Tolerance of a Vascularized Composite Allograft Achieved in MHC Class-I-mismatch Swine via Mixed Chimerism

Alexandre G. Lellouch; Alec R. Andrews; Gaelle Saviane; Zhi Yang Ng; Ilse M. Schol; Marion Goutard; Amon Ra Gama; Ivy A. Rosales; Robert B. Colvin; Laurent A. Lantieri; Mark A. Randolph; Gilles Benichou; Curtis L. Cetrulo

doi:10.3389/fimmu.2022.829406

Tolerance of a Vascularized Composite Allograft Achieved in MHC Class-I-mismatch Swine via Mixed Chimerism

Alexandre G. Lellouch, Alec R. Andrews, Gaelle Saviane, Zhi Yang Ng, Ilse M. Schol, Marion Goutard, Amon Ra Gama, Ivy A. Rosales, Robert B. Colvin, Laurent A. Lantieri, Mark A. Randolph, Gilles Benichou, Curtis L. Cetrulo

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18 Citations (Scopus)

Résumé

Background: Vascularized composite allografts (VCAs) allow reconstruction of devastating injuries and amputations, yet require lifelong immunosuppression that is associated with significant morbidity. Induction of immune tolerance of VCAs would permit widespread use of these procedures. VCAs are acquired from deceased donors most likely to be fully-MHC-mismatched (in contrast to living-related renal transplant donor-recipient pairs matched at one MHC haplotype). After achieving VCA tolerance in a swine model equivalent to clinical living-related renal transplants (single-haplotype MHC mismatches: e.g., “mother-daughter”/haploidentical), we tested our protocol in MHC class I, class II, and fully-MHC-mismatched pairs. Although class II mismatched swine demonstrated similar results as the haploidentical scenario (stable mixed chimerism and tolerance), our protocol failed to prevent rejection of class I and full mismatch VCAs. Here, we describe a new adapted conditioning protocol that successfully achieved tolerance across MHC class-I-mismatch barriers in swine. Methods: Swine were treated with non-myeloablative total body and thymic irradiation two days prior to infusion of bone marrow cells from an MHC class I-mismatched donor. They also received a short-term treatment with CTLA4-Ig (Belatacept^®) and anti-IL6R mAb (Tociluzimab^®) and were transplanted with an osteomyocutaneous VCA from the same donor. Results: Stable mixed chimerism and tolerance of MHC class-I-mismatched VCAs was achieved in 3 recipients. Allograft tolerance was associated with a sustained lack of anti-donor T cell response and a concomitant expansion of double negative CD4^-CD8^- T cells producing IL-10. Conclusions: This study demonstrates the first successful mixed chimerism-induced VCA tolerance in a large animal model across a MHC class-I-mismatch. Future studies aimed at fully-mismatched donor-recipient pairs are under investigation with this protocol.

langue originale	Anglais
Numéro d'article	829406
journal	Frontiers in Immunology
Volume	13
Les DOIs	https://doi.org/10.3389/fimmu.2022.829406
état	Publié - 10 mai 2022
Modification externe	Oui

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10.3389/fimmu.2022.829406

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Lellouch, A. G., Andrews, A. R., Saviane, G., Ng, Z. Y., Schol, I. M., Goutard, M., Gama, A. R., Rosales, I. A., Colvin, R. B., Lantieri, L. A., Randolph, M. A., Benichou, G., & Cetrulo, C. L. (2022). Tolerance of a Vascularized Composite Allograft Achieved in MHC Class-I-mismatch Swine via Mixed Chimerism. Frontiers in Immunology, 13, Article 829406. https://doi.org/10.3389/fimmu.2022.829406

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title = "Tolerance of a Vascularized Composite Allograft Achieved in MHC Class-I-mismatch Swine via Mixed Chimerism",

abstract = "Background: Vascularized composite allografts (VCAs) allow reconstruction of devastating injuries and amputations, yet require lifelong immunosuppression that is associated with significant morbidity. Induction of immune tolerance of VCAs would permit widespread use of these procedures. VCAs are acquired from deceased donors most likely to be fully-MHC-mismatched (in contrast to living-related renal transplant donor-recipient pairs matched at one MHC haplotype). After achieving VCA tolerance in a swine model equivalent to clinical living-related renal transplants (single-haplotype MHC mismatches: e.g., “mother-daughter”/haploidentical), we tested our protocol in MHC class I, class II, and fully-MHC-mismatched pairs. Although class II mismatched swine demonstrated similar results as the haploidentical scenario (stable mixed chimerism and tolerance), our protocol failed to prevent rejection of class I and full mismatch VCAs. Here, we describe a new adapted conditioning protocol that successfully achieved tolerance across MHC class-I-mismatch barriers in swine. Methods: Swine were treated with non-myeloablative total body and thymic irradiation two days prior to infusion of bone marrow cells from an MHC class I-mismatched donor. They also received a short-term treatment with CTLA4-Ig (Belatacept{\textregistered}) and anti-IL6R mAb (Tociluzimab{\textregistered}) and were transplanted with an osteomyocutaneous VCA from the same donor. Results: Stable mixed chimerism and tolerance of MHC class-I-mismatched VCAs was achieved in 3 recipients. Allograft tolerance was associated with a sustained lack of anti-donor T cell response and a concomitant expansion of double negative CD4-CD8- T cells producing IL-10. Conclusions: This study demonstrates the first successful mixed chimerism-induced VCA tolerance in a large animal model across a MHC class-I-mismatch. Future studies aimed at fully-mismatched donor-recipient pairs are under investigation with this protocol.",

