Antigen-specific modulation of chronic experimental autoimmune encephalomyelitis in humanized mice by TCR-like antibody targeting autoreactive T-cell epitope
The development and application of human TCR-like (TCRL) antibodies recognizing disease-specific MHC-peptide complexes may prove as an important tool for basic research and therapeutic applications. Multiple sclerosis is characterized by aberrant CD4 T-cell response to self-antigens presented by MHC...
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description | The development and application of human TCR-like (TCRL) antibodies recognizing disease-specific MHC-peptide complexes may prove as an important tool for basic research and therapeutic applications. Multiple sclerosis is characterized by aberrant CD4 T-cell response to self-antigens presented by MHC class II molecules. This led us to select a panel of TCRL Abs targeting the immunodominant autoantigenic epitope MOG
derived from myelin oligodendrocyte glycoprotein (MOG) presented on HLA-DR2, which is associated with multiple sclerosis (MS). We demonstrate that these TCRL Abs bind with high specificity to human HLA-DR2/MOG
-derived MHC class II molecules and can detect APCs that naturally present the MS-associated autoantigen in the humanized EAE transgenic mouse model. The TCRL Abs can block ex vivo and in vivo CD4 T-cell proliferation in response to MOG
stimulation in an antigen-specific manner. Most significantly, administration of TCRL Abs to MOG
-induced EAE model in HLA-DR2 transgenic mice both prevents and regresses established EAE. TCRL function was associated with a reduction in autoreactive pathogenic T-cell infiltration into the CNS, along with modulation of activated CD11b+ macrophages/microglial APCs. Collectively, these findings demonstrate the combined action of TCRL Abs in blocking TCR-MHC interactions and modulating APC presentation and activation, leading to a profound antigen-specific inhibitory effect on the neuroinflammatory process, resulting in regression of EAE. Our study constitutes an in vivo proof of concept for the utility of TCR-like antibodies as antigen-specific immunomodulators for CD4-mediated autoimmune diseases such as MS, validating the importance of the TCR-MHC axis as a therapeutic target for various autoimmune and inflammatory diseases. |
doi_str_mv | 10.26508/lsa.202402996 |
format | Article |
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derived from myelin oligodendrocyte glycoprotein (MOG) presented on HLA-DR2, which is associated with multiple sclerosis (MS). We demonstrate that these TCRL Abs bind with high specificity to human HLA-DR2/MOG
-derived MHC class II molecules and can detect APCs that naturally present the MS-associated autoantigen in the humanized EAE transgenic mouse model. The TCRL Abs can block ex vivo and in vivo CD4 T-cell proliferation in response to MOG
stimulation in an antigen-specific manner. Most significantly, administration of TCRL Abs to MOG
-induced EAE model in HLA-DR2 transgenic mice both prevents and regresses established EAE. TCRL function was associated with a reduction in autoreactive pathogenic T-cell infiltration into the CNS, along with modulation of activated CD11b+ macrophages/microglial APCs. Collectively, these findings demonstrate the combined action of TCRL Abs in blocking TCR-MHC interactions and modulating APC presentation and activation, leading to a profound antigen-specific inhibitory effect on the neuroinflammatory process, resulting in regression of EAE. Our study constitutes an in vivo proof of concept for the utility of TCR-like antibodies as antigen-specific immunomodulators for CD4-mediated autoimmune diseases such as MS, validating the importance of the TCR-MHC axis as a therapeutic target for various autoimmune and inflammatory diseases.</description><identifier>ISSN: 2575-1077</identifier><identifier>EISSN: 2575-1077</identifier><identifier>DOI: 10.26508/lsa.202402996</identifier><identifier>PMID: 39496501</identifier><language>eng</language><publisher>United States: Life Science Alliance LLC</publisher><subject>Animals ; Autoantigens - immunology ; CD4-Positive T-Lymphocytes - immunology ; CD4-Positive T-Lymphocytes - metabolism ; Cell Proliferation ; Disease Models, Animal ; Encephalomyelitis, Autoimmune, Experimental - immunology ; Epitopes, T-Lymphocyte - immunology ; HLA-DR2 Antigen - immunology ; Humans ; Mice ; Mice, Transgenic ; Multiple Sclerosis - immunology ; Myelin-Oligodendrocyte Glycoprotein - immunology ; Peptide Fragments - immunology ; Receptors, Antigen, T-Cell - immunology ; Receptors, Antigen, T-Cell - metabolism</subject><ispartof>Life science alliance, 2025-01, Vol.8 (1), p.e202402996</ispartof><rights>2024 Goor et al.