Improving the therapeutic index of CpG oligodeoxynucleotides by intralymphatic administration
Signal transduction initiated by TLR such as TLR9, a natural receptor for unmethylated cytosine‐guanine‐rich motifs (CpG), results in activation of transcription factors, including NF‐κB, with substantial impact on the innate and adaptive immunity. However, practical application of new adjuvants suc...
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| Veröffentlicht in: | European journal of immunology 2005-06, Vol.35 (6), p.1869-1876 |
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| container_title | European journal of immunology |
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| creator | von Beust, Barbara R. Johansen, Pål Smith, Kent A. Bot, Adrian Storni, Tazio Kündig, Thomas M. |
| description | Signal transduction initiated by TLR such as TLR9, a natural receptor for unmethylated cytosine‐guanine‐rich motifs (CpG), results in activation of transcription factors, including NF‐κB, with substantial impact on the innate and adaptive immunity. However, practical application of new adjuvants such as CpG oligodeoxynucleotides (ODN) remains a challenge, since prominent systemic activation of NF‐κB may result in severe side effects reminiscent of septic shock, thus limiting their therapeutic index (TI). Low‐dose administration of CpG ODN into lymph nodes has been evaluated as a means to reduce systemic side effects while retaining strong adjuvant properties. To this aim, a prototype immune‐stimulating CpG ODN was used to enhance the antibody production against the antigen phospholipase A2 and the CD8+ T cell responses to ovalbumin in mice. When administered subcutaneously, high CpG ODN doses (>10 nmol) were required to enhance antibody and CD8+ T cell responses. In contrast, when administered directly into a lymph node, much lower amounts of CpG ( |
| doi_str_mv | 10.1002/eji.200526124 |
| format | Article |
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However, practical application of new adjuvants such as CpG oligodeoxynucleotides (ODN) remains a challenge, since prominent systemic activation of NF‐κB may result in severe side effects reminiscent of septic shock, thus limiting their therapeutic index (TI). Low‐dose administration of CpG ODN into lymph nodes has been evaluated as a means to reduce systemic side effects while retaining strong adjuvant properties. To this aim, a prototype immune‐stimulating CpG ODN was used to enhance the antibody production against the antigen phospholipase A2 and the CD8+ T cell responses to ovalbumin in mice. When administered subcutaneously, high CpG ODN doses (>10 nmol) were required to enhance antibody and CD8+ T cell responses. In contrast, when administered directly into a lymph node, much lower amounts of CpG (<0.1 nmol) were sufficient for a similar immune‐enhancing effect. Systemic adverse reactions induced by CpG ODN were only detected at higher doses (1–10 nmol), independently of the route of administration. Finally, low‐dose CpG ODN, administered in a targeted fashion to HLA‐A2.1+ transgenic mice, greatly elevated anti‐tumor CD8+ T cell immunity. Thus, intralymphatic administration of CpG ODN considerably improves the TI and may greatly enable a safe and effective use in the clinic.</description><identifier>ISSN: 0014-2980</identifier><identifier>EISSN: 1521-4141</identifier><identifier>DOI: 10.1002/eji.200526124</identifier><identifier>PMID: 15909311</identifier><language>eng</language><publisher>Weinheim: WILEY‐VCH Verlag</publisher><subject>Acute-Phase Reaction ; Adjuvants, Immunologic - administration & dosage ; Animals ; CD8-Positive T-Lymphocytes - immunology ; Cytotoxicity, Immunologic - drug effects ; Dendritic Cells - drug effects ; Dendritic Cells - physiology ; Humans ; Lymph Nodes - drug effects ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Oligodeoxyribonucleotides - administration & dosage ; Oligodeoxyribonucleotides - toxicity ; Splenomegaly - chemically induced ; Th1 Cells - immunology</subject><ispartof>European journal of immunology, 2005-06, Vol.35 (6), p.1869-1876</ispartof><rights>Copyright © 2005 WILEY‐VCH Verlag GmbH & Co. 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However, practical application of new adjuvants such as CpG oligodeoxynucleotides (ODN) remains a challenge, since prominent systemic activation of NF‐κB may result in severe side effects reminiscent of septic shock, thus limiting their therapeutic index (TI). Low‐dose administration of CpG ODN into lymph nodes has been evaluated as a means to reduce systemic side effects while retaining strong adjuvant properties. To this aim, a prototype immune‐stimulating CpG ODN was used to enhance the antibody production against the antigen phospholipase A2 and the CD8+ T cell responses to ovalbumin in mice. When administered subcutaneously, high CpG ODN doses (>10 nmol) were required to enhance antibody and CD8+ T cell responses. In contrast, when administered directly into a lymph node, much lower amounts of CpG (<0.1 nmol) were sufficient for a similar immune‐enhancing effect. Systemic adverse reactions induced by CpG ODN were only detected at higher doses (1–10 nmol), independently of the route of administration. Finally, low‐dose CpG ODN, administered in a targeted fashion to HLA‐A2.1+ transgenic mice, greatly elevated anti‐tumor CD8+ T cell immunity. Thus, intralymphatic administration of CpG ODN considerably improves the TI and may greatly enable a safe and effective use in the clinic.