Islet Allograft Rejection Is Independent of Toll-Like Receptor Signaling in Mice
Islet transplantation is a promising therapy for type 1 diabetes; however, most islet grafts fail within 5 years. Innate immunity has been suggested to play a role in islet allograft rejection, potentially mediated by toll-like receptors (TLRs), a class of innate immune receptors. Lack of TLR4, in p...
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| Veröffentlicht in: | Transplantation 2009-11, Vol.88 (9), p.1075-1080 |
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| creator | HUTTON, Meredith J. H WESTWELL-ROPER, Clara SOUKHATCHEVA, Galina PLESNER, Annette DUTZ, Jan P VERCHERE, C. Bruce |
| description | Islet transplantation is a promising therapy for type 1 diabetes; however, most islet grafts fail within 5 years. Innate immunity has been suggested to play a role in islet allograft rejection, potentially mediated by toll-like receptors (TLRs), a class of innate immune receptors. Lack of TLR4, in particular, has been reported to improve allograft survival. Therefore, we hypothesized that TLRs may be involved in islet allograft rejection, and that deletion of TLR4 may improve islet graft survival.
Islets were isolated from C57BL/10ScNJ (Tlr4(-/-)) and C57BL/10 (wild-type [WT]) animals and transplanted into Balb/cJ recipients with streptozotocin-induced diabetes. Blood glucose levels were used to determine graft viability and immunostaining to assess graft morphology and immune cell infiltration. The roles of the TLR4 adaptor molecules MyD88 and TLR adaptor molecule 1 (Ticam-1) were assessed using islets isolated from mice lacking MyD88 (MyD88(-/-)), Ticam-1 (Ticam-1(-/-)), or the combined double knockout (MyD88(-/-)/Ticam-1(-/-)).
Contrary to our hypothesis, Tlr4(-/-) and WT islet allografts had similar failure rates; grafts failed at 23.2+/-1.2 and 24.5+/-1.5 days posttransplant, respectively (P=NS). Syngeneic grafts of Tlr4(-/-) and WT islets maintained normoglycemia for up to 10 weeks posttransplant, indicating that failure of Tlr4(-/-) islet allografts could not be attributed to an intrinsic defect in Tlr4(-/-) islets. Similarly, islet allotransplants from MyD88(-/-), Ticam-1(-/-), and MyD88(-/-)/Ticam-1(-/-) donors did not have improved allograft survival compared with WT controls.
These findings indicate that islet allograft rejection in mice is independent of TLR4 and the TLR adaptor molecules MyD88 and Ticam-1, speaking against an essential role for TLR signaling in islet allograft rejection. |
| doi_str_mv | 10.1097/TP.0b013e3181bd3fe2 |
| format | Article |
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Islets were isolated from C57BL/10ScNJ (Tlr4(-/-)) and C57BL/10 (wild-type [WT]) animals and transplanted into Balb/cJ recipients with streptozotocin-induced diabetes. Blood glucose levels were used to determine graft viability and immunostaining to assess graft morphology and immune cell infiltration. The roles of the TLR4 adaptor molecules MyD88 and TLR adaptor molecule 1 (Ticam-1) were assessed using islets isolated from mice lacking MyD88 (MyD88(-/-)), Ticam-1 (Ticam-1(-/-)), or the combined double knockout (MyD88(-/-)/Ticam-1(-/-)).
Contrary to our hypothesis, Tlr4(-/-) and WT islet allografts had similar failure rates; grafts failed at 23.2+/-1.2 and 24.5+/-1.5 days posttransplant, respectively (P=NS). Syngeneic grafts of Tlr4(-/-) and WT islets maintained normoglycemia for up to 10 weeks posttransplant, indicating that failure of Tlr4(-/-) islet allografts could not be attributed to an intrinsic defect in Tlr4(-/-) islets. Similarly, islet allotransplants from MyD88(-/-), Ticam-1(-/-), and MyD88(-/-)/Ticam-1(-/-) donors did not have improved allograft survival compared with WT controls.
