Localized Immunomodulation with PD-L1 Results in Sustained Survival and Function of Allogeneic Islets without Chronic Immunosuppression.
Identifieur interne : 000096 ( Main/Exploration ); précédent : 000095; suivant : 000097Localized Immunomodulation with PD-L1 Results in Sustained Survival and Function of Allogeneic Islets without Chronic Immunosuppression.
Auteurs : Lalit Batra [États-Unis] ; Pradeep Shrestha [États-Unis] ; Hong Zhao [États-Unis] ; Kyle B. Woodward [États-Unis] ; Alper Togay [États-Unis] ; Min Tan [États-Unis] ; Orlando Grimany-Nuno [États-Unis] ; Mohammad Tariq Malik [États-Unis] ; María M. Coronel [États-Unis] ; Andrés J. García [États-Unis] ; Haval Shirwan [États-Unis] ; Esma S. Yolcu [États-Unis]Source :
- Journal of immunology (Baltimore, Md. : 1950) [ 1550-6606 ] ; 2020.
Abstract
Allogeneic islet transplantation is limited by adverse effects of chronic immunosuppression used to control rejection. The programmed cell death 1 pathway as an important immune checkpoint has the potential to obviate the need for chronic immunosuppression. We generated an oligomeric form of programmed cell death 1 ligand chimeric with core streptavidin (SA-PDL1) that inhibited the T effector cell response to alloantigens and converted T conventional cells into CD4+Foxp3+ T regulatory cells. The SA-PDL1 protein was effectively displayed on the surface of biotinylated mouse islets without a negative impact islet viability and insulin secretion. Transplantation of SA-PDL1-engineered islet grafts with a short course of rapamycin regimen resulted in sustained graft survival and function in >90% of allogeneic recipients over a 100-d observation period. Long-term survival was associated with increased levels of intragraft transcripts for innate and adaptive immune regulatory factors, including IDO-1, arginase-1, Foxp3, TGF-β, IL-10, and decreased levels of proinflammatory T-bet, IL-1β, TNF-α, and IFN-γ as assessed on day 3 posttransplantation. T cells of long-term graft recipients generated a proliferative response to donor Ags at a similar magnitude to T cells of naive animals, suggestive of the localized nature of tolerance. Immunohistochemical analyses showed intense peri-islet infiltration of T regulatory cells in long-term grafts and systemic depletion of this cell population resulted in prompt rejection. The transient display of SA-PDL1 protein on the surface of islets serves as a practical means of localized immunomodulation that accomplishes sustained graft survival in the absence of chronic immunosuppression with potential clinical implications.
DOI: 10.4049/jimmunol.2000055
PubMed: 32253240
PubMed Central: PMC7334868
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Woodward</name><affiliation wicri:level="2"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation></author><author><name sortKey="Togay, Alper" sort="Togay, Alper" uniqKey="Togay A" first="Alper" last="Togay">Alper Togay</name><affiliation wicri:level="2"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation></author><author><name sortKey="Tan, Min" sort="Tan, Min" uniqKey="Tan M" first="Min" last="Tan">Min Tan</name><affiliation wicri:level="2"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation></author><author><name sortKey="Grimany Nuno, Orlando" sort="Grimany Nuno, Orlando" uniqKey="Grimany Nuno O" first="Orlando" last="Grimany-Nuno">Orlando Grimany-Nuno</name><affiliation wicri:level="2"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation></author><author><name sortKey="Malik, Mohammad Tariq" sort="Malik, Mohammad Tariq" uniqKey="Malik M" first="Mohammad Tariq" last="Malik">Mohammad Tariq Malik</name><affiliation wicri:level="2"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation></author><author><name sortKey="Coronel, Maria M" sort="Coronel, Maria M" uniqKey="Coronel M" first="María M" last="Coronel">María M. Coronel</name><affiliation wicri:level="2"><nlm:affiliation>Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta</wicri:cityArea></affiliation></author><author><name sortKey="Garcia, Andres J" sort="Garcia, Andres J" uniqKey="Garcia A" first="Andrés J" last="García">Andrés J. García</name><affiliation wicri:level="2"><nlm:affiliation>Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332; and.