Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function.
Identifieur interne : 000673 ( PubMed/Checkpoint ); précédent : 000672; suivant : 000674Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function.
Auteurs : Epameinondas Gousopoulos [Suisse] ; Steven T. Proulx [Suisse] ; Samia B. Bachmann [Suisse] ; Jeannette Scholl [Suisse] ; Dimitris Dionyssiou [Grèce] ; Efterpi Demiri [Grèce] ; Cornelia Halin [Suisse] ; Lothar C. Dieterich [Suisse] ; Michael Detmar [Suisse]Source :
- JCI insight [ 2379-3708 ] ; 2016.
Abstract
Secondary lymphedema is a common postcancer treatment complication, but the underlying pathological processes are poorly understood and no curative treatment exists. To investigate lymphedema pathomechanisms, a top-down approach was applied, using genomic data and validating the role of a single target. RNA sequencing of lymphedematous mouse skin indicated upregulation of many T cell-related networks, and indeed depletion of CD4(+) cells attenuated lymphedema. The significant upregulation of Foxp3, a transcription factor specifically expressed by regulatory T cells (Tregs), along with other Treg-related genes, implied a potential role of Tregs in lymphedema. Indeed, increased infiltration of Tregs was identified in mouse lymphedematous skin and in human lymphedema specimens. To investigate the role of Tregs during disease progression, loss-of-function and gain-of-function studies were performed. Depletion of Tregs in transgenic mice with Tregs expressing the primate diphtheria toxin receptor and green fluorescent protein (Foxp3-DTR-GFP) mice led to exacerbated edema, concomitant with increased infiltration of immune cells and a mixed TH1/TH2 cytokine profile. Conversely, expansion of Tregs using IL-2/anti-IL-2 mAb complexes significantly reduced lymphedema development. Therapeutic application of adoptively transferred Tregs upon lymphedema establishment reversed all of the major hallmarks of lymphedema, including edema, inflammation, and fibrosis, and also promoted lymphatic drainage function. Collectively, our results reveal that Treg application constitutes a potential new curative treatment modality for lymphedema.
DOI: 10.1172/jci.insight.89081
PubMed: 27734032
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Dieterich</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, ETH Zurich</wicri:regionArea><placeName><settlement type="city">Zurich</settlement><region nuts="3" type="region">Canton de Zurich</region></placeName><orgName type="university">École polytechnique fédérale de Zurich</orgName></affiliation></author><author><name sortKey="Detmar, Michael" sort="Detmar, Michael" uniqKey="Detmar M" first="Michael" last="Detmar">Michael Detmar</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, ETH Zurich</wicri:regionArea><placeName><settlement type="city">Zurich</settlement><region nuts="3" type="region">Canton de Zurich</region></placeName><orgName type="university">École polytechnique fédérale de Zurich</orgName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27734032</idno><idno type="pmid">27734032</idno><idno type="doi">10.1172/jci.insight.89081</idno><idno type="wicri:Area/PubMed/Corpus">000582</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000582</idno><idno type="wicri:Area/PubMed/Curation">000582</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000582</idno><idno type="wicri:Area/PubMed/Checkpoint">000582</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000582</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function.</title><author><name sortKey="Gousopoulos, Epameinondas" sort="Gousopoulos, Epameinondas" uniqKey="Gousopoulos E" first="Epameinondas" last="Gousopoulos">Epameinondas Gousopoulos</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, ETH Zurich</wicri:regionArea><placeName><settlement type="city">Zurich</settlement><region nuts="3" type="region">Canton de Zurich</region></placeName><orgName type="university">École polytechnique fédérale de Zurich</orgName></affiliation></author><author><name sortKey="Proulx, Steven T" sort="Proulx, Steven T" uniqKey="Proulx S" first="Steven T" last="Proulx">Steven T. Proulx</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, ETH Zurich</wicri:regionArea><placeName><settlement type="city">Zurich</settlement><region nuts="3" type="region">Canton de Zurich</region></placeName><orgName type="university">École polytechnique fédérale de Zurich</orgName></affiliation></author><author><name sortKey="Bachmann, Samia B" sort="Bachmann, Samia B" uniqKey="Bachmann S" first="Samia B" last="Bachmann">Samia B. Bachmann</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, ETH Zurich</wicri:regionArea><placeName><settlement type="city">Zurich</settlement><region nuts="3" type="region">Canton de Zurich</region></placeName><orgName type="university">École polytechnique fédérale de Zurich</orgName></affiliation></author><author><name sortKey="Scholl, Jeannette" sort="Scholl, Jeannette" uniqKey="Scholl J" first="Jeannette" last="Scholl">Jeannette Scholl</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, ETH Zurich</wicri:regionArea><placeName><settlement type="city">Zurich</settlement><region nuts="3" type="region">Canton de Zurich</region></placeName><orgName type="university">École polytechnique fédérale de Zurich</orgName></affiliation></author><author><name sortKey="Dionyssiou, Dimitris" sort="Dionyssiou, Dimitris" uniqKey="Dionyssiou D" first="Dimitris" last="Dionyssiou">Dimitris Dionyssiou</name><affiliation wicri:level="1"><nlm:affiliation>Department of Plastic Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece.