Extended survival versus accelerated rejection of nonhuman primate islet allografts: Effect of mesenchymal stem cell source and timing
Mesenchymal stem cells (MSC) have been shown to be immunomodulatory, tissue regenerative, and graft promoting; however, several questions remain with regard to ideal MSC source and timing of administration. In this study, we utilized a rigorous preclinical model of allogeneic islet cell transplantat...
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| Veröffentlicht in: | American journal of transplantation 2021-11, Vol.21 (11), p.3524-3537 |
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| creator | Kenyon, Norma S. Willman, Melissa A. Han, Dongmei Leeman, Rachel S. Rabassa, Alex Diaz, Waldo L. Geary, James C. Poumian‐Ruiz, Ena Griswold, Anthony J. Van Booven, Derek J. Thompson, Ryan Ordoukhanian, Philip Head, Steven R. Kenyon, Norman M. McHenry, Kenton G. Salomon, Daniel R. Bartholomew, Amelia M. Berman, Dora M. |
| description | Mesenchymal stem cells (MSC) have been shown to be immunomodulatory, tissue regenerative, and graft promoting; however, several questions remain with regard to ideal MSC source and timing of administration. In this study, we utilized a rigorous preclinical model of allogeneic islet cell transplantation, incorporating reduced immune suppression and near to complete mismatch of major histocompatibility antigens between the diabetic cynomolgus monkey recipient and the islet donor, to evaluate both the graft promoting impact of MSC source, that is, derived from the islet recipient, the islet donor or an unrelated third party as well as the impact of timing. Co‐transplant of MSC and islets on post‐operative day 0, followed by additional IV MSC infusions in the first posttransplant month, resulted in prolongation of rejection free and overall islet survival and superior metabolic control for animals treated with recipient as compared to donor or third‐party MSC. Immunological analyses demonstrated that infusion of MSC from either source did not prevent alloantibody formation to the islet or MSC donor; however, treatment with recipient MSC resulted in significant downregulation of memory T cells, decreased anti‐donor T cell proliferation, and a trend toward increased Tregulatory:Tconventional ratios.
Intrahepatic cotransplantation of islet and recipient‐derived, compared to donor‐ or third party‐derived mesenchymal stem cells, followed by additional mesenchymal stem cell infusions in the first posttransplant month, prolongs overall and rejection‐free islet survival and superior metabolic control. |
| doi_str_mv | 10.1111/ajt.16693 |
| format | Article |
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Intrahepatic cotransplantation of islet and recipient‐derived, compared to donor‐ or third party‐derived mesenchymal stem cells, followed by additional mesenchymal stem cell infusions in the first posttransplant month, prolongs overall and rejection‐free islet survival and superior metabolic control.</description><identifier>ISSN: 1600-6135</identifier><identifier>EISSN: 1600-6143</identifier><identifier>DOI: 10.1111/ajt.16693</identifier><identifier>PMID: 34008325</identifier><language>eng</language><publisher>United States: Elsevier Limited</publisher><subject>Alloantibodies ; Allografts ; Animals ; Antigens ; Cell proliferation ; Clinical outcomes ; Diabetes mellitus ; Graft rejection ; Histocompatibility ; Immune system ; Immunological memory ; Immunomodulation ; Islet cells ; Islets of Langerhans Transplantation ; Lymphocytes T ; Macaca fascicularis ; Memory cells ; Mesenchymal Stem Cells ; Pancreatic islet transplantation ; Stem cell transplantation ; Stem cells ; Transplantation, Homologous</subject><ispartof>American journal of transplantation, 2021-11, Vol.21 (11), p.3524-3537</ispartof><rights>2021 The American Society of Transplantation and the American Society of Transplant Surgeons</rights><rights>2021 The American Society of Transplantation and the American Society of Transplant Surgeons.