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta</wicri:cityArea></affiliation></author><author><name sortKey="Shirwan, Haval" sort="Shirwan, Haval" uniqKey="Shirwan H" first="Haval" last="Shirwan">Haval Shirwan</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202; haval.shirwan@louisville.edu esma.yolcu@louisville.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:regionArea><wicri:noRegion>Louisville</wicri:noRegion></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Child Health, School of Medicine, University of Missouri, Columbia, MO 65211.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Missouri (État)</region></placeName><wicri:cityArea>Department of Child Health, School of Medicine, University of Missouri, Columbia</wicri:cityArea></affiliation></author><author><name sortKey="Yolcu, Esma S" sort="Yolcu, Esma S" uniqKey="Yolcu E" first="Esma S" last="Yolcu">Esma S. Yolcu</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202; haval.shirwan@louisville.edu esma.yolcu@louisville.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:regionArea><wicri:noRegion>Louisville</wicri:noRegion></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Child Health, School of Medicine, University of Missouri, Columbia, MO 65211.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Missouri (État)</region></placeName><wicri:cityArea>Department of Child Health, School of Medicine, University of Missouri, Columbia</wicri:cityArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32253240</idno><idno type="pmid">32253240</idno><idno type="doi">10.4049/jimmunol.2000055</idno><idno type="pmc">PMC7334868</idno><idno type="wicri:Area/Main/Corpus">000093</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000093</idno><idno type="wicri:Area/Main/Curation">000093</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000093</idno><idno type="wicri:Area/Main/Exploration">000093</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Localized Immunomodulation with PD-L1 Results in Sustained Survival and Function of Allogeneic Islets without Chronic Immunosuppression.</title><author><name sortKey="Batra, Lalit" sort="Batra, Lalit" uniqKey="Batra L" first="Lalit" last="Batra">Lalit Batra</name><affiliation wicri:level="2"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation></author><author><name sortKey="Shrestha, Pradeep" sort="Shrestha, Pradeep" uniqKey="Shrestha P" first="Pradeep" last="Shrestha">Pradeep Shrestha</name><affiliation wicri:level="2"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation></author><author><name sortKey="Zhao, Hong" sort="Zhao, Hong" uniqKey="Zhao H" first="Hong" last="Zhao">Hong Zhao</name><affiliation wicri:level="2"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation></author><author><name sortKey="Woodward, Kyle B" sort="Woodward, Kyle B" uniqKey="Woodward K" first="Kyle B" last="Woodward">Kyle B. Woodward</name><affiliation wicri:level="2"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation></author><author><name sortKey="Togay, Alper" sort="Togay, Alper" uniqKey="Togay A" first="Alper" last="Togay">Alper Togay</name><affiliation wicri:level="2"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation></author><author><name sortKey="Tan, Min" sort="Tan, Min" uniqKey="Tan M" first="Min" last="Tan">Min Tan</name><affiliation wicri:level="2"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation></author><author><name sortKey="Grimany Nuno, Orlando" sort="Grimany Nuno, Orlando" uniqKey="Grimany Nuno O" first="Orlando" last="Grimany-Nuno">Orlando Grimany-Nuno</name><affiliation wicri:level="2"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation></author><author><name sortKey="Malik, Mohammad Tariq" sort="Malik, Mohammad Tariq" uniqKey="Malik M" first="Mohammad Tariq" last="Malik">Mohammad Tariq Malik</name><affiliation wicri:level="2"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation></author><author><name sortKey="Coronel, Maria M" sort="Coronel, Maria M" uniqKey="Coronel M" first="María M" last="Coronel">María M. Coronel</name><affiliation wicri:level="2"><nlm:affiliation>Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta</wicri:cityArea></affiliation></author><author><name sortKey="Garcia, Andres J" sort="Garcia, Andres J" uniqKey="Garcia A" first="Andrés J" last="García">Andrés J. García</name><affiliation wicri:level="2"><nlm:affiliation>Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332; and.