Inhibition of T-cell activation by the CTLA4-Fc Abatacept is sufficient to ameliorate proteinuric kidney disease
Diabetic nephropathy (DN) remains an unmet medical challenge as its prevalence is projected to continue to increase and specific medicines for treatment remain undeveloped. Activation of the immune system, in particular T-cells, is emerging as a possible mechanism underlying DN disease progression i...
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| Veröffentlicht in: | American journal of physiology. Renal physiology 2017-04, Vol.312 (4), p.F748-F759 |
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| creator | Herrera, Marcela Söderberg, Magnus Sabirsh, Alan Valastro, Barbara Mölne, Johan Santamaria, Beatriz Valverde, Angela M Guionaud, Silvia Heasman, Stephanie Bigley, Alison Jermutus, Lutz Rondinone, Cristina Coghlan, Matthew Baker, David Quinn, Carol Moreno |
| description | Diabetic nephropathy (DN) remains an unmet medical challenge as its prevalence is projected to continue to increase and specific medicines for treatment remain undeveloped. Activation of the immune system, in particular T-cells, is emerging as a possible mechanism underlying DN disease progression in humans and animal models. We hypothesized that inhibition of T-cell activation will ameliorate DN. Interaction of B7-1 (CD80) on the surface of antigen presenting cells with its binding partners, CTLA4 (CD152) and CD28 on T-cells, is essential for T-cell activation. In this study we used the soluble CTLA4-Fc fusion protein Abatacept to block cell surface B7-1, preventing the cellular interaction and inhibiting T-cell activation. When Abatacept was dosed in an animal model of diabetes-induced albuminuria, it reduced albuminuria in both prevention and intervention modes. The number of T-cells infiltrating the kidneys of DN animals correlated with the degree of albuminuria, and treatment with Abatacept reduced the number of renal T-cells. As B7-1 induction has been recently proposed to underlie podocyte damage in DN, Abatacept could be efficacious in DN by protecting podocytes. However, this does not appear to be the case as B7-1 was not expressed in
) kidneys of DN animals;
) stimulated human podocytes in culture; or
) glomeruli of DN patients. We conclude that Abatacept ameliorates DN by blocking systemic T-cell activation and not by interacting with podocytes. |
| doi_str_mv | 10.1152/ajprenal.00179.2016 |
| format | Article |
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) kidneys of DN animals;
) stimulated human podocytes in culture; or
) glomeruli of DN patients. We conclude that Abatacept ameliorates DN by blocking systemic T-cell activation and not by interacting with podocytes.</description><identifier>ISSN: 1931-857X</identifier><identifier>EISSN: 1522-1466</identifier><identifier>DOI: 10.1152/ajprenal.00179.2016</identifier><identifier>PMID: 27440778</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Abatacept - pharmacology ; Albuminuria - drug therapy ; Albuminuria - immunology ; Albuminuria - metabolism ; Albuminuria - pathology ; Animals ; Antigens ; B7-1 Antigen - immunology ; B7-1 Antigen - metabolism ; Cell Line ; Collagen Type IV - metabolism ; Diabetes ; Diabetes Mellitus, Experimental - chemically induced ; Diabetes Mellitus, Experimental - immunology ; Diabetes Mellitus, Type 1 - chemically induced ; Diabetes Mellitus, Type 1 - immunology ; Diabetic Nephropathies - drug therapy ; Diabetic Nephropathies - immunology ; Diabetic Nephropathies - metabolism ; Diabetic Nephropathies - pathology ; Diet, High-Fat ; Humans ; Immune system ; Immunosuppressive Agents - pharmacology ; Kidney - drug effects ; Kidney - immunology ; Kidney - metabolism ; Kidney - pathology ; Lymphocyte Activation - drug effects ; Medical treatment ; Mice, Inbred C57BL ; Podocytes - drug effects ; Podocytes - immunology ; Podocytes - metabolism ; Streptozocin ; T cell receptors ; T-Lymphocytes - drug effects ; T-Lymphocytes - immunology ; Time Factors</subject><ispartof>American journal of physiology. Renal physiology, 2017-04, Vol.312 (4), p.F748-F759</ispartof><rights>Copyright © 2017 the American Physiological Society.