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4433-78b5b5c5dc1d5798c4ce91f840c8206dc2cc6a3a236543bdf5f0a5cfe5bb94ce3</citedby><cites>FETCH-LOGICAL-c4433-78b5b5c5dc1d5798c4ce91f840c8206dc2cc6a3a236543bdf5f0a5cfe5bb94ce3</cites><orcidid>0000-0001-7817-9387 ; 0000-0003-3157-339X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fajt.16693$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fajt.16693$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34008325$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kenyon, Norma S.</creatorcontrib><creatorcontrib>Willman, Melissa A.</creatorcontrib><creatorcontrib>Han, Dongmei</creatorcontrib><creatorcontrib>Leeman, Rachel S.</creatorcontrib><creatorcontrib>Rabassa, Alex</creatorcontrib><creatorcontrib>Diaz, Waldo L.</creatorcontrib><creatorcontrib>Geary, James C.</creatorcontrib><creatorcontrib>Poumian‐Ruiz, Ena</creatorcontrib><creatorcontrib>Griswold, Anthony J.</creatorcontrib><creatorcontrib>Van Booven, Derek J.</creatorcontrib><creatorcontrib>Thompson, Ryan</creatorcontrib><creatorcontrib>Ordoukhanian, Philip</creatorcontrib><creatorcontrib>Head, Steven R.</creatorcontrib><creatorcontrib>Kenyon, Norman M.</creatorcontrib><creatorcontrib>McHenry, Kenton G.</creatorcontrib><creatorcontrib>Salomon, Daniel R.</creatorcontrib><creatorcontrib>Bartholomew, Amelia M.</creatorcontrib><creatorcontrib>Berman, Dora M.</creatorcontrib><title>Extended survival versus accelerated rejection of nonhuman primate islet allografts: Effect of mesenchymal stem cell source and timing</title><title>American journal of transplantation</title><addtitle>Am J Transplant</addtitle><description>Mesenchymal stem cells (MSC) have been shown to be immunomodulatory, tissue regenerative, and graft promoting; however, several questions remain with regard to ideal MSC source and timing of administration. In this study, we utilized a rigorous preclinical model of allogeneic islet cell transplantation, incorporating reduced immune suppression and near to complete mismatch of major histocompatibility antigens between the diabetic cynomolgus monkey recipient and the islet donor, to evaluate both the graft promoting impact of MSC source, that is, derived from the islet recipient, the islet donor or an unrelated third party as well as the impact of timing. Co‐transplant of MSC and islets on post‐operative day 0, followed by additional IV MSC infusions in the first posttransplant month, resulted in prolongation of rejection free and overall islet survival and superior metabolic control for animals treated with recipient as compared to donor or third‐party MSC. Immunological analyses demonstrated that infusion of MSC from either source did not prevent alloantibody formation to the islet or MSC donor; however, treatment with recipient MSC resulted in significant downregulation of memory T cells, decreased anti‐donor T cell proliferation, and a trend toward increased Tregulatory:Tconventional ratios.
Intrahepatic cotransplantation of islet and recipient‐derived, compared to donor‐ or third party‐derived mesenchymal stem cells, followed by additional mesenchymal stem cell infusions in the first posttransplant month, prolongs overall and rejection‐free islet survival and superior metabolic control.</description><subject>Alloantibodies</subject><subject>Allografts</subject><subject>Animals</subject><subject>Antigens</subject><subject>Cell proliferation</subject><subject>Clinical outcomes</subject><subject>Diabetes mellitus</subject><subject>Graft rejection</subject><subject>Histocompatibility</subject><subject>Immune system</subject><subject>Immunological memory</subject><subject>Immunomodulation</subject><subject>Islet cells</subject><subject>Islets of Langerhans Transplantation</subject><subject>Lymphocytes T</subject><subject>Macaca fascicularis</subject><subject>Memory cells</subject><subject>Mesenchymal Stem Cells</subject><subject>Pancreatic islet transplantation</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Transplantation, Homologous</subject><issn>1600-6135</issn><issn>1600-6143</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1uEzEURi0EoiWw4AWQJTZ0kdYejyceFpWqKvypEpuytjye68TRjF1sTyAvwHP3pikRIOGNr3SPju6nj5DXnJ1zfBdmU85507TiCTnlDWPzhtfi6XEW8oS8yHnDGF9UqnpOTkTNmBKVPCW_lj8LhB56mqe09Vsz0C2kPGVqrIUBkim4S7ABW3wMNDoaYlhPown0LvkR19TnAQo1wxBXybiS39Olc8jv4REyBLvejSjOBUaKUpzilCxQE3pa_OjD6iV55syQ4dXjPyPfPixvrz_Nb75-_Hx9dTO3dS3EfKE62Ukre8t7uWiVrS203KmaWVWxpreVtY0RphKNrEXXO-mYkdaB7LoWWTEjlwfv3dSN0FsIJZlBPyRJOx2N139vgl_rVdzqlgm8QKHg3aMgxe8T5KJHn_eZTIA4ZV3JSrVVrbCMGXn7D7rB2AHjIdUyzhUTC6TODpRNMecE7ngMZ3rfrsZ29UO7yL758_oj-btOBC4OwA8_wO7_Jn315fagvAd2ybK7</recordid><startdate>202111</startdate><enddate>202111</enddate><creator>Kenyon, Norma S.