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Induction of partial immune tolerance to factor VIII through prior mucosal exposure to the factor VIII C2 domain
Background: The development of anti‐factor VIII (FVIII) neutralizing antibodies (inhibitors) is a significant obstacle to FVIII replacement therapy. Objective: As mucosal administration of an antigen may induce immune tolerance we have evaluated the efficacy of mucosal antigen exposure to achieve to...
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| Published in: | Journal of thrombosis and haemostasis 2006-10, Vol.4 (10), p.2172-2179 |
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| container_end_page | 2179 |
| container_issue | 10 |
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| container_title | Journal of thrombosis and haemostasis |
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| creator | RAWLE, F. E. PRATT, K. P. LABELLE, A. WEINER, H. L. HOUGH, C. LILLICRAP, D. |
| description | Background: The development of anti‐factor VIII (FVIII) neutralizing antibodies (inhibitors) is a significant obstacle to FVIII replacement therapy. Objective: As mucosal administration of an antigen may induce immune tolerance we have evaluated the efficacy of mucosal antigen exposure to achieve tolerance to FVIII. Methods: We investigated the effects of oral and nasal administration of the purified FVIII C2 domain (FVIII‐C2) to FVIII‐deficient BALB/c mice prior to FVIII protein challenge. Mice received oral or nasal doses of FVIII‐C2, followed by a subcutaneous challenge of either FVIII‐C2 or FVIII. The development of anti‐FVIII inhibitors, cytokine production by splenocytes in vitro, and adoptive transfer assays were analyzed. Results and Conclusions: Mucosal administration of FVIII‐C2 decreases the titer of anti‐FVIII‐C2 inhibitors after FVIII‐C2 challenge, and decreases the percentage of FVIII‐C2 specific antibodies after challenge with full‐length FVIII. Tolerance induction to FVIII‐C2 is associated with increased IL‐10 production by splenocytes in vitro, and can be adoptively transferred to naïve mice. This study is the first to demonstrate that tolerance to the FVIII‐C2 domain can be induced via the mucosal route. Based on these results, the potential use of FVIII‐specific mucosal tolerance induction as an immunotherapy treatment for anti‐FVIII inhibitor development warrants further investigation. |
| doi_str_mv | 10.1111/j.1538-7836.2006.02118.x |
| format | article |
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E. ; PRATT, K. P. ; LABELLE, A. ; WEINER, H. L. ; HOUGH, C. ; LILLICRAP, D.</creator><creatorcontrib>RAWLE, F. E. ; PRATT, K. P. ; LABELLE, A. ; WEINER, H. L. ; HOUGH, C. ; LILLICRAP, D.</creatorcontrib><description>Background: The development of anti‐factor VIII (FVIII) neutralizing antibodies (inhibitors) is a significant obstacle to FVIII replacement therapy. Objective: As mucosal administration of an antigen may induce immune tolerance we have evaluated the efficacy of mucosal antigen exposure to achieve tolerance to FVIII. Methods: We investigated the effects of oral and nasal administration of the purified FVIII C2 domain (FVIII‐C2) to FVIII‐deficient BALB/c mice prior to FVIII protein challenge. Mice received oral or nasal doses of FVIII‐C2, followed by a subcutaneous challenge of either FVIII‐C2 or FVIII. The development of anti‐FVIII inhibitors, cytokine production by splenocytes in vitro, and adoptive transfer assays were analyzed. Results and Conclusions: Mucosal administration of FVIII‐C2 decreases the titer of anti‐FVIII‐C2 inhibitors after FVIII‐C2 challenge, and decreases the percentage of FVIII‐C2 specific antibodies after challenge with full‐length FVIII. Tolerance induction to FVIII‐C2 is associated with increased IL‐10 production by splenocytes in vitro, and can be adoptively transferred to naïve mice. This study is the first to demonstrate that tolerance to the FVIII‐C2 domain can be induced via the mucosal route. Based on these results, the potential use of FVIII‐specific mucosal tolerance induction as an immunotherapy treatment for anti‐FVIII inhibitor development warrants further investigation.