</rights><rights>Copyright American Physiological Society Apr 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c378t-d379e344ff69b13cf9547c1f4933cd4ca5d7219fc970acfb24484e339154fb053</citedby><cites>FETCH-LOGICAL-c378t-d379e344ff69b13cf9547c1f4933cd4ca5d7219fc970acfb24484e339154fb053</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3025,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27440778$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Herrera, Marcela</creatorcontrib><creatorcontrib>Söderberg, Magnus</creatorcontrib><creatorcontrib>Sabirsh, Alan</creatorcontrib><creatorcontrib>Valastro, Barbara</creatorcontrib><creatorcontrib>Mölne, Johan</creatorcontrib><creatorcontrib>Santamaria, Beatriz</creatorcontrib><creatorcontrib>Valverde, Angela M</creatorcontrib><creatorcontrib>Guionaud, Silvia</creatorcontrib><creatorcontrib>Heasman, Stephanie</creatorcontrib><creatorcontrib>Bigley, Alison</creatorcontrib><creatorcontrib>Jermutus, Lutz</creatorcontrib><creatorcontrib>Rondinone, Cristina</creatorcontrib><creatorcontrib>Coghlan, Matthew</creatorcontrib><creatorcontrib>Baker, David</creatorcontrib><creatorcontrib>Quinn, Carol Moreno</creatorcontrib><title>Inhibition of T-cell activation by the CTLA4-Fc Abatacept is sufficient to ameliorate proteinuric kidney disease</title><title>American journal of physiology. Renal physiology</title><addtitle>Am J Physiol Renal Physiol</addtitle><description>Diabetic nephropathy (DN) remains an unmet medical challenge as its prevalence is projected to continue to increase and specific medicines for treatment remain undeveloped. Activation of the immune system, in particular T-cells, is emerging as a possible mechanism underlying DN disease progression in humans and animal models. We hypothesized that inhibition of T-cell activation will ameliorate DN. Interaction of B7-1 (CD80) on the surface of antigen presenting cells with its binding partners, CTLA4 (CD152) and CD28 on T-cells, is essential for T-cell activation. In this study we used the soluble CTLA4-Fc fusion protein Abatacept to block cell surface B7-1, preventing the cellular interaction and inhibiting T-cell activation. When Abatacept was dosed in an animal model of diabetes-induced albuminuria, it reduced albuminuria in both prevention and intervention modes. The number of T-cells infiltrating the kidneys of DN animals correlated with the degree of albuminuria, and treatment with Abatacept reduced the number of renal T-cells. As B7-1 induction has been recently proposed to underlie podocyte damage in DN, Abatacept could be efficacious in DN by protecting podocytes. However, this does not appear to be the case as B7-1 was not expressed in
) kidneys of DN animals;
) stimulated human podocytes in culture; or
) glomeruli of DN patients. We conclude that Abatacept ameliorates DN by blocking systemic T-cell activation and not by interacting with podocytes.</description><subject>Abatacept - pharmacology</subject><subject>Albuminuria - drug therapy</subject><subject>Albuminuria - immunology</subject><subject>Albuminuria - metabolism</subject><subject>Albuminuria - pathology</subject><subject>Animals</subject><subject>Antigens</subject><subject>B7-1 Antigen - immunology</subject><subject>B7-1 Antigen - metabolism</subject><subject>Cell Line</subject><subject>Collagen Type IV - metabolism</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Experimental - chemically induced</subject><subject>Diabetes Mellitus, Experimental - immunology</subject><subject>Diabetes Mellitus, Type 1 - chemically induced</subject><subject>Diabetes Mellitus, Type 1 - immunology</subject><subject>Diabetic Nephropathies - drug therapy</subject><subject>Diabetic Nephropathies - immunology</subject><subject>Diabetic Nephropathies - metabolism</subject><subject>Diabetic Nephropathies - pathology</subject><subject>Diet, High-Fat</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immunosuppressive Agents - pharmacology</subject><subject>Kidney - drug effects</subject><subject>Kidney - immunology</subject><subject>Kidney - metabolism</subject><subject>Kidney - pathology</subject><subject>Lymphocyte Activation - drug effects</subject><subject>Medical treatment</subject><subject>Mice, Inbred