Absence of IL-4, and Not Suppression of the Th2 Response, Prevents Development of Experimental Autoimmune Graves' Disease
In autoimmune Graves' disease (GD), autoantibodies bind to the thyrotropin receptor (TSHR) and cause hyperthyroidism. We studied the effects of fms-like tyrosine kinase receptor 3 ligand (Flt3-L) or GM-CSF treatment on the development of experimental autoimmune GD (EAGD) in mice, a slowly progr...
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Veröffentlicht in: | The Journal of immunology (1950) 2003-02, Vol.170 (4), p.2195-2204 |
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description | In autoimmune Graves' disease (GD), autoantibodies bind to the thyrotropin receptor (TSHR) and cause hyperthyroidism. We studied the effects of fms-like tyrosine kinase receptor 3 ligand (Flt3-L) or GM-CSF treatment on the development of experimental autoimmune GD (EAGD) in mice, a slowly progressing Ab-mediated organ-specific autoimmune disease of the thyroid induced by immunization with syngeneic cells expressing TSHR. Flt3-L and GM-CSF treatment resulted in up-regulation of CD8a(+) and CD8a(-) dendritic cells, and skewing of cytokine and immune responses to TSHR in favor of Th1 and Th2, respectively. However, this skewing did not persist until the later stages, and thus failed to affect the course or severity of the disease. To determine whether the total absence of either IL-4 or IFN-gamma could affect the development of EAGD, we immunized wild-type, IFN-gamma(-/-) and IL-4(-/-) BALB/c mice with TSHR. Nearly 100% of the wild-type and IFN-gamma(-/-) mice developed EAGD with optimal TSHR-specific immune responses, while IL-4(-/-) mice completely resisted disease and showed delayed and suboptimal pathogenic Ab response. These data demonstrated that skewing immune responses to TSHR, using either Flt3-L or GM-CSF, in favor of Th1 or Th2, respectively, may not be sufficient to alter the course of the disease, while the complete absence of IL-4, but not IFN-gamma, can prevent the development of EAGD. |
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We studied the effects of fms-like tyrosine kinase receptor 3 ligand (Flt3-L) or GM-CSF treatment on the development of experimental autoimmune GD (EAGD) in mice, a slowly progressing Ab-mediated organ-specific autoimmune disease of the thyroid induced by immunization with syngeneic cells expressing TSHR. Flt3-L and GM-CSF treatment resulted in up-regulation of CD8a(+) and CD8a(-) dendritic cells, and skewing of cytokine and immune responses to TSHR in favor of Th1 and Th2, respectively. However, this skewing did not persist until the later stages, and thus failed to affect the course or severity of the disease. To determine whether the total absence of either IL-4 or IFN-gamma could affect the development of EAGD, we immunized wild-type, IFN-gamma(-/-) and IL-4(-/-) BALB/c mice with TSHR. Nearly 100% of the wild-type and IFN-gamma(-/-) mice developed EAGD with optimal TSHR-specific immune responses, while IL-4(-/-) mice completely resisted disease and showed delayed and suboptimal pathogenic Ab response. These data demonstrated that skewing immune responses to TSHR, using either Flt3-L or GM-CSF, in favor of Th1 or Th2, respectively, may not be sufficient to alter the course of the disease, while the complete absence of IL-4, but not IFN-gamma, can prevent the development of EAGD.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.170.4.2195</identifier><identifier>PMID: 12574393</identifier><language>eng</language><publisher>United States: Am Assoc Immnol</publisher><subject>Animals ; Cell Line ; CHO Cells ; Cricetinae ; Cytokines - biosynthesis ; Dendritic Cells - immunology ; Dendritic Cells - metabolism ; Disease Progression ; Female ; Granulocyte-Macrophage Colony-Stimulating Factor - administration & dosage ; Graves Disease - genetics ; Graves Disease - immunology ; Graves Disease - prevention & control ; Humans ; Immunophenotyping ; Injections, Intraperitoneal ; Interferon-gamma - deficiency ; Interferon-gamma - genetics ; Interleukin-4 - deficiency ; Interleukin-4 - genetics ; Interleukin-4 - physiology ; Ligands ; Membrane Proteins - administration & dosage ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Protein Structure, Tertiary - physiology ; Receptors, Thyrotropin - biosynthesis ; Receptors, Thyrotropin - physiology ; Self Tolerance - genetics ; Th1 Cells - immunology ; Th2 Cells - immunology ; Th2 Cells - metabolism</subject><ispartof>The Journal of immunology (1950), 2003-02, Vol.170 (4), p.2195-2204</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c409t-16e2e9d3c3f9759a43529b12ec2e5779018a4744b0fec983504ae59dc013666c3</citedby><cites>FETCH-LOGICAL-c409t-16e2e9d3c3f9759a43529b12ec2e5779018a4744b0fec983504ae59dc013666c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12574393$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dogan, Rukiye-Nazan E</creatorcontrib><creatorcontrib>Vasu, Chenthamarakshan</creatorcontrib><creatorcontrib>Holterman, Mark J</creatorcontrib><creatorcontrib>Prabhakar, Bellur S</creatorcontrib><title>Absence of IL-4, and Not Suppression of the Th2 Response, Prevents Development of Experimental Autoimmune Graves' Disease</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>In autoimmune Graves' disease (GD), autoantibodies bind to the thyrotropin receptor (TSHR) and cause hyperthyroidism. We studied the effects of fms-like tyrosine kinase receptor 3 ligand (Flt3-L) or GM-CSF treatment on the development of experimental autoimmune GD (EAGD) in mice, a slowly progressing Ab-mediated organ-specific autoimmune disease of the thyroid induced by immunization with syngeneic cells expressing TSHR. Flt3-L and GM-CSF treatment resulted in up-regulation of CD8a(+) and CD8a(-) dendritic cells, and skewing of cytokine and immune responses to TSHR in favor of Th1 and Th2, respectively. However, this skewing did not persist until the later stages, and thus failed to affect the course or severity of the disease. To determine whether the total absence of either IL-4 or IFN-gamma could affect the development of EAGD, we immunized wild-type, IFN-gamma(-/-) and IL-4(-/-) BALB/c mice with TSHR. Nearly 100% of the wild-type and IFN-gamma(-/-) mice developed EAGD with optimal TSHR-specific immune responses, while IL-4(-/-) mice completely resisted disease and showed delayed and suboptimal pathogenic Ab response. These data demonstrated that skewing immune responses to TSHR, using either Flt3-L or GM-CSF, in favor of Th1 or Th2, respectively, may not be sufficient to alter the course of the disease, while the complete absence of IL-4, but not IFN-gamma, can prevent the development of EAGD.</description><subject>Animals</subject><subject>Cell Line</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cytokines - biosynthesis</subject><subject>Dendritic Cells - immunology</subject><subject>Dendritic Cells - metabolism</subject><subject>Disease Progression</subject><subject>Female</subject><subject>Granulocyte-Macrophage Colony-Stimulating Factor - administration & dosage</subject><subject>Graves Disease - genetics</subject><subject>Graves Disease - immunology</subject><subject>Graves Disease - prevention & control</subject><subject>Humans</subject><subject>Immunophenotyping</subject><subject>Injections, Intraperitoneal</subject><subject>Interferon-gamma - deficiency</subject><subject>Interferon-gamma - genetics</subject><subject>Interleukin-4 - deficiency</subject><subject>Interleukin-4 - genetics</subject><subject>Interleukin-4 - physiology</subject><subject>Ligands</subject><subject>Membrane Proteins - administration & dosage</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Knockout</subject><subject>Protein Structure, Tertiary - physiology</subject><subject>Receptors, Thyrotropin - biosynthesis</subject><subject>Receptors, Thyrotropin - physiology</subject><subject>Self Tolerance - genetics</subject><subject>Th1 Cells - immunology</subject><subject>Th2 Cells - immunology</subject><subject>Th2 Cells - metabolism</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1vEzEQhi0EoiH0FyAhn-ilG8bf8TFqS6kUQVXas-VsZslWu-vF3m3ov8dLguDGaTQzz7yy9RDyjsFCgrQfH-u2HbvQLJjJkwVnVr0gM6YUFFqDfklmAJwXzGhzQt6k9AgAGrh8TU4YV0YKK2bkebVJ2JVIQ0Vv1oU8p77b0i9hoN_Gvo-YUh26aTnskN7vOL3D1Icu4Tm9jfiE3ZDoZa5N6NvcTOTVzx5jPXW-oatxCL_fifQ6-idMZ_SyTugTviWvKt8kPD3WOXn4dHV_8blYf72-uViti1KCHQqmkaPdilJU1ijrpVDcbhjHkqMyxgJbemmk3ECFpV0KBdKjstsSmNBal2JOPhxy-xh-jJgG19apxKbxHYYxOSNAgIHlf0G21FqpTM-JOIBlDClFrFyf_-vjs2PgJjXujxqX1TjpJjX56v0xfty0uP17c3SRgbMDsKu_7_Z1RJda3zQZZ26_3_8T9Qux9Zkz</recordid><startdate>20030215</startdate><enddate>20030215</enddate><creator>Dogan, Rukiye-Nazan E</creator><creator>Vasu, Chenthamarakshan</creator><creator>Holterman, Mark J</creator><creator>Prabhakar, Bellur S</creator><general>Am Assoc Immnol</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>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20030215</creationdate><title>Absence of IL-4, and Not Suppression of the Th2 Response, Prevents Development of Experimental Autoimmune Graves' Disease</title><author>Dogan, Rukiye-Nazan E ; Vasu, Chenthamarakshan ; Holterman, Mark J ; Prabhakar, Bellur S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c409t-16e2e9d3c3f9759a43529b12ec2e5779018a4744b0fec983504ae59dc013666c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Cell