</description><identifier>ISSN: 1538-7933</identifier><identifier>ISSN: 1538-7836</identifier><identifier>EISSN: 1538-7836</identifier><identifier>DOI: 10.1111/j.1538-7836.2006.02118.x</identifier><identifier>PMID: 16824190</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Administration, Intranasal ; Animals ; CD4-Positive T-Lymphocytes - metabolism ; Cytokines - metabolism ; Enzyme-Linked Immunosorbent Assay ; factor VIII ; Factor VIII - chemistry ; Factor VIII - genetics ; Factor VIII - metabolism ; Factor VIII - therapeutic use ; Female ; hemophilia ; Hemophilia A - blood ; Hemophilia A - genetics ; Immune Tolerance ; inhibitors ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Mucous Membrane - metabolism ; Mucous Membrane - pathology ; oral tolerance ; Protein Structure, Tertiary ; Spleen - cytology ; Time Factors</subject><ispartof>Journal of thrombosis and haemostasis, 2006-10, Vol.4 (10), p.2172-2179</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3988-871653a8d30e8941266c715b83e8b8c70814ab954dfbf9bb1291ba18f6f3fbb63</citedby><cites>FETCH-LOGICAL-c3988-871653a8d30e8941266c715b83e8b8c70814ab954dfbf9bb1291ba18f6f3fbb63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1538-7836.2006.02118.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1538-7836.2006.02118.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,786,790,27957,27958,50923,51032</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16824190$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>RAWLE, F. E.</creatorcontrib><creatorcontrib>PRATT, K. P.</creatorcontrib><creatorcontrib>LABELLE, A.</creatorcontrib><creatorcontrib>WEINER, H. L.</creatorcontrib><creatorcontrib>HOUGH, C.</creatorcontrib><creatorcontrib>LILLICRAP, D.</creatorcontrib><title>Induction of partial immune tolerance to factor VIII through prior mucosal exposure to the factor VIII C2 domain</title><title>Journal of thrombosis and haemostasis</title><addtitle>J Thromb Haemost</addtitle><description>Background: The development of anti‐factor VIII (FVIII) neutralizing antibodies (inhibitors) is a significant obstacle to FVIII replacement therapy. Objective: As mucosal administration of an antigen may induce immune tolerance we have evaluated the efficacy of mucosal antigen exposure to achieve tolerance to FVIII. Methods: We investigated the effects of oral and nasal administration of the purified FVIII C2 domain (FVIII‐C2) to FVIII‐deficient BALB/c mice prior to FVIII protein challenge. Mice received oral or nasal doses of FVIII‐C2, followed by a subcutaneous challenge of either FVIII‐C2 or FVIII. The development of anti‐FVIII inhibitors, cytokine production by splenocytes in vitro, and adoptive transfer assays were analyzed. Results and Conclusions: Mucosal administration of FVIII‐C2 decreases the titer of anti‐FVIII‐C2 inhibitors after FVIII‐C2 challenge, and decreases the percentage of FVIII‐C2 specific antibodies after challenge with full‐length FVIII. Tolerance induction to FVIII‐C2 is associated with increased IL‐10 production by splenocytes in vitro, and can be adoptively transferred to naïve mice. This study is the first to demonstrate that tolerance to the FVIII‐C2 domain can be induced via the mucosal route. Based on these results, the potential use of FVIII‐specific mucosal tolerance induction as an immunotherapy treatment for anti‐FVIII inhibitor development warrants further investigation.</description><subject>Administration, Intranasal</subject><subject>Animals</subject><subject>CD4-Positive T-Lymphocytes - metabolism</subject><subject>Cytokines - metabolism</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>factor VIII</subject><subject>Factor VIII - chemistry</subject><subject>Factor VIII - genetics</subject><subject>Factor VIII - metabolism</subject><subject>Factor VIII - therapeutic use</subject><subject>Female</subject><subject>hemophilia</subject><subject>Hemophilia A - blood</subject><subject>Hemophilia A - genetics</subject><subject>Immune Tolerance</subject><subject>inhibitors</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Knockout</subject><subject>Mucous Membrane - metabolism</subject><subject>Mucous Membrane - pathology</subject><subject>oral tolerance</subject><subject>Protein Structure, Tertiary</subject><subject>Spleen - cytology</subject><subject>Time Factors</subject><issn>1538-7933</issn><issn>1538-7836</issn><issn>1538-7836</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><recordid>eNqNkM1u3CAURlGVqvlpX6Fild24XGPjy6KLapQ2jiJ1k3aLAEPHI9u4YCuTt6-dmTbKrmz4BOe7iEMIBZbBsj7tMyg5birkIssZExnLATA7vCEX_y7O_mbJ-Tm5TGnPGMgyZ-_IOQjMC5Dsgoz10Mx2asNAg6ejjlOrO9r2_Tw4OoXORT3YNVGv7RQi_VnXNZ12Mcy_dnSM7XLUzzakpeUOY0hzfKannXvV2Oa0Cb1uh_fkrdddch9O-xX58fXmYXu7uf_-rd5-ud9YLhE3WIEoucaGM4eygFwIW0FpkDs0aCuGUGgjy6LxxktjIJdgNKAXnntjBL8i18e5Ywy_Z5cm1bfJuq7TgwtzUgJRQlVUC4hH0MaQUnReLb_qdXxSwNRqW-3VKlKtUtVqWz3bVoel-vH0xmx617wUT3oX4PMReGw79_Tfg9Xdw-2a-B-mn443</recordid><startdate>200610</startdate><enddate>200610</enddate><creator>RAWLE, F. E.</creator><creator>PRATT, K. P.</creator><creator>LABELLE, A.</creator><creator>WEINER, H. L.</creator><creator>HOUGH, C.</creator><creator>LILLICRAP, D.