C57BL</subject><subject>Podocytes - drug effects</subject><subject>Podocytes - immunology</subject><subject>Podocytes - metabolism</subject><subject>Streptozocin</subject><subject>T cell receptors</subject><subject>T-Lymphocytes - drug effects</subject><subject>T-Lymphocytes - immunology</subject><subject>Time Factors</subject><issn>1931-857X</issn><issn>1522-1466</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkV1LwzAUhoMobk5_gSABb7zpzFeb5nIMPwYDbyZ4V9L0hGV2bU1SYf_e7kMvvErIed7DOXkQuqVkSmnKHvWm89DoekoIlWrKCM3O0HiosISKLDsf7orTJE_lxwhdhbAhA0gZvUQjJoUgUuZj1C2atStddG2DW4tXiYG6xtpE960Pj-UOxzXg-Wo5E8mzwbNSR22gi9gFHHprnXHQRBxbrLdQu9brCLjzbQTX9N4Z_OmqBna4cgF0gGt0YXUd4OZ0TtD789Nq_pos314W89kyMVzmMam4VMCFsDZTJeXGqlRIQ61QnJtKGJ1WklFljZJEG1syIXIBnCuaCluSlE_Qw7HvMMpXDyEWWxf2y-kG2j4UNGeZZCpjZEDv_6GbtvfDz-6pPFcpzYUcKH6kjG9D8GCLzrut9ruCkmIvpPgVUhyEFHshQ-ru1Lsvt1D9ZX4N8B_pCoie</recordid><startdate>20170401</startdate><enddate>20170401</enddate><creator>Herrera, Marcela</creator><creator>Söderberg, Magnus</creator><creator>Sabirsh, Alan</creator><creator>Valastro, Barbara</creator><creator>Mölne, Johan</creator><creator>Santamaria, Beatriz</creator><creator>Valverde, Angela M</creator><creator>Guionaud, Silvia</creator><creator>Heasman, Stephanie</creator><creator>Bigley, Alison</creator><creator>Jermutus, Lutz</creator><creator>Rondinone, Cristina</creator><creator>Coghlan, Matthew</creator><creator>Baker, David</creator><creator>Quinn, Carol Moreno</creator><general>American Physiological Society</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>20170401</creationdate><title>Inhibition of T-cell activation by the CTLA4-Fc Abatacept is sufficient to ameliorate proteinuric kidney disease</title><author>Herrera, Marcela ; Söderberg, Magnus ; Sabirsh, Alan ; Valastro, Barbara ; Mölne, Johan ; Santamaria, Beatriz ; Valverde, Angela M ; Guionaud, Silvia ; Heasman, Stephanie ; Bigley, Alison ; Jermutus, Lutz ; Rondinone, Cristina ; Coghlan, Matthew ; Baker, David ; Quinn, Carol Moreno</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c378t-d379e344ff69b13cf9547c1f4933cd4ca5d7219fc970acfb24484e339154fb053</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Abatacept - pharmacology</topic><topic>Albuminuria - drug therapy</topic><topic>Albuminuria - immunology</topic><topic>Albuminuria - metabolism</topic><topic>Albuminuria - pathology</topic><topic>Animals</topic><topic>Antigens</topic><topic>B7-1 Antigen - immunology</topic><topic>B7-1 Antigen - metabolism</topic><topic>Cell Line</topic><topic>Collagen Type IV - metabolism</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Experimental - chemically induced</topic><topic>Diabetes Mellitus, Experimental - immunology</topic><topic>Diabetes Mellitus, Type 1 - chemically induced</topic><topic>Diabetes Mellitus, Type 1 - immunology</topic><topic>Diabetic Nephropathies - drug therapy</topic><topic>Diabetic Nephropathies - immunology</topic><topic>Diabetic Nephropathies - metabolism</topic><topic>Diabetic Nephropathies - pathology</topic><topic>Diet, High-Fat</topic><topic>Humans</topic><topic>Immune system</topic><topic>Immunosuppressive Agents - pharmacology</topic><topic>Kidney - drug effects</topic><topic>Kidney - immunology</topic><topic>Kidney - metabolism</topic><topic>Kidney - pathology</topic><topic>Lymphocyte Activation - drug effects</topic><topic>Medical treatment</topic><topic>Mice, Inbred C57BL</topic><topic>Podocytes - drug effects</topic><topic>Podocytes - immunology</topic><topic>Podocytes - metabolism</topic><topic>Streptozocin</topic><topic>T cell receptors</topic><topic>T-Lymphocytes - drug effects</topic><topic>T-Lymphocytes - immunology</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Herrera, Marcela</creatorcontrib><creatorcontrib>Söderberg, Magnus</creatorcontrib><creatorcontrib>Sabirsh, Alan</creatorcontrib><creatorcontrib>Valastro, Barbara</creatorcontrib><creatorcontrib>Mölne, Johan</creatorcontrib><creatorcontrib>Santamaria, Beatriz</creatorcontrib><creatorcontrib>Valverde, Angela M</creatorcontrib><creatorcontrib>Guionaud, Silvia</creatorcontrib><creatorcontrib>Heasman, Stephanie</creatorcontrib><creatorcontrib>Bigley, Alison</creatorcontrib><creatorcontrib>Jermutus, Lutz</creatorcontrib><creatorcontrib>Rondinone, Cristina</creatorcontrib><creatorcontrib>Coghlan, Matthew</creatorcontrib><creatorcontrib>Baker, David</creatorcontrib><creatorcontrib>Quinn, Carol