</rights><rights>2024 Goor et al. 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c276t-d45ac22d46100e820e799d182427a986f043516ecf6c0bcbfab2827776eb887c3</cites><orcidid>0000-0002-9616-8144</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536346/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536346/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39496501$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Goor, Alona</creatorcontrib><creatorcontrib>Altman, Efrat</creatorcontrib><creatorcontrib>Arman, Inbar</creatorcontrib><creatorcontrib>Erez, Shir</creatorcontrib><creatorcontrib>Haus-Cohen, Maya</creatorcontrib><creatorcontrib>Reiter, Yoram</creatorcontrib><title>Antigen-specific modulation of chronic experimental autoimmune encephalomyelitis in humanized mice by TCR-like antibody targeting autoreactive T-cell epitope</title><title>Life science alliance</title><addtitle>Life Sci Alliance</addtitle><description>The development and application of human TCR-like (TCRL) antibodies recognizing disease-specific MHC-peptide complexes may prove as an important tool for basic research and therapeutic applications. Multiple sclerosis is characterized by aberrant CD4 T-cell response to self-antigens presented by MHC class II molecules. This led us to select a panel of TCRL Abs targeting the immunodominant autoantigenic epitope MOG
derived from myelin oligodendrocyte glycoprotein (MOG) presented on HLA-DR2, which is associated with multiple sclerosis (MS). We demonstrate that these TCRL Abs bind with high specificity to human HLA-DR2/MOG
-derived MHC class II molecules and can detect APCs that naturally present the MS-associated autoantigen in the humanized EAE transgenic mouse model. The TCRL Abs can block ex vivo and in vivo CD4 T-cell proliferation in response to MOG
stimulation in an antigen-specific manner. Most significantly, administration of TCRL Abs to MOG
-induced EAE model in HLA-DR2 transgenic mice both prevents and regresses established EAE. TCRL function was associated with a reduction in autoreactive pathogenic T-cell infiltration into the CNS, along with modulation of activated CD11b+ macrophages/microglial APCs. Collectively, these findings demonstrate the combined action of TCRL Abs in blocking TCR-MHC interactions and modulating APC presentation and activation, leading to a profound antigen-specific inhibitory effect on the neuroinflammatory process, resulting in regression of EAE. Our study constitutes an in vivo proof of concept for the utility of TCR-like antibodies as antigen-specific immunomodulators for CD4-mediated autoimmune diseases such as MS, validating the importance of the TCR-MHC axis as a therapeutic target for various autoimmune and inflammatory diseases.</description><subject>Animals</subject><subject>Autoantigens - immunology</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>CD4-Positive T-Lymphocytes - metabolism</subject><subject>Cell Proliferation</subject><subject>Disease Models, Animal</subject><subject>Encephalomyelitis, Autoimmune, Experimental - immunology</subject><subject>Epitopes, T-Lymphocyte - immunology</subject><subject>HLA-DR2 Antigen - immunology</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Multiple Sclerosis - immunology</subject><subject>Myelin-Oligodendrocyte Glycoprotein - immunology</subject><subject>Peptide Fragments - immunology</subject><subject>Receptors, Antigen, T-Cell - immunology</subject><subject>Receptors, Antigen, T-Cell - metabolism</subject><issn>2575-1077</issn><issn>2575-1077</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUuLFDEUhYMozjDO1qVk6abaJJVKqlYyNOoIA4K065BK3eqO5lEmqcH2v_hfzTxsRggk3Hvy3Xs4CL2mZMNER_p3LusNI4wTNgziGTpnnewaSqR8_uR9hi5z_k4IYfXwjr9EZ-3Ahwqg5-jPVSh2D6HJCxg7W4N9nFani40BxxmbQ4qhVuHXAsl6CEU7rNcSrfdrAAzBwHLQLvojOFtsxjbgw-p1sL9hwt4awOMR77ZfG2d_ANZ13BinIy467aHYsL-nJdCm2FvAu8aAcxgWW-ICr9CLWbsMl4_3Bfr28cNue93cfPn0eXt10xgmRWkm3mnD2MQFJQR6RkAOw0R7xpnUQy9mwtuOCjCzMGQ046xH1jMppYCx76VpL9D7B-6yjh4mU20m7dRSHet0VFFb9X8n2IPax1tFadeKlotKePtISPHnCrkob_OdFR0grlm1lHHKOjK0Vbp5kJoUc04wn-ZQou5zVTVXdcq1fnjzdLuT_F-K7V9H-KNV</recordid><startdate>202501</startdate><enddate>202501</enddate><creator>Goor, Alona</creator><creator>Altman, Efrat</creator><creator>Arman, Inbar</creator><creator>Erez, Shir</creator><creator>Haus-Cohen, Maya</creator><creator>Reiter, Yoram</creator><general>Life Science Alliance LLC</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><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9616-8144</orcidid></search><sort><creationdate>202501</creationdate><title>Antigen-specific modulation of chronic experimental autoimmune encephalomyelitis in humanized mice by TCR-like antibody targeting autoreactive T-cell