</creator><general>Blackwell Publishing Ltd</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>7X8</scope></search><sort><creationdate>200610</creationdate><title>Induction of partial immune tolerance to factor VIII through prior mucosal exposure to the factor VIII C2 domain</title><author>RAWLE, F. E. ; PRATT, K. P. ; LABELLE, A. ; WEINER, H. L. ; HOUGH, C. ; LILLICRAP, D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3988-871653a8d30e8941266c715b83e8b8c70814ab954dfbf9bb1291ba18f6f3fbb63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Administration, Intranasal</topic><topic>Animals</topic><topic>CD4-Positive T-Lymphocytes - metabolism</topic><topic>Cytokines - metabolism</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>factor VIII</topic><topic>Factor VIII - chemistry</topic><topic>Factor VIII - genetics</topic><topic>Factor VIII - metabolism</topic><topic>Factor VIII - therapeutic use</topic><topic>Female</topic><topic>hemophilia</topic><topic>Hemophilia A - blood</topic><topic>Hemophilia A - genetics</topic><topic>Immune Tolerance</topic><topic>inhibitors</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Knockout</topic><topic>Mucous Membrane - metabolism</topic><topic>Mucous Membrane - pathology</topic><topic>oral tolerance</topic><topic>Protein Structure, Tertiary</topic><topic>Spleen - cytology</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>RAWLE, F. E.</creatorcontrib><creatorcontrib>PRATT, K. P.</creatorcontrib><creatorcontrib>LABELLE, A.</creatorcontrib><creatorcontrib>WEINER, H. L.</creatorcontrib><creatorcontrib>HOUGH, C.</creatorcontrib><creatorcontrib>LILLICRAP, D.</creatorcontrib><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>Journal of thrombosis and haemostasis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>RAWLE, F. E.</au><au>PRATT, K. P.</au><au>LABELLE, A.</au><au>WEINER, H. L.</au><au>HOUGH, C.</au><au>LILLICRAP, D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Induction of partial immune tolerance to factor VIII through prior mucosal exposure to the factor VIII C2 domain</atitle><jtitle>Journal of thrombosis and haemostasis</jtitle><addtitle>J Thromb Haemost</addtitle><date>2006-10</date><risdate>2006</risdate><volume>4</volume><issue>10</issue><spage>2172</spage><epage>2179</epage><pages>2172-2179</pages><issn>1538-7933</issn><issn>1538-7836</issn><eissn>1538-7836</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Background: The development of anti‐factor VIII (FVIII) neutralizing antibodies (inhibitors) is a significant obstacle to FVIII replacement therapy. Objective: As mucosal administration of an antigen may induce immune tolerance we have evaluated the efficacy of mucosal antigen exposure to achieve tolerance to FVIII. Methods: We investigated the effects of oral and nasal administration of the purified FVIII C2 domain (FVIII‐C2) to FVIII‐deficient BALB/c mice prior to FVIII protein challenge. Mice received oral or nasal doses of FVIII‐C2, followed by a subcutaneous challenge of either FVIII‐C2 or FVIII. The development of anti‐FVIII inhibitors, cytokine production by splenocytes in vitro, and adoptive transfer assays were analyzed. Results and Conclusions: Mucosal administration of FVIII‐C2 decreases the titer of anti‐FVIII‐C2 inhibitors after FVIII‐C2 challenge, and decreases the percentage of FVIII‐C2 specific antibodies after challenge with full‐length FVIII. Tolerance induction to FVIII‐C2 is associated with increased IL‐10 production by splenocytes in vitro, and can be adoptively transferred to naïve mice. This study is the first to demonstrate that tolerance to the FVIII‐C2 domain can be induced via the mucosal route. Based on these results, the potential use of FVIII‐specific mucosal tolerance induction as an immunotherapy treatment for anti‐FVIII inhibitor development warrants further investigation.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>16824190</pmid><doi>10.1111/j.1538-7836.2006.02118.x</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of thrombosis and haemostasis, 2006-10, Vol.4 (10), p.2172-2179 |
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| language | eng |
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| source | Wiley-Blackwell Journals; EZB Electronic Journals Library |
| subjects | Administration, Intranasal Animals CD4-Positive T-Lymphocytes - metabolism Cytokines - metabolism Enzyme-Linked Immunosorbent Assay factor VIII Factor VIII - chemistry Factor VIII - genetics Factor VIII - metabolism Factor VIII - therapeutic use Female hemophilia Hemophilia A - blood Hemophilia A - genetics Immune Tolerance inhibitors Male Mice Mice, Inbred BALB C Mice, Knockout Mucous Membrane - metabolism Mucous Membrane - pathology oral tolerance Protein Structure, Tertiary Spleen - cytology Time Factors |
| title | Induction of partial immune tolerance to factor VIII through prior mucosal exposure to the factor VIII C2 domain |
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