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta</wicri:cityArea></affiliation></author><author><name sortKey="Shirwan, Haval" sort="Shirwan, Haval" uniqKey="Shirwan H" first="Haval" last="Shirwan">Haval Shirwan</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202; haval.shirwan@louisville.edu esma.yolcu@louisville.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:regionArea><wicri:noRegion>Louisville</wicri:noRegion></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Child Health, School of Medicine, University of Missouri, Columbia, MO 65211.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Missouri (État)</region></placeName><wicri:cityArea>Department of Child Health, School of Medicine, University of Missouri, Columbia</wicri:cityArea></affiliation></author><author><name sortKey="Yolcu, Esma S" sort="Yolcu, Esma S" uniqKey="Yolcu E" first="Esma S" last="Yolcu">Esma S. Yolcu</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202; haval.shirwan@louisville.edu esma.yolcu@louisville.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville</wicri:regionArea><wicri:noRegion>Louisville</wicri:noRegion></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kentucky</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Child Health, School of Medicine, University of Missouri, Columbia, MO 65211.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Missouri (État)</region></placeName><wicri:cityArea>Department of Child Health, School of Medicine, University of Missouri, Columbia</wicri:cityArea></affiliation></author></analytic><series><title level="j">Journal of immunology (Baltimore, Md. : 1950)</title><idno type="eISSN">1550-6606</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Allogeneic islet transplantation is limited by adverse effects of chronic immunosuppression used to control rejection. The programmed cell death 1 pathway as an important immune checkpoint has the potential to obviate the need for chronic immunosuppression. We generated an oligomeric form of programmed cell death 1 ligand chimeric with core streptavidin (SA-PDL1) that inhibited the T effector cell response to alloantigens and converted T conventional cells into CD4<sup>+</sup>Foxp3<sup>+</sup> T regulatory cells. The SA-PDL1 protein was effectively displayed on the surface of biotinylated mouse islets without a negative impact islet viability and insulin secretion. Transplantation of SA-PDL1-engineered islet grafts with a short course of rapamycin regimen resulted in sustained graft survival and function in >90% of allogeneic recipients over a 100-d observation period. Long-term survival was associated with increased levels of intragraft transcripts for innate and adaptive immune regulatory factors, including IDO-1, arginase-1, Foxp3, TGF-β, IL-10, and decreased levels of proinflammatory T-bet, IL-1β, TNF-α, and IFN-γ as assessed on day 3 posttransplantation. T cells of long-term graft recipients generated a proliferative response to donor Ags at a similar magnitude to T cells of naive animals, suggestive of the localized nature of tolerance. Immunohistochemical analyses showed intense peri-islet infiltration of T regulatory cells in long-term grafts and systemic depletion of this cell population resulted in prompt rejection. The transient display of SA-PDL1 protein on the surface of islets serves as a practical means of localized immunomodulation that accomplishes sustained graft survival in the absence of chronic immunosuppression with potential clinical implications.</div></front></TEI><pubmed><MedlineCitation Status="In-Data-Review" Owner="NLM"><PMID Version="1">32253240</PMID><DateRevised><Year>2020</Year><Month>11</Month><Day>15</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1550-6606</ISSN><JournalIssue CitedMedium="Internet"><Volume>204</Volume><Issue>10</Issue><PubDate><Year>2020</Year><Month>May</Month><Day>15</Day></PubDate></JournalIssue><Title>Journal of immunology (Baltimore, Md. : 1950)</Title><ISOAbbreviation>J Immunol</ISOAbbreviation></Journal><ArticleTitle>Localized Immunomodulation with PD-L1 Results in Sustained Survival and Function of Allogeneic Islets without Chronic Immunosuppression.