These findings indicate that islet allograft rejection in mice is independent of TLR4 and the TLR adaptor molecules MyD88 and Ticam-1, speaking against an essential role for TLR signaling in islet allograft rejection.</description><identifier>ISSN: 0041-1337</identifier><identifier>EISSN: 1534-6080</identifier><identifier>DOI: 10.1097/TP.0b013e3181bd3fe2</identifier><identifier>PMID: 19898202</identifier><identifier>CODEN: TRPLAU</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>Animals ; Biological and medical sciences ; Blood Glucose - metabolism ; CD8-Positive T-Lymphocytes - immunology ; Diabetes Mellitus, Experimental - blood ; Diabetes Mellitus, Experimental - surgery ; Diabetes Mellitus, Type 1 - surgery ; DNA Primers ; Fundamental and applied biological sciences. Psychology ; Fundamental immunology ; Immune Tolerance ; Immunity, Innate ; Islets of Langerhans Transplantation - immunology ; Islets of Langerhans Transplantation - pathology ; Male ; Medical sciences ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Reverse Transcriptase Polymerase Chain Reaction ; RNA - genetics ; RNA - isolation & purification ; Signal Transduction - physiology ; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases ; Tissue, organ and graft immunology ; Toll-Like Receptors - genetics ; Toll-Like Receptors - immunology ; Toll-Like Receptors - physiology ; Transplantation, Homologous - pathology</subject><ispartof>Transplantation, 2009-11, Vol.88 (9), p.1075-1080</ispartof><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c379t-ecfc946c0768e6dccf6132f24ebf72e293b165f5eca5a489bb31dad635d7dc663</citedby><cites>FETCH-LOGICAL-c379t-ecfc946c0768e6dccf6132f24ebf72e293b165f5eca5a489bb31dad635d7dc663</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22114572$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19898202$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>HUTTON, Meredith J. H</creatorcontrib><creatorcontrib>WESTWELL-ROPER, Clara</creatorcontrib><creatorcontrib>SOUKHATCHEVA, Galina</creatorcontrib><creatorcontrib>PLESNER, Annette</creatorcontrib><creatorcontrib>DUTZ, Jan P</creatorcontrib><creatorcontrib>VERCHERE, C. Bruce</creatorcontrib><title>Islet Allograft Rejection Is Independent of Toll-Like Receptor Signaling in Mice</title><title>Transplantation</title><addtitle>Transplantation</addtitle><description>Islet transplantation is a promising therapy for type 1 diabetes; however, most islet grafts fail within 5 years. Innate immunity has been suggested to play a role in islet allograft rejection, potentially mediated by toll-like receptors (TLRs), a class of innate immune receptors. Lack of TLR4, in particular, has been reported to improve allograft survival. Therefore, we hypothesized that TLRs may be involved in islet allograft rejection, and that deletion of TLR4 may improve islet graft survival.
Islets were isolated from C57BL/10ScNJ (Tlr4(-/-)) and C57BL/10 (wild-type [WT]) animals and transplanted into Balb/cJ recipients with streptozotocin-induced diabetes. Blood glucose levels were used to determine graft viability and immunostaining to assess graft morphology and immune cell infiltration. The roles of the TLR4 adaptor molecules MyD88 and TLR adaptor molecule 1 (Ticam-1) were assessed using islets isolated from mice lacking MyD88 (MyD88(-/-)), Ticam-1 (Ticam-1(-/-)), or the combined double knockout (MyD88(-/-)/Ticam-1(-/-)).
Contrary to our hypothesis, Tlr4(-/-) and WT islet allografts had similar failure rates; grafts failed at 23.2+/-1.2 and 24.5+/-1.5 days posttransplant, respectively (P=NS). Syngeneic grafts of Tlr4(-/-) and WT islets maintained normoglycemia for up to 10 weeks posttransplant, indicating that failure of Tlr4(-/-) islet allografts could not be attributed to an intrinsic defect in Tlr4(-/-) islets. Similarly, islet allotransplants from MyD88(-/-), Ticam-1(-/-), and MyD88(-/-)/Ticam-1(-/-) donors did not have improved allograft survival compared with WT controls.
