25-OR: ADA Presidents' Select Abstract: Preclinical Evaluation of TYK2 Inhibitors in Type 1 Diabetes
Interferon-α (IFNα) plays a prominent role in type 1 diabetes (T1D) pathogenesis and mediates its effects through the IFN receptor (IFNAR) and the protein tyrosine kinases JAK1 and TYK2. Polymorphisms that decrease TYK2 activity are protective against T1D, and TYK2 inhibitors (TYKi) are being evalua...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2023-06, Vol.72 (Supplement_1), p.1 |
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| creator | SYED, FAROOQ BALLEW, OLIVIA LEE, CHIH-CHUN RANA, JYOTI CASTELA