</nlm:affiliation><country xml:lang="fr">Grèce</country><wicri:regionArea>Department of Plastic Surgery, Aristotle University of Thessaloniki, Thessaloniki</wicri:regionArea><wicri:noRegion>Thessaloniki</wicri:noRegion></affiliation></author><author><name sortKey="Demiri, Efterpi" sort="Demiri, Efterpi" uniqKey="Demiri E" first="Efterpi" last="Demiri">Efterpi Demiri</name><affiliation wicri:level="1"><nlm:affiliation>Department of Plastic Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece.</nlm:affiliation><country xml:lang="fr">Grèce</country><wicri:regionArea>Department of Plastic Surgery, Aristotle University of Thessaloniki, Thessaloniki</wicri:regionArea><wicri:noRegion>Thessaloniki</wicri:noRegion></affiliation></author><author><name sortKey="Halin, Cornelia" sort="Halin, Cornelia" uniqKey="Halin C" first="Cornelia" last="Halin">Cornelia Halin</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, ETH Zurich</wicri:regionArea><placeName><settlement type="city">Zurich</settlement><region nuts="3" type="region">Canton de Zurich</region></placeName><orgName type="university">École polytechnique fédérale de Zurich</orgName></affiliation></author><author><name sortKey="Dieterich, Lothar C" sort="Dieterich, Lothar C" uniqKey="Dieterich L" first="Lothar C" last="Dieterich">Lothar C. Dieterich</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, ETH Zurich</wicri:regionArea><placeName><settlement type="city">Zurich</settlement><region nuts="3" type="region">Canton de Zurich</region></placeName><orgName type="university">École polytechnique fédérale de Zurich</orgName></affiliation></author><author><name sortKey="Detmar, Michael" sort="Detmar, Michael" uniqKey="Detmar M" first="Michael" last="Detmar">Michael Detmar</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, ETH Zurich</wicri:regionArea><placeName><settlement type="city">Zurich</settlement><region nuts="3" type="region">Canton de Zurich</region></placeName><orgName type="university">École polytechnique fédérale de Zurich</orgName></affiliation></author></analytic><series><title level="j">JCI insight</title><idno type="ISSN">2379-3708</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Secondary lymphedema is a common postcancer treatment complication, but the underlying pathological processes are poorly understood and no curative treatment exists. To investigate lymphedema pathomechanisms, a top-down approach was applied, using genomic data and validating the role of a single target. RNA sequencing of lymphedematous mouse skin indicated upregulation of many T cell-related networks, and indeed depletion of CD4(+) cells attenuated lymphedema. The significant upregulation of Foxp3, a transcription factor specifically expressed by regulatory T cells (Tregs), along with other Treg-related genes, implied a potential role of Tregs in lymphedema. Indeed, increased infiltration of Tregs was identified in mouse lymphedematous skin and in human lymphedema specimens. To investigate the role of Tregs during disease progression, loss-of-function and gain-of-function studies were performed. Depletion of Tregs in transgenic mice with Tregs expressing the primate diphtheria toxin receptor and green fluorescent protein (Foxp3-DTR-GFP) mice led to exacerbated edema, concomitant with increased infiltration of immune cells and a mixed TH1/TH2 cytokine profile. Conversely, expansion of Tregs using IL-2/anti-IL-2 mAb complexes significantly reduced lymphedema development. Therapeutic application of adoptively transferred Tregs upon lymphedema establishment reversed all of the major hallmarks of lymphedema, including edema, inflammation, and fibrosis, and also promoted lymphatic drainage function. Collectively, our results reveal that Treg application constitutes a potential new curative treatment modality for lymphedema.</div></front></TEI><pubmed><MedlineCitation Status="In-Data-Review" Owner="NLM"><PMID Version="1">27734032</PMID><DateCreated><Year>2016</Year><Month>10</Month><Day>13</Day></DateCreated><DateRevised><Year>2017</Year><Month>02</Month><Day>20</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Print">2379-3708</ISSN><JournalIssue CitedMedium="Print"><Volume>1</Volume><Issue>16</Issue><PubDate><Year>2016</Year><Month>Oct</Month><Day>06</Day></PubDate></JournalIssue><Title>JCI insight</Title><ISOAbbreviation>JCI Insight</ISOAbbreviation></Journal><ArticleTitle>Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function.