These findings indicate that islet allograft rejection in mice is independent of TLR4 and the TLR adaptor molecules MyD88 and Ticam-1, speaking against an essential role for TLR signaling in islet allograft rejection.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood Glucose - metabolism</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>Diabetes Mellitus, Experimental - blood</subject><subject>Diabetes Mellitus, Experimental - surgery</subject><subject>Diabetes Mellitus, Type 1 - surgery</subject><subject>DNA Primers</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Fundamental immunology</subject><subject>Immune Tolerance</subject><subject>Immunity, Innate</subject><subject>Islets of Langerhans Transplantation - immunology</subject><subject>Islets of Langerhans Transplantation - pathology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Inbred C57BL</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA - genetics</subject><subject>RNA - isolation & purification</subject><subject>Signal Transduction - physiology</subject><subject>Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases</subject><subject>Tissue, organ and graft immunology</subject><subject>Toll-Like Receptors - genetics</subject><subject>Toll-Like Receptors - immunology</subject><subject>Toll-Like Receptors - physiology</subject><subject>Transplantation, Homologous - pathology</subject><issn>0041-1337</issn><issn>1534-6080</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpd0DtPwzAUBWALgWgp_AIk5AUxpfiR2PFYIR6RiqggzJHjXFcurlPidODfE9QIJJZ7l--c4SB0ScmcEiVvy9Wc1IRy4DSndcMtsCM0pRlPE0FycoymhKQ0oZzLCTqLcUMIybiUp2hCVa5yRtgUrYrooccL79t1p22PX2EDpndtwEXERWhgB8MJPW4tLlvvk6X7gEEZ2PVth9_cOmjvwhq7gJ-dgXN0YrWPcDH-GXp_uC_vnpLly2Nxt1gmhkvVJ2CsUakwRIocRGOMFZQzy1KorWTAFK-pyGwGRmc6zVVdc9roRvCskY0Rgs_QzaF317Wfe4h9tXXRgPc6QLuPleQpZUrlZJD8IE3XxtiBrXad2-ruq6Kk-lmyKlfV_yWH1NXYv6-30PxlxukGcD0CHY32ttPBuPjrGKM0zSTj31fbfXw</recordid><startdate>20091115</startdate><enddate>20091115</enddate><creator>HUTTON, Meredith J. H</creator><creator>WESTWELL-ROPER, Clara</creator><creator>SOUKHATCHEVA, Galina</creator><creator>PLESNER, Annette</creator><creator>DUTZ, Jan P</creator><creator>VERCHERE, C. Bruce</creator><general>Lippincott Williams & Wilkins</general><scope>IQODW</scope><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>7X8</scope></search><sort><creationdate>20091115</creationdate><title>Islet Allograft Rejection Is Independent of Toll-Like Receptor Signaling in Mice</title><author>HUTTON, Meredith J. H ; WESTWELL-ROPER, Clara ; SOUKHATCHEVA, Galina ; PLESNER, Annette ; DUTZ, Jan P ; VERCHERE, C. Bruce</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c379t-ecfc946c0768e6dccf6132f24ebf72e293b165f5eca5a489bb31dad635d7dc663</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood Glucose - metabolism</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>Diabetes Mellitus, Experimental - blood</topic><topic>Diabetes Mellitus, Experimental - surgery</topic><topic>Diabetes Mellitus, Type 1 - surgery</topic><topic>DNA Primers</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Fundamental immunology</topic><topic>Immune Tolerance</topic><topic>Immunity, Innate</topic><topic>Islets of Langerhans Transplantation - immunology</topic><topic>Islets of Langerhans Transplantation - pathology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Inbred C57BL</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA - genetics</topic><topic>RNA - isolation & purification</topic><topic>Signal Transduction - physiology</topic><topic>Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases</topic><topic>Tissue, organ and graft immunology</topic><topic>Toll-Like Receptors - genetics</topic><topic>Toll-Like Receptors - immunology</topic><topic>Toll-Like Receptors - physiology</topic><topic>Transplantation, Homologous - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>HUTTON, Meredith