keywords = "bone marrow transplantation, co-stimulatory blockade, MHC class I, mixed chimerism, skin tolerance, Vascularized composite allotransplantation (VCA)",

author = "Lellouch, {Alexandre G.} and Andrews, {Alec R.} and Gaelle Saviane and Ng, {Zhi Yang} and Schol, {Ilse M.} and Marion Goutard and Gama, {Amon Ra} and Rosales, {Ivy A.} and Colvin, {Robert B.} and Lantieri, {Laurent A.} and Randolph, {Mark A.} and Gilles Benichou and Cetrulo, {Curtis L.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 Lellouch, Andrews, Saviane, Ng, Schol, Goutard, Gama, Rosales, Colvin, Lantieri, Randolph, Benichou and Cetrulo.",

year = "2022",

month = may,

day = "10",

doi = "10.3389/fimmu.2022.829406",

language = "English",

volume = "13",

journal = "Frontiers in Immunology",

issn = "1664-3224",

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T1 - Tolerance of a Vascularized Composite Allograft Achieved in MHC Class-I-mismatch Swine via Mixed Chimerism

AU - Lellouch, Alexandre G.

AU - Andrews, Alec R.

AU - Saviane, Gaelle

AU - Ng, Zhi Yang

AU - Schol, Ilse M.

AU - Goutard, Marion

AU - Gama, Amon Ra

AU - Rosales, Ivy A.

AU - Colvin, Robert B.

AU - Lantieri, Laurent A.

AU - Randolph, Mark A.

AU - Benichou, Gilles

AU - Cetrulo, Curtis L.

PY - 2022/5/10

Y1 - 2022/5/10

N2 - Background: Vascularized composite allografts (VCAs) allow reconstruction of devastating injuries and amputations, yet require lifelong immunosuppression that is associated with significant morbidity. Induction of immune tolerance of VCAs would permit widespread use of these procedures. VCAs are acquired from deceased donors most likely to be fully-MHC-mismatched (in contrast to living-related renal transplant donor-recipient pairs matched at one MHC haplotype). After achieving VCA tolerance in a swine model equivalent to clinical living-related renal transplants (single-haplotype MHC mismatches: e.g., “mother-daughter”/haploidentical), we tested our protocol in MHC class I, class II, and fully-MHC-mismatched pairs. Although class II mismatched swine demonstrated similar results as the haploidentical scenario (stable mixed chimerism and tolerance), our protocol failed to prevent rejection of class I and full mismatch VCAs. Here, we describe a new adapted conditioning protocol that successfully achieved tolerance across MHC class-I-mismatch barriers in swine. Methods: Swine were treated with non-myeloablative total body and thymic irradiation two days prior to infusion of bone marrow cells from an MHC class I-mismatched donor. They also received a short-term treatment with CTLA4-Ig (Belatacept®) and anti-IL6R mAb (Tociluzimab®) and were transplanted with an osteomyocutaneous VCA from the same donor. Results: Stable mixed chimerism and tolerance of MHC class-I-mismatched VCAs was achieved in 3 recipients. Allograft tolerance was associated with a sustained lack of anti-donor T cell response and a concomitant expansion of double negative CD4-CD8- T cells producing IL-10. Conclusions: This study demonstrates the first successful mixed chimerism-induced VCA tolerance in a large animal model across a MHC class-I-mismatch. Future studies aimed at fully-mismatched donor-recipient pairs are under investigation with this protocol.

AB - Background: Vascularized composite allografts (VCAs) allow reconstruction of devastating injuries and amputations, yet require lifelong immunosuppression that is associated with significant morbidity. Induction of immune tolerance of VCAs would permit widespread use of these procedures. VCAs are acquired from deceased donors most likely to be fully-MHC-mismatched (in contrast to living-related renal transplant donor-recipient pairs matched at one MHC haplotype). After achieving VCA tolerance in a swine model equivalent to clinical living-related renal transplants (single-haplotype MHC mismatches: e.g., “mother-daughter”/haploidentical), we tested our protocol in MHC class I, class II, and fully-MHC-mismatched pairs. Although class II mismatched swine demonstrated similar results as the haploidentical scenario (stable mixed chimerism and tolerance), our protocol failed to prevent rejection of class I and full mismatch VCAs. Here, we describe a new adapted conditioning protocol that successfully achieved tolerance across MHC class-I-mismatch barriers in swine. Methods: Swine were treated with non-myeloablative total body and thymic irradiation two days prior to infusion of bone marrow cells from an MHC class I-mismatched donor. They also received a short-term treatment with CTLA4-Ig (Belatacept®) and anti-IL6R mAb (Tociluzimab®) and were transplanted with an osteomyocutaneous VCA from the same donor. Results: Stable mixed chimerism and tolerance of MHC class-I-mismatched VCAs was achieved in 3 recipients. Allograft tolerance was associated with a sustained lack of anti-donor T cell response and a concomitant expansion of double negative CD4-CD8- T cells producing IL-10. Conclusions: This study demonstrates the first successful mixed chimerism-induced VCA tolerance in a large animal model across a MHC class-I-mismatch. Future studies aimed at fully-mismatched donor-recipient pairs are under investigation with this protocol.

KW - bone marrow transplantation

KW - co-stimulatory blockade

KW - MHC class I

KW - mixed chimerism

KW - skin tolerance

KW - Vascularized composite allotransplantation (VCA)

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