epitope</title><author>Goor, Alona ; Altman, Efrat ; Arman, Inbar ; Erez, Shir ; Haus-Cohen, Maya ; Reiter, Yoram</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c276t-d45ac22d46100e820e799d182427a986f043516ecf6c0bcbfab2827776eb887c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Animals</topic><topic>Autoantigens - immunology</topic><topic>CD4-Positive T-Lymphocytes - immunology</topic><topic>CD4-Positive T-Lymphocytes - metabolism</topic><topic>Cell Proliferation</topic><topic>Disease Models, Animal</topic><topic>Encephalomyelitis, Autoimmune, Experimental - immunology</topic><topic>Epitopes, T-Lymphocyte - immunology</topic><topic>HLA-DR2 Antigen - immunology</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Multiple Sclerosis - immunology</topic><topic>Myelin-Oligodendrocyte Glycoprotein - immunology</topic><topic>Peptide Fragments - immunology</topic><topic>Receptors, Antigen, T-Cell - immunology</topic><topic>Receptors, Antigen, T-Cell - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Goor, Alona</creatorcontrib><creatorcontrib>Altman, Efrat</creatorcontrib><creatorcontrib>Arman, Inbar</creatorcontrib><creatorcontrib>Erez, Shir</creatorcontrib><creatorcontrib>Haus-Cohen, Maya</creatorcontrib><creatorcontrib>Reiter, Yoram</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Life science alliance</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Goor, Alona</au><au>Altman, Efrat</au><au>Arman, Inbar</au><au>Erez, Shir</au><au>Haus-Cohen, Maya</au><au>Reiter, Yoram</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antigen-specific modulation of chronic experimental autoimmune encephalomyelitis in humanized mice by TCR-like antibody targeting autoreactive T-cell epitope</atitle><jtitle>Life science alliance</jtitle><addtitle>Life Sci Alliance</addtitle><date>2025-01</date><risdate>2025</risdate><volume>8</volume><issue>1</issue><spage>e202402996</spage><pages>e202402996-</pages><issn>2575-1077</issn><eissn>2575-1077</eissn><abstract>The development and application of human TCR-like (TCRL) antibodies recognizing disease-specific MHC-peptide complexes may prove as an important tool for basic research and therapeutic applications. Multiple sclerosis is characterized by aberrant CD4 T-cell response to self-antigens presented by MHC class II molecules. This led us to select a panel of TCRL Abs targeting the immunodominant autoantigenic epitope MOG
derived from myelin oligodendrocyte glycoprotein (MOG) presented on HLA-DR2, which is associated with multiple sclerosis (MS). We demonstrate that these TCRL Abs bind with high specificity to human HLA-DR2/MOG
-derived MHC class II molecules and can detect APCs that naturally present the MS-associated autoantigen in the humanized EAE transgenic mouse model. The TCRL Abs can block ex vivo and in vivo CD4 T-cell proliferation in response to MOG
stimulation in an antigen-specific manner. Most significantly, administration of TCRL Abs to MOG
-induced EAE model in HLA-DR2 transgenic mice both prevents and regresses established EAE. TCRL function was associated with a reduction in autoreactive pathogenic T-cell infiltration into the CNS, along with modulation of activated CD11b+ macrophages/microglial APCs. Collectively, these findings demonstrate the combined action of TCRL Abs in blocking TCR-MHC interactions and modulating APC presentation and activation, leading to a profound antigen-specific inhibitory effect on the neuroinflammatory process, resulting in regression of EAE. Our study constitutes an in vivo proof of concept for the utility of TCR-like antibodies as antigen-specific immunomodulators for CD4-mediated autoimmune diseases such as MS, validating the importance of the TCR-MHC axis as a therapeutic target for various autoimmune and inflammatory diseases.</abstract><cop>United States</cop><pub>Life Science Alliance LLC</pub><pmid>39496501</pmid><doi>10.26508/lsa.202402996</doi><orcidid>https://orcid.org/0000-0002-9616-8144</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Autoantigens - immunology CD4-Positive T-Lymphocytes - immunology CD4-Positive T-Lymphocytes - metabolism Cell Proliferation Disease Models, Animal Encephalomyelitis, Autoimmune, Experimental - immunology Epitopes, T-Lymphocyte - immunology HLA-DR2 Antigen - immunology Humans Mice Mice, Transgenic Multiple Sclerosis - immunology Myelin-Oligodendrocyte Glycoprotein - immunology Peptide Fragments - immunology Receptors, Antigen, T-Cell - immunology Receptors, Antigen, T-Cell - metabolism |
title | Antigen-specific modulation of chronic experimental autoimmune encephalomyelitis in humanized mice by TCR-like antibody targeting autoreactive T-cell epitope |
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