</description><subject>Acute-Phase Reaction</subject><subject>Adjuvants, Immunologic - administration & dosage</subject><subject>Animals</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>Cytotoxicity, Immunologic - drug effects</subject><subject>Dendritic Cells - drug effects</subject><subject>Dendritic Cells - physiology</subject><subject>Humans</subject><subject>Lymph Nodes - drug effects</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Inbred CBA</subject><subject>Oligodeoxyribonucleotides - administration & dosage</subject><subject>Oligodeoxyribonucleotides - toxicity</subject><subject>Splenomegaly - chemically induced</subject><subject>Th1 Cells - immunology</subject><issn>0014-2980</issn><issn>1521-4141</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kDFPwzAQhS0EoqUwsqJMbCk-x26SEVUFiiqxwIgsx7m0rpI4xAmQf49LK7oxnO50992T3iPkGugUKGV3uDVTRqlgM2D8hIxBMAg5cDglY0qBhyxN6IhcOLellKYzkZ6TEYiUphHAmLwvq6a1n6ZeB90Gd9WqBvvO6MDUOX4HtgjmzWNgS7O2Odrvoe51ibYzObogGzzVtaocqmajdk8qr0xtnN91xtaX5KxQpcOrQ5-Qt4fF6_wpXL08Luf3q1DzWPBQo2JKg6BFDIqxRPshoQmqBDKeQiRyoRikcRGxbJYnNI1_b95ExgRmPJqQ272u9_LRo-tkZZzGslQ12t5JiJM4inxNSLgHdWuda7GQTWsq1Q4SqNzlKX2e8i9Pz98chPuswvxIHwL0QLwHvkyJw_9qcvG8PEr_AHQlgkI</recordid><startdate>200506</startdate><enddate>200506</enddate><creator>von Beust, Barbara R.</creator><creator>Johansen, Pål</creator><creator>Smith, Kent A.</creator><creator>Bot, Adrian</creator><creator>Storni, Tazio</creator><creator>Kündig, Thomas M.</creator><general>WILEY‐VCH Verlag</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></search><sort><creationdate>200506</creationdate><title>Improving the therapeutic index of CpG oligodeoxynucleotides by intralymphatic administration</title><author>von Beust, Barbara R. ; Johansen, Pål ; Smith, Kent A. ; Bot, Adrian ; Storni, Tazio ; Kündig, Thomas M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4754-cea2ac150f71a228c0f7808ea81b49135d5a2197f32b6d80978ea81590b25eb43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Acute-Phase Reaction</topic><topic>Adjuvants, Immunologic - administration & dosage</topic><topic>Animals</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>Cytotoxicity, Immunologic - drug effects</topic><topic>Dendritic Cells - drug effects</topic><topic>Dendritic Cells - physiology</topic><topic>Humans</topic><topic>Lymph Nodes - drug effects</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Inbred CBA</topic><topic>Oligodeoxyribonucleotides - administration & dosage</topic><topic>Oligodeoxyribonucleotides - toxicity</topic><topic>Splenomegaly - chemically induced</topic><topic>Th1 Cells - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>von Beust, Barbara R.</creatorcontrib><creatorcontrib>Johansen, Pål</creatorcontrib><creatorcontrib>Smith, Kent A.</creatorcontrib><creatorcontrib>Bot, Adrian</creatorcontrib><creatorcontrib>Storni, Tazio</creatorcontrib><creatorcontrib>Kündig, Thomas M.</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><jtitle>European journal of immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>von Beust, Barbara R.</au><au>Johansen, Pål</au><au>Smith, Kent A.</au><au>Bot, Adrian</au><au>Storni, Tazio</au><au>Kündig, Thomas M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Improving the therapeutic index of CpG oligodeoxynucleotides by intralymphatic administration</atitle><jtitle>European journal of immunology</jtitle><addtitle>Eur J Immunol</addtitle><date>2005-06</date><risdate>2005</risdate><volume>35</volume><issue>6</issue><spage>1869</spage><epage>1876</epage><pages>1869-1876</pages><issn>0014-2980</issn><eissn>1521-4141</eissn><abstract>Signal transduction initiated by TLR such as TLR9, a natural receptor for unmethylated cytosine‐guanine‐rich motifs (CpG), results in activation of transcription factors, including NF‐κB, with substantial impact on the innate and adaptive immunity. However, practical application of new adjuvants such as CpG oligodeoxynucleotides (ODN) remains a challenge, since prominent systemic activation of NF‐κB may result in severe side effects reminiscent of septic shock, thus limiting their therapeutic index (TI). Low‐dose administration of CpG ODN into lymph nodes has been evaluated as a means to reduce systemic side effects while retaining strong adjuvant properties. To this aim, a prototype immune‐stimulating CpG ODN was used to enhance the antibody production against the antigen phospholipase A2 and the CD8+ T cell responses to ovalbumin in mice. When administered subcutaneously, high CpG ODN doses (>10 nmol) were required to enhance antibody and CD8+ T cell responses. In contrast, when administered directly into a lymph node, much lower amounts of CpG (<0.1 nmol) were sufficient for a similar immune‐enhancing effect. Systemic adverse reactions induced by CpG ODN were only detected at higher doses (1–10 nmol), independently of the route of administration. Finally, low‐dose CpG ODN, administered in a targeted fashion to HLA‐A2.1+ transgenic mice, greatly elevated anti‐tumor CD8+ T cell immunity. Thus, intralymphatic administration of CpG ODN considerably improves the TI and may greatly enable a safe and effective use in the clinic.</abstract><cop>Weinheim</cop><pub>WILEY‐VCH Verlag</pub><pmid>15909311</pmid><doi>10.1002/eji.200526124</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Acute-Phase Reaction Adjuvants, Immunologic - administration & dosage Animals CD8-Positive T-Lymphocytes - immunology Cytotoxicity, Immunologic - drug effects Dendritic Cells - drug effects Dendritic Cells - physiology Humans Lymph Nodes - drug effects Mice Mice, Inbred C57BL Mice, Inbred CBA Oligodeoxyribonucleotides - administration & dosage Oligodeoxyribonucleotides - toxicity Splenomegaly - chemically induced Th1 Cells - immunology |
| title | Improving the therapeutic index of CpG oligodeoxynucleotides by intralymphatic administration |
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