</ArticleTitle><Pagination><MedlinePgn>e89081</MedlinePgn></Pagination><Abstract><AbstractText>Secondary lymphedema is a common postcancer treatment complication, but the underlying pathological processes are poorly understood and no curative treatment exists. To investigate lymphedema pathomechanisms, a top-down approach was applied, using genomic data and validating the role of a single target. RNA sequencing of lymphedematous mouse skin indicated upregulation of many T cell-related networks, and indeed depletion of CD4(+) cells attenuated lymphedema. The significant upregulation of Foxp3, a transcription factor specifically expressed by regulatory T cells (Tregs), along with other Treg-related genes, implied a potential role of Tregs in lymphedema. Indeed, increased infiltration of Tregs was identified in mouse lymphedematous skin and in human lymphedema specimens. To investigate the role of Tregs during disease progression, loss-of-function and gain-of-function studies were performed. Depletion of Tregs in transgenic mice with Tregs expressing the primate diphtheria toxin receptor and green fluorescent protein (Foxp3-DTR-GFP) mice led to exacerbated edema, concomitant with increased infiltration of immune cells and a mixed TH1/TH2 cytokine profile. Conversely, expansion of Tregs using IL-2/anti-IL-2 mAb complexes significantly reduced lymphedema development. Therapeutic application of adoptively transferred Tregs upon lymphedema establishment reversed all of the major hallmarks of lymphedema, including edema, inflammation, and fibrosis, and also promoted lymphatic drainage function. Collectively, our results reveal that Treg application constitutes a potential new curative treatment modality for lymphedema.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Gousopoulos</LastName><ForeName>Epameinondas</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Proulx</LastName><ForeName>Steven T</ForeName><Initials>ST</Initials><AffiliationInfo><Affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bachmann</LastName><ForeName>Samia B</ForeName><Initials>SB</Initials><AffiliationInfo><Affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Scholl</LastName><ForeName>Jeannette</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dionyssiou</LastName><ForeName>Dimitris</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Plastic Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Demiri</LastName><ForeName>Efterpi</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Department of Plastic Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Halin</LastName><ForeName>Cornelia</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dieterich</LastName><ForeName>Lothar C</ForeName><Initials>LC</Initials><AffiliationInfo><Affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Detmar</LastName><ForeName>Michael</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>10</Month><Day>06</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>JCI Insight</MedlineTA><NlmUniqueID>101676073</NlmUniqueID><ISSNLinking>2379-3708</ISSNLinking></MedlineJournalInfo><CommentsCorrectionsList><CommentsCorrections RefType="Cites"><RefSource>Science. 2006 Mar 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Version="1">25516281</PMID></CommentsCorrections></CommentsCorrectionsList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2016</Year><Month>10</Month><Day>14</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>10</Month><Day>14</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2016</Year><Month>10</Month><Day>14</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">27734032</ArticleId><ArticleId IdType="doi">10.1172/jci.insight.89081</ArticleId><ArticleId IdType="pii">89081</ArticleId><ArticleId IdType="pmc">PMC5054740</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Grèce</li><li>Suisse</li></country><region><li>Canton de Zurich</li></region><settlement><li>Zurich</li></settlement><orgName><li>École polytechnique fédérale de Zurich</li></orgName></list><tree><country name="Suisse"><region name="Canton de Zurich"><name sortKey="Gousopoulos, Epameinondas" sort="Gousopoulos, Epameinondas" uniqKey="Gousopoulos E" first="Epameinondas" last="Gousopoulos">Epameinondas Gousopoulos</name></region><name sortKey="Bachmann, Samia B" sort="Bachmann, Samia B" uniqKey="Bachmann S" first="Samia B" last="Bachmann">Samia B. Bachmann</name><name sortKey="Detmar, Michael" sort="Detmar, Michael" uniqKey="Detmar M" first="Michael" last="Detmar">Michael Detmar</name><name sortKey="Dieterich, Lothar C" sort="Dieterich, Lothar C" uniqKey="Dieterich L" first="Lothar C" last="Dieterich">Lothar C. Dieterich</name><name sortKey="Halin, Cornelia" sort="Halin, Cornelia" uniqKey="Halin C" first="Cornelia" last="Halin">Cornelia Halin</name><name sortKey="Proulx, Steven T" sort="Proulx, Steven T" uniqKey="Proulx S" first="Steven T" last="Proulx">Steven T. Proulx</name><name sortKey="Scholl, Jeannette" sort="Scholl, Jeannette" uniqKey="Scholl J" first="Jeannette" last="Scholl">Jeannette Scholl</name></country><country name="Grèce"><noRegion><name sortKey="Dionyssiou, Dimitris" sort="Dionyssiou, Dimitris" uniqKey="Dionyssiou D" first="Dimitris" last="Dionyssiou">Dimitris Dionyssiou</name></noRegion><name sortKey="Demiri, Efterpi" sort="Demiri, Efterpi" uniqKey="Demiri E" first="Efterpi" last="Demiri">Efterpi Demiri</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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