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Vascularized Bone Marrow Cellular Depletion or Discontinuity Abrogates Protection of Vascularized Composite Allografts in Nonhuman Primates
BACKGROUND. Vascularized composite allografts (VCA) have demonstrated good clinical outcomes dependent on chronic immunosuppression. Previous work by our group and others supports that cotransplanted vascularized bone marrow (VBM) as a component of VCA offers immunologic protection to prolong graft...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Lippincott Williams & Wilkins
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837879/ https://www.ncbi.nlm.nih.gov/pubmed/33521248 http://dx.doi.org/10.1097/TXD.0000000000001107 |
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author | Shockcor, Nicole Buckingham, Evan B. Hassanein, Wessam Dhru, Urmil Khalifeh, Ali Uluer, Mehmet Woodall, Jhade Brazio, Philip Drachenberg, Cynthia Nam, Arthur J. Barth, Rolf N. |
author_facet | Shockcor, Nicole Buckingham, Evan B. Hassanein, Wessam Dhru, Urmil Khalifeh, Ali Uluer, Mehmet Woodall, Jhade Brazio, Philip Drachenberg, Cynthia Nam, Arthur J. Barth, Rolf N. |
author_sort | Shockcor, Nicole |
collection | PubMed |
description | BACKGROUND. Vascularized composite allografts (VCA) have demonstrated good clinical outcomes dependent on chronic immunosuppression. Previous work by our group and others supports that cotransplanted vascularized bone marrow (VBM) as a component of VCA offers immunologic protection to prolong graft survival. We aimed to characterize the requirements and potential mechanisms of VBM-mediated protection of VCA by modifying grafts through various strategies. METHODS. Experimental groups of mismatched cynomolgus macaque recipients received VCA transplants modified by the following approaches: heterotopic separation of the VCA and VBM components; T-cell depletion of either donor or recipient; irradiation of donor VCA; and infusion of donor bone marrow. All groups received standard immunosuppression with tacrolimus and mycophenolate mofetil. RESULTS. Experimental modifications to donor, recipient, or graft all demonstrated short-graft survivals (31 d). Chimerism levels without bone marrow infusion were transient and minimal when detected and were not associated with prolonged survival. Donor bone marrow infusion increased levels of chimerism but resulted in alloantibody production and did not improve graft survival. CONCLUSIONS. VCA graft survival is significantly reduced compared with previously reported VCA with VBM transplants (348 d; P = 0.01) when the hematopoietic niche is removed, altered, or destroyed via irradiation, depletion, or topographical rearrangement. These experimental manipulations resulted in similar outcomes to VCA grafts without cotransplanted VBM (25 d). These data support the presence of a radiosensitive, T-cell population within the VBM compartment not reconstituted by reinfusion of bone marrow cells. |
format | Online Article Text |
id | pubmed-7837879 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-78378792021-01-28 Vascularized Bone Marrow Cellular Depletion or Discontinuity Abrogates Protection of Vascularized Composite Allografts in Nonhuman Primates Shockcor, Nicole Buckingham, Evan B. Hassanein, Wessam Dhru, Urmil Khalifeh, Ali Uluer, Mehmet Woodall, Jhade Brazio, Philip Drachenberg, Cynthia Nam, Arthur J. Barth, Rolf N. Transplant Direct Hand and Composite Tissue Allotransplantation BACKGROUND. Vascularized composite allografts (VCA) have demonstrated good clinical outcomes dependent on chronic immunosuppression. Previous work by our group and others supports that cotransplanted vascularized bone marrow (VBM) as a component of VCA offers immunologic protection to prolong graft survival. We aimed to characterize the requirements and potential mechanisms of VBM-mediated protection of VCA by modifying grafts through various strategies. METHODS. Experimental groups of mismatched cynomolgus macaque recipients received VCA transplants modified by the following approaches: heterotopic separation of the VCA and VBM components; T-cell depletion of either donor or recipient; irradiation of donor VCA; and infusion of donor bone marrow. All groups received standard immunosuppression with tacrolimus and mycophenolate mofetil. RESULTS. Experimental modifications to donor, recipient, or graft all demonstrated short-graft survivals (31 d). Chimerism levels without bone marrow infusion were transient and minimal when detected and were not associated with prolonged survival. Donor bone marrow infusion increased levels of chimerism but resulted in alloantibody production and did not improve graft survival. CONCLUSIONS. VCA graft survival is significantly reduced compared with previously reported VCA with VBM transplants (348 d; P = 0.01) when the hematopoietic niche is removed, altered, or destroyed via irradiation, depletion, or topographical rearrangement. These experimental manipulations resulted in similar outcomes to VCA grafts without cotransplanted VBM (25 d). These data support the presence of a radiosensitive, T-cell population within the VBM compartment not reconstituted by reinfusion of bone marrow cells. Lippincott Williams & Wilkins 2021-01-26 /pmc/articles/PMC7837879/ /pubmed/33521248 http://dx.doi.org/10.1097/TXD.0000000000001107 Text en Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
spellingShingle | Hand and Composite Tissue Allotransplantation Shockcor, Nicole Buckingham, Evan B. Hassanein, Wessam Dhru, Urmil Khalifeh, Ali Uluer, Mehmet Woodall, Jhade Brazio, Philip Drachenberg, Cynthia Nam, Arthur J. Barth, Rolf N. Vascularized Bone Marrow Cellular Depletion or Discontinuity Abrogates Protection of Vascularized Composite Allografts in Nonhuman Primates |
title | Vascularized Bone Marrow Cellular Depletion or Discontinuity Abrogates Protection of Vascularized Composite Allografts in Nonhuman Primates |
title_full | Vascularized Bone Marrow Cellular Depletion or Discontinuity Abrogates Protection of Vascularized Composite Allografts in Nonhuman Primates |
title_fullStr | Vascularized Bone Marrow Cellular Depletion or Discontinuity Abrogates Protection of Vascularized Composite Allografts in Nonhuman Primates |
title_full_unstemmed | Vascularized Bone Marrow Cellular Depletion or Discontinuity Abrogates Protection of Vascularized Composite Allografts in Nonhuman Primates |
title_short | Vascularized Bone Marrow Cellular Depletion or Discontinuity Abrogates Protection of Vascularized Composite Allografts in Nonhuman Primates |
title_sort | vascularized bone marrow cellular depletion or discontinuity abrogates protection of vascularized composite allografts in nonhuman primates |
topic | Hand and Composite Tissue Allotransplantation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837879/ https://www.ncbi.nlm.nih.gov/pubmed/33521248 http://dx.doi.org/10.1097/TXD.0000000000001107 |
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