Line</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cytokines - biosynthesis</topic><topic>Dendritic Cells - immunology</topic><topic>Dendritic Cells - metabolism</topic><topic>Disease Progression</topic><topic>Female</topic><topic>Granulocyte-Macrophage Colony-Stimulating Factor - administration & dosage</topic><topic>Graves Disease - genetics</topic><topic>Graves Disease - immunology</topic><topic>Graves Disease - prevention & control</topic><topic>Humans</topic><topic>Immunophenotyping</topic><topic>Injections, Intraperitoneal</topic><topic>Interferon-gamma - deficiency</topic><topic>Interferon-gamma - genetics</topic><topic>Interleukin-4 - deficiency</topic><topic>Interleukin-4 - genetics</topic><topic>Interleukin-4 - physiology</topic><topic>Ligands</topic><topic>Membrane Proteins - administration & dosage</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Knockout</topic><topic>Protein Structure, Tertiary - physiology</topic><topic>Receptors, Thyrotropin - biosynthesis</topic><topic>Receptors, Thyrotropin - physiology</topic><topic>Self Tolerance - genetics</topic><topic>Th1 Cells - immunology</topic><topic>Th2 Cells - immunology</topic><topic>Th2 Cells - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dogan, Rukiye-Nazan E</creatorcontrib><creatorcontrib>Vasu, Chenthamarakshan</creatorcontrib><creatorcontrib>Holterman, Mark J</creatorcontrib><creatorcontrib>Prabhakar, Bellur S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dogan, Rukiye-Nazan E</au><au>Vasu, Chenthamarakshan</au><au>Holterman, Mark J</au><au>Prabhakar, Bellur S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Absence of IL-4, and Not Suppression of the Th2 Response, Prevents Development of Experimental Autoimmune Graves' Disease</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2003-02-15</date><risdate>2003</risdate><volume>170</volume><issue>4</issue><spage>2195</spage><epage>2204</epage><pages>2195-2204</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>In autoimmune Graves' disease (GD), autoantibodies bind to the thyrotropin receptor (TSHR) and cause hyperthyroidism. We studied the effects of fms-like tyrosine kinase receptor 3 ligand (Flt3-L) or GM-CSF treatment on the development of experimental autoimmune GD (EAGD) in mice, a slowly progressing Ab-mediated organ-specific autoimmune disease of the thyroid induced by immunization with syngeneic cells expressing TSHR. Flt3-L and GM-CSF treatment resulted in up-regulation of CD8a(+) and CD8a(-) dendritic cells, and skewing of cytokine and immune responses to TSHR in favor of Th1 and Th2, respectively. However, this skewing did not persist until the later stages, and thus failed to affect the course or severity of the disease. To determine whether the total absence of either IL-4 or IFN-gamma could affect the development of EAGD, we immunized wild-type, IFN-gamma(-/-) and IL-4(-/-) BALB/c mice with TSHR. Nearly 100% of the wild-type and IFN-gamma(-/-) mice developed EAGD with optimal TSHR-specific immune responses, while IL-4(-/-) mice completely resisted disease and showed delayed and suboptimal pathogenic Ab response. These data demonstrated that skewing immune responses to TSHR, using either Flt3-L or GM-CSF, in favor of Th1 or Th2, respectively, may not be sufficient to alter the course of the disease, while the complete absence of IL-4, but not IFN-gamma, can prevent the development of EAGD.</abstract><cop>United States</cop><pub>Am Assoc Immnol</pub><pmid>12574393</pmid><doi>10.4049/jimmunol.170.4.2195</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Cell Line CHO Cells Cricetinae Cytokines - biosynthesis Dendritic Cells - immunology Dendritic Cells - metabolism Disease Progression Female Granulocyte-Macrophage Colony-Stimulating Factor - administration & dosage Graves Disease - genetics Graves Disease - immunology Graves Disease - prevention & control Humans Immunophenotyping Injections, Intraperitoneal Interferon-gamma - deficiency Interferon-gamma - genetics Interleukin-4 - deficiency Interleukin-4 - genetics Interleukin-4 - physiology Ligands Membrane Proteins - administration & dosage Mice Mice, Inbred BALB C Mice, Knockout Protein Structure, Tertiary - physiology Receptors, Thyrotropin - biosynthesis Receptors, Thyrotropin - physiology Self Tolerance - genetics Th1 Cells - immunology Th2 Cells - immunology Th2 Cells - metabolism |
title | Absence of IL-4, and Not Suppression of the Th2 Response, Prevents Development of Experimental Autoimmune Graves' Disease |
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