</ArticleTitle><Pagination><MedlinePgn>2840-2851</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.4049/jimmunol.2000055</ELocationID><Abstract><AbstractText>Allogeneic islet transplantation is limited by adverse effects of chronic immunosuppression used to control rejection. The programmed cell death 1 pathway as an important immune checkpoint has the potential to obviate the need for chronic immunosuppression. We generated an oligomeric form of programmed cell death 1 ligand chimeric with core streptavidin (SA-PDL1) that inhibited the T effector cell response to alloantigens and converted T conventional cells into CD4<sup>+</sup>Foxp3<sup>+</sup> T regulatory cells. The SA-PDL1 protein was effectively displayed on the surface of biotinylated mouse islets without a negative impact islet viability and insulin secretion. Transplantation of SA-PDL1-engineered islet grafts with a short course of rapamycin regimen resulted in sustained graft survival and function in >90% of allogeneic recipients over a 100-d observation period. Long-term survival was associated with increased levels of intragraft transcripts for innate and adaptive immune regulatory factors, including IDO-1, arginase-1, Foxp3, TGF-β, IL-10, and decreased levels of proinflammatory T-bet, IL-1β, TNF-α, and IFN-γ as assessed on day 3 posttransplantation. T cells of long-term graft recipients generated a proliferative response to donor Ags at a similar magnitude to T cells of naive animals, suggestive of the localized nature of tolerance. Immunohistochemical analyses showed intense peri-islet infiltration of T regulatory cells in long-term grafts and systemic depletion of this cell population resulted in prompt rejection. The transient display of SA-PDL1 protein on the surface of islets serves as a practical means of localized immunomodulation that accomplishes sustained graft survival in the absence of chronic immunosuppression with potential clinical implications.</AbstractText><CopyrightInformation>Copyright © 2020 by The American Association of Immunologists, Inc.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Batra</LastName><ForeName>Lalit</ForeName><Initials>L</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-4375-9004</Identifier><AffiliationInfo><Affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shrestha</LastName><ForeName>Pradeep</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhao</LastName><ForeName>Hong</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Woodward</LastName><ForeName>Kyle B</ForeName><Initials>KB</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-5524-6011</Identifier><AffiliationInfo><Affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Togay</LastName><ForeName>Alper</ForeName><Initials>A</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-5256-0064</Identifier><AffiliationInfo><Affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tan</LastName><ForeName>Min</ForeName><Initials>M</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-1986-8438</Identifier><AffiliationInfo><Affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Grimany-Nuno</LastName><ForeName>Orlando</ForeName><Initials>O</Initials><AffiliationInfo><Affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Malik</LastName><ForeName>Mohammad Tariq</ForeName><Initials>MT</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-9972-5850</Identifier><AffiliationInfo><Affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Coronel</LastName><ForeName>María M</ForeName><Initials>MM</Initials><AffiliationInfo><Affiliation>Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>García</LastName><ForeName>Andrés J</ForeName><Initials>AJ</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-6602-2518</Identifier><AffiliationInfo><Affiliation>Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332; and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shirwan</LastName><ForeName>Haval</ForeName><Initials>H</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-1657-9470</Identifier><AffiliationInfo><Affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202; haval.shirwan@louisville.edu esma.yolcu@louisville.edu.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Child Health, School of Medicine, University of Missouri, Columbia, MO 65211.