J. H</creatorcontrib><creatorcontrib>WESTWELL-ROPER, Clara</creatorcontrib><creatorcontrib>SOUKHATCHEVA, Galina</creatorcontrib><creatorcontrib>PLESNER, Annette</creatorcontrib><creatorcontrib>DUTZ, Jan P</creatorcontrib><creatorcontrib>VERCHERE, C. Bruce</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Transplantation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>HUTTON, Meredith J. H</au><au>WESTWELL-ROPER, Clara</au><au>SOUKHATCHEVA, Galina</au><au>PLESNER, Annette</au><au>DUTZ, Jan P</au><au>VERCHERE, C. Bruce</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Islet Allograft Rejection Is Independent of Toll-Like Receptor Signaling in Mice</atitle><jtitle>Transplantation</jtitle><addtitle>Transplantation</addtitle><date>2009-11-15</date><risdate>2009</risdate><volume>88</volume><issue>9</issue><spage>1075</spage><epage>1080</epage><pages>1075-1080</pages><issn>0041-1337</issn><eissn>1534-6080</eissn><coden>TRPLAU</coden><abstract>Islet transplantation is a promising therapy for type 1 diabetes; however, most islet grafts fail within 5 years. Innate immunity has been suggested to play a role in islet allograft rejection, potentially mediated by toll-like receptors (TLRs), a class of innate immune receptors. Lack of TLR4, in particular, has been reported to improve allograft survival. Therefore, we hypothesized that TLRs may be involved in islet allograft rejection, and that deletion of TLR4 may improve islet graft survival.
Islets were isolated from C57BL/10ScNJ (Tlr4(-/-)) and C57BL/10 (wild-type [WT]) animals and transplanted into Balb/cJ recipients with streptozotocin-induced diabetes. Blood glucose levels were used to determine graft viability and immunostaining to assess graft morphology and immune cell infiltration. The roles of the TLR4 adaptor molecules MyD88 and TLR adaptor molecule 1 (Ticam-1) were assessed using islets isolated from mice lacking MyD88 (MyD88(-/-)), Ticam-1 (Ticam-1(-/-)), or the combined double knockout (MyD88(-/-)/Ticam-1(-/-)).
Contrary to our hypothesis, Tlr4(-/-) and WT islet allografts had similar failure rates; grafts failed at 23.2+/-1.2 and 24.5+/-1.5 days posttransplant, respectively (P=NS). Syngeneic grafts of Tlr4(-/-) and WT islets maintained normoglycemia for up to 10 weeks posttransplant, indicating that failure of Tlr4(-/-) islet allografts could not be attributed to an intrinsic defect in Tlr4(-/-) islets. Similarly, islet allotransplants from MyD88(-/-), Ticam-1(-/-), and MyD88(-/-)/Ticam-1(-/-) donors did not have improved allograft survival compared with WT controls.
These findings indicate that islet allograft rejection in mice is independent of TLR4 and the TLR adaptor molecules MyD88 and Ticam-1, speaking against an essential role for TLR signaling in islet allograft rejection.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>19898202</pmid><doi>10.1097/TP.0b013e3181bd3fe2</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological and medical sciences Blood Glucose - metabolism CD8-Positive T-Lymphocytes - immunology Diabetes Mellitus, Experimental - blood Diabetes Mellitus, Experimental - surgery Diabetes Mellitus, Type 1 - surgery DNA Primers Fundamental and applied biological sciences. Psychology Fundamental immunology Immune Tolerance Immunity, Innate Islets of Langerhans Transplantation - immunology Islets of Langerhans Transplantation - pathology Male Medical sciences Mice Mice, Inbred BALB C Mice, Inbred C57BL Reverse Transcriptase Polymerase Chain Reaction RNA - genetics RNA - isolation & purification Signal Transduction - physiology Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases Tissue, organ and graft immunology Toll-Like Receptors - genetics Toll-Like Receptors - immunology Toll-Like Receptors - physiology Transplantation, Homologous - pathology |
| title | Islet Allograft Rejection Is Independent of Toll-Like Receptor Signaling in Mice |
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