasilic, Giorgio Raimondi, W. P.Andrew Lee, Robert A. Montgomery, Zhaoli Sun, Gerald Brandacher

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9 Scopus citations

Abstract

Background Candidates for vascularized composite allotransplantation (VCA) are frequently sensitized, putting them at risk for antibody-mediated rejection. Current desensitization strategies are imperfect and require a living-donor setting. Here we investigated the impact of sensitization on and the efficacy of a desensitization protocol utilizing syngeneic hematopoietic stem cell transplantation (HSCT) to prevent antibody-mediated rejection in VCA. Methods Skin transplants from Dark Agouti to Lewis rats were performed for sensitization. Orthotopic hind limb transplants from Dark Agouti donors were performed to sensitized and nonsensitized recipients, and the animals were treated with either daily tacrolimus or no immunosuppression. A desensitization protocol consisting of total body irradiation, fludarabine, and syngeneic HSCT was applied to sensitized animals. Graft rejection was monitored by clinical assessment and histological analysis. Serum levels of donor-specific antibodies (DSA IgG) were measured using flow cytometry. Results Sensitized recipients exhibited accelerated rejection by 5.5 ± 1.2 days without immunosuppression and 10.2 ± 3.6 days with daily tacrolimus compared with 8.7 ± 1.2 days and longer than 30 days in nonsensitized recipients, respectively. Serum levels of DSA IgG were markedly elevated (37.3 ± 3.34-fold from baseline) in sensitized recipients after VCA and correlated with histologic evidence of rejection and C4d deposition. Desensitization significantly reduced DSA compared with sensitized controls (2.6 ± 0.5-fold vs 6.0 ± 1.2-fold, P < 0.01) and along with daily tacrolimus led to improved VCA survival longer than 30 days without evidence of C4d deposition (n = 6). Conclusions In summary, sensitization leads to accelerated rejection of VCA, and syngeneic HSCT combined with conventional immunosuppression effectively reduces DSA and improves allograft survival in sensitized rats.

Original language	English (US)
Pages (from-to)	593-600
Number of pages	8
Journal	Transplantation
Volume	102
Issue number	4
DOIs	https://doi.org/10.1097/TP.0000000000002070
State	Published - Apr 1 2018
Externally published	Yes

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Transplantation

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10.1097/TP.0000000000002070

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Wang, H. D., Fidder, S. A. J., Miller, D. T., Furtmüller, G. J., Ahmadi, A. R., Nägele, F., Lopez, J., Quan, A., Budihardjo, J., Lough, D. M., Akpinarli, B., Etra, J. W., Vasilic, D., Raimondi, G., Lee, W. P. A., Montgomery, R. A., Sun, Z., & Brandacher, G. (2018). Desensitization and prevention of antibody-mediated rejection in vascularized composite allotransplantation by syngeneic hematopoietic stem cell transplantation. Transplantation, 102(4), 593-600. https://doi.org/10.1097/TP.0000000000002070

Wang, HD, Fidder, SAJ, Miller, DT, Furtmüller, GJ, Ahmadi, AR, Nägele, F, Lopez, J, Quan, A, Budihardjo, J, Lough, DM, Akpinarli, B, Etra, JW, Vasilic, D, Raimondi, G, Lee, WPA, Montgomery, RA, Sun, Z & Brandacher, G 2018, 'Desensitization and prevention of antibody-mediated rejection in vascularized composite allotransplantation by syngeneic hematopoietic stem cell transplantation', Transplantation, vol. 102, no. 4, pp. 593-600. https://doi.org/10.1097/TP.0000000000002070

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title = "Desensitization and prevention of antibody-mediated rejection in vascularized composite allotransplantation by syngeneic hematopoietic stem cell transplantation",

abstract = "Background Candidates for vascularized composite allotransplantation (VCA) are frequently sensitized, putting them at risk for antibody-mediated rejection. Current desensitization strategies are imperfect and require a living-donor setting. Here we investigated the impact of sensitization on and the efficacy of a desensitization protocol utilizing syngeneic hematopoietic stem cell transplantation (HSCT) to prevent antibody-mediated rejection in VCA. Methods Skin transplants from Dark Agouti to Lewis rats were performed for sensitization. Orthotopic hind limb transplants from Dark Agouti donors were performed to sensitized and nonsensitized recipients, and the animals were treated with either daily tacrolimus or no immunosuppression. A desensitization protocol consisting of total body irradiation, fludarabine, and syngeneic HSCT was applied to sensitized animals. Graft rejection was monitored by clinical assessment and histological analysis. Serum levels of donor-specific antibodies (DSA IgG) were measured using flow cytometry. Results Sensitized recipients exhibited accelerated rejection by 5.5 ± 1.2 days without immunosuppression and 10.2 ± 3.6 days with daily tacrolimus compared with 8.7 ± 1.2 days and longer than 30 days in nonsensitized recipients, respectively. Serum levels of DSA IgG were markedly elevated (37.3 ± 3.34-fold from baseline) in sensitized recipients after VCA and correlated with histologic evidence of rejection and C4d deposition. Desensitization significantly reduced DSA compared with sensitized controls (2.6 ± 0.5-fold vs 6.0 ± 1.2-fold, P < 0.01) and along with daily tacrolimus led to improved VCA survival longer than 30 days without evidence of C4d deposition (n = 6). Conclusions In summary, sensitization leads to accelerated rejection of VCA, and syngeneic HSCT combined with conventional immunosuppression effectively reduces DSA and improves allograft survival in sensitized rats.",