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yolcu</LastName><ForeName>Esma S</ForeName><Initials>ES</Initials><AffiliationInfo><Affiliation>Institute for Cellular Therapeutics, School of Medicine, University of Louisville, Louisville, KY 40202; haval.shirwan@louisville.edu esma.yolcu@louisville.edu.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Child Health, School of Medicine, University of Missouri, Columbia, MO 65211.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 AI121281</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 HL134664</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R21 EB020107</GrantID><Acronym>EB</Acronym><Agency>NIBIB NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>U01 AI132817</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>04</Month><Day>06</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Immunol</MedlineTA><NlmUniqueID>2985117R</NlmUniqueID><ISSNLinking>0022-1767</ISSNLinking></MedlineJournalInfo><CitationSubset>AIM</CitationSubset><CitationSubset>IM</CitationSubset></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2020</Year><Month>01</Month><Day>17</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>03</Month><Day>17</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>4</Month><Day>8</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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Coronel</name><name sortKey="Garcia, Andres J" sort="Garcia, Andres J" uniqKey="Garcia A" first="Andrés J" last="García">Andrés J. García</name><name sortKey="Garcia, Andres J" sort="Garcia, Andres J" uniqKey="Garcia A" first="Andrés J" last="García">Andrés J. García</name><name sortKey="Grimany Nuno, Orlando" sort="Grimany Nuno, Orlando" uniqKey="Grimany Nuno O" first="Orlando" last="Grimany-Nuno">Orlando Grimany-Nuno</name><name sortKey="Grimany Nuno, Orlando" sort="Grimany Nuno, Orlando" uniqKey="Grimany Nuno O" first="Orlando" last="Grimany-Nuno">Orlando Grimany-Nuno</name><name sortKey="Malik, Mohammad Tariq" sort="Malik, Mohammad Tariq" uniqKey="Malik M" first="Mohammad Tariq" last="Malik">Mohammad Tariq Malik</name><name sortKey="Malik, Mohammad Tariq" sort="Malik, Mohammad Tariq" uniqKey="Malik M" first="Mohammad Tariq" last="Malik">Mohammad Tariq Malik</name><name sortKey="Shirwan, Haval" sort="Shirwan, Haval" uniqKey="Shirwan H" first="Haval" last="Shirwan">Haval Shirwan</name><name sortKey="Shirwan, Haval" sort="Shirwan, Haval" uniqKey="Shirwan H" first="Haval" last="Shirwan">Haval Shirwan</name><name sortKey="Shirwan, Haval" sort="Shirwan, Haval" uniqKey="Shirwan H" first="Haval" last="Shirwan">Haval Shirwan</name><name sortKey="Shrestha, Pradeep" sort="Shrestha, Pradeep" uniqKey="Shrestha P" first="Pradeep" last="Shrestha">Pradeep Shrestha</name><name sortKey="Shrestha, Pradeep" sort="Shrestha, Pradeep" uniqKey="Shrestha P" first="Pradeep" last="Shrestha">Pradeep Shrestha</name><name sortKey="Tan, Min" sort="Tan, Min" uniqKey="Tan M" first="Min" last="Tan">Min Tan</name><name sortKey="Tan, Min" sort="Tan, Min" uniqKey="Tan M" first="Min" last="Tan">Min Tan</name><name sortKey="Togay, Alper" sort="Togay, Alper" uniqKey="Togay A" first="Alper" last="Togay">Alper Togay</name><name sortKey="Woodward, Kyle B" sort="Woodward, Kyle B" uniqKey="Woodward K" first="Kyle B" last="Woodward">Kyle B. Woodward</name><name sortKey="Woodward, Kyle B" sort="Woodward, Kyle B" uniqKey="Woodward K" first="Kyle B" last="Woodward">Kyle B. Woodward</name><name sortKey="Yolcu, Esma S" sort="Yolcu, Esma S" uniqKey="Yolcu E" first="Esma S" last="Yolcu">Esma S. Yolcu</name><name sortKey="Yolcu, Esma S" sort="Yolcu, Esma S" uniqKey="Yolcu E" first="Esma S" last="Yolcu">Esma S. Yolcu</name><name sortKey="Yolcu, Esma S" sort="Yolcu, Esma S" uniqKey="Yolcu E" first="Esma S" last="Yolcu">Esma S. Yolcu</name><name sortKey="Zhao, Hong" sort="Zhao, Hong" uniqKey="Zhao H" first="Hong" last="Zhao">Hong Zhao</name><name sortKey="Zhao, Hong" sort="Zhao, Hong" uniqKey="Zhao H" first="Hong" last="Zhao">Hong Zhao</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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|texte= Localized Immunomodulation with PD-L1 Results in Sustained Survival and Function of Allogeneic Islets without Chronic Immunosuppression.
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