</creator><creator>Willman, Melissa A.</creator><creator>Han, Dongmei</creator><creator>Leeman, Rachel S.</creator><creator>Rabassa, Alex</creator><creator>Diaz, Waldo L.</creator><creator>Geary, James C.</creator><creator>Poumian‐Ruiz, Ena</creator><creator>Griswold, Anthony J.</creator><creator>Van Booven, Derek J.</creator><creator>Thompson, Ryan</creator><creator>Ordoukhanian, Philip</creator><creator>Head, Steven R.</creator><creator>Kenyon, Norman M.</creator><creator>McHenry, Kenton G.</creator><creator>Salomon, Daniel R.</creator><creator>Bartholomew, Amelia M.</creator><creator>Berman, Dora M.</creator><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7T5</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7817-9387</orcidid><orcidid>https://orcid.org/0000-0003-3157-339X</orcidid></search><sort><creationdate>202111</creationdate><title>Extended survival versus accelerated rejection of nonhuman primate islet allografts: Effect of mesenchymal stem cell source and timing</title><author>Kenyon, Norma S. ; 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however, several questions remain with regard to ideal MSC source and timing of administration. In this study, we utilized a rigorous preclinical model of allogeneic islet cell transplantation, incorporating reduced immune suppression and near to complete mismatch of major histocompatibility antigens between the diabetic cynomolgus monkey recipient and the islet donor, to evaluate both the graft promoting impact of MSC source, that is, derived from the islet recipient, the islet donor or an unrelated third party as well as the impact of timing. Co‐transplant of MSC and islets on post‐operative day 0, followed by additional IV MSC infusions in the first posttransplant month, resulted in prolongation of rejection free and overall islet survival and superior metabolic control for animals treated with recipient as compared to donor or third‐party MSC. Immunological analyses demonstrated that infusion of MSC from either source did not prevent alloantibody formation to the islet or MSC donor; however, treatment with recipient MSC resulted in significant downregulation of memory T cells, decreased anti‐donor T cell proliferation, and a trend toward increased Tregulatory:Tconventional ratios.
Intrahepatic cotransplantation of islet and recipient‐derived, compared to donor‐ or third party‐derived mesenchymal stem cells, followed by additional mesenchymal stem cell infusions in the first posttransplant month, prolongs overall and rejection‐free islet survival and superior metabolic control.</abstract><cop>United States</cop><pub>Elsevier Limited</pub><pmid>34008325</pmid><doi>10.1111/ajt.16693</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0001-7817-9387</orcidid><orcidid>https://orcid.org/0000-0003-3157-339X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Alloantibodies Allografts Animals Antigens Cell proliferation Clinical outcomes Diabetes mellitus Graft rejection Histocompatibility Immune system Immunological memory Immunomodulation Islet cells Islets of Langerhans Transplantation Lymphocytes T Macaca fascicularis Memory cells Mesenchymal Stem Cells Pancreatic islet transplantation Stem cell transplantation Stem cells Transplantation, Homologous |
| title | Extended survival versus accelerated rejection of nonhuman primate islet allografts: Effect of mesenchymal stem cell source and timing |
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