Moreno</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>American journal of physiology. Renal physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Herrera, Marcela</au><au>Söderberg, Magnus</au><au>Sabirsh, Alan</au><au>Valastro, Barbara</au><au>Mölne, Johan</au><au>Santamaria, Beatriz</au><au>Valverde, Angela M</au><au>Guionaud, Silvia</au><au>Heasman, Stephanie</au><au>Bigley, Alison</au><au>Jermutus, Lutz</au><au>Rondinone, Cristina</au><au>Coghlan, Matthew</au><au>Baker, David</au><au>Quinn, Carol Moreno</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of T-cell activation by the CTLA4-Fc Abatacept is sufficient to ameliorate proteinuric kidney disease</atitle><jtitle>American journal of physiology. Renal physiology</jtitle><addtitle>Am J Physiol Renal Physiol</addtitle><date>2017-04-01</date><risdate>2017</risdate><volume>312</volume><issue>4</issue><spage>F748</spage><epage>F759</epage><pages>F748-F759</pages><issn>1931-857X</issn><eissn>1522-1466</eissn><abstract>Diabetic nephropathy (DN) remains an unmet medical challenge as its prevalence is projected to continue to increase and specific medicines for treatment remain undeveloped. Activation of the immune system, in particular T-cells, is emerging as a possible mechanism underlying DN disease progression in humans and animal models. We hypothesized that inhibition of T-cell activation will ameliorate DN. Interaction of B7-1 (CD80) on the surface of antigen presenting cells with its binding partners, CTLA4 (CD152) and CD28 on T-cells, is essential for T-cell activation. In this study we used the soluble CTLA4-Fc fusion protein Abatacept to block cell surface B7-1, preventing the cellular interaction and inhibiting T-cell activation. When Abatacept was dosed in an animal model of diabetes-induced albuminuria, it reduced albuminuria in both prevention and intervention modes. The number of T-cells infiltrating the kidneys of DN animals correlated with the degree of albuminuria, and treatment with Abatacept reduced the number of renal T-cells. As B7-1 induction has been recently proposed to underlie podocyte damage in DN, Abatacept could be efficacious in DN by protecting podocytes. However, this does not appear to be the case as B7-1 was not expressed in
) kidneys of DN animals;
) stimulated human podocytes in culture; or
) glomeruli of DN patients. We conclude that Abatacept ameliorates DN by blocking systemic T-cell activation and not by interacting with podocytes.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>27440778</pmid><doi>10.1152/ajprenal.00179.2016</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | American journal of physiology. Renal physiology, 2017-04, Vol.312 (4), p.F748-F759 |
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| source | MEDLINE; American Physiological Society; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Abatacept - pharmacology Albuminuria - drug therapy Albuminuria - immunology Albuminuria - metabolism Albuminuria - pathology Animals Antigens B7-1 Antigen - immunology B7-1 Antigen - metabolism Cell Line Collagen Type IV - metabolism Diabetes Diabetes Mellitus, Experimental - chemically induced Diabetes Mellitus, Experimental - immunology Diabetes Mellitus, Type 1 - chemically induced Diabetes Mellitus, Type 1 - immunology Diabetic Nephropathies - drug therapy Diabetic Nephropathies - immunology Diabetic Nephropathies - metabolism Diabetic Nephropathies - pathology Diet, High-Fat Humans Immune system Immunosuppressive Agents - pharmacology Kidney - drug effects Kidney - immunology Kidney - metabolism Kidney - pathology Lymphocyte Activation - drug effects Medical treatment Mice, Inbred C57BL Podocytes - drug effects Podocytes - immunology Podocytes - metabolism Streptozocin T cell receptors T-Lymphocytes - drug effects T-Lymphocytes - immunology Time Factors |
| title | Inhibition of T-cell activation by the CTLA4-Fc Abatacept is sufficient to ameliorate proteinuric kidney disease |
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