author = "Wang, {Howard D.} and Fidder, {Samuel A.J.} and Miller, {Devin T.} and Furtm{\"u}ller, {Georg J.} and Ahmadi, {Ali R.} and Felix N{\"a}gele and Joseph Lopez and Amy Quan and Joshua Budihardjo and Lough, {Denver M.} and Burcu Akpinarli and Etra, {Joanna W.} and Dalibor Vasilic and Giorgio Raimondi and Lee, {W. P.Andrew} and Montgomery, {Robert A.} and Zhaoli Sun and Gerald Brandacher",

year = "2018",

month = apr,

day = "1",

doi = "10.1097/TP.0000000000002070",

language = "English (US)",

volume = "102",

pages = "593--600",

journal = "Transplantation",

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TY - JOUR

T1 - Desensitization and prevention of antibody-mediated rejection in vascularized composite allotransplantation by syngeneic hematopoietic stem cell transplantation

AU - Wang, Howard D.

AU - Fidder, Samuel A.J.

AU - Miller, Devin T.

AU - Furtmüller, Georg J.

AU - Ahmadi, Ali R.

AU - Nägele, Felix

AU - Lopez, Joseph

AU - Quan, Amy

AU - Budihardjo, Joshua

AU - Lough, Denver M.

AU - Akpinarli, Burcu

AU - Etra, Joanna W.

AU - Vasilic, Dalibor

AU - Raimondi, Giorgio

AU - Lee, W. P.Andrew

AU - Montgomery, Robert A.

AU - Sun, Zhaoli

AU - Brandacher, Gerald

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Background Candidates for vascularized composite allotransplantation (VCA) are frequently sensitized, putting them at risk for antibody-mediated rejection. Current desensitization strategies are imperfect and require a living-donor setting. Here we investigated the impact of sensitization on and the efficacy of a desensitization protocol utilizing syngeneic hematopoietic stem cell transplantation (HSCT) to prevent antibody-mediated rejection in VCA. Methods Skin transplants from Dark Agouti to Lewis rats were performed for sensitization. Orthotopic hind limb transplants from Dark Agouti donors were performed to sensitized and nonsensitized recipients, and the animals were treated with either daily tacrolimus or no immunosuppression. A desensitization protocol consisting of total body irradiation, fludarabine, and syngeneic HSCT was applied to sensitized animals. Graft rejection was monitored by clinical assessment and histological analysis. Serum levels of donor-specific antibodies (DSA IgG) were measured using flow cytometry. Results Sensitized recipients exhibited accelerated rejection by 5.5 ± 1.2 days without immunosuppression and 10.2 ± 3.6 days with daily tacrolimus compared with 8.7 ± 1.2 days and longer than 30 days in nonsensitized recipients, respectively. Serum levels of DSA IgG were markedly elevated (37.3 ± 3.34-fold from baseline) in sensitized recipients after VCA and correlated with histologic evidence of rejection and C4d deposition. Desensitization significantly reduced DSA compared with sensitized controls (2.6 ± 0.5-fold vs 6.0 ± 1.2-fold, P < 0.01) and along with daily tacrolimus led to improved VCA survival longer than 30 days without evidence of C4d deposition (n = 6). Conclusions In summary, sensitization leads to accelerated rejection of VCA, and syngeneic HSCT combined with conventional immunosuppression effectively reduces DSA and improves allograft survival in sensitized rats.

AB - Background Candidates for vascularized composite allotransplantation (VCA) are frequently sensitized, putting them at risk for antibody-mediated rejection. Current desensitization strategies are imperfect and require a living-donor setting. Here we investigated the impact of sensitization on and the efficacy of a desensitization protocol utilizing syngeneic hematopoietic stem cell transplantation (HSCT) to prevent antibody-mediated rejection in VCA. Methods Skin transplants from Dark Agouti to Lewis rats were performed for sensitization. Orthotopic hind limb transplants from Dark Agouti donors were performed to sensitized and nonsensitized recipients, and the animals were treated with either daily tacrolimus or no immunosuppression. A desensitization protocol consisting of total body irradiation, fludarabine, and syngeneic HSCT was applied to sensitized animals. Graft rejection was monitored by clinical assessment and histological analysis. Serum levels of donor-specific antibodies (DSA IgG) were measured using flow cytometry. Results Sensitized recipients exhibited accelerated rejection by 5.5 ± 1.2 days without immunosuppression and 10.2 ± 3.6 days with daily tacrolimus compared with 8.7 ± 1.2 days and longer than 30 days in nonsensitized recipients, respectively. Serum levels of DSA IgG were markedly elevated (37.3 ± 3.34-fold from baseline) in sensitized recipients after VCA and correlated with histologic evidence of rejection and C4d deposition. Desensitization significantly reduced DSA compared with sensitized controls (2.6 ± 0.5-fold vs 6.0 ± 1.2-fold, P < 0.01) and along with daily tacrolimus led to improved VCA survival longer than 30 days without evidence of C4d deposition (n = 6). Conclusions In summary, sensitization leads to accelerated rejection of VCA, and syngeneic HSCT combined with conventional immunosuppression effectively reduces DSA and improves allograft survival in sensitized rats.

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Desensitization and prevention of antibody-mediated rejection in vascularized composite allotransplantation by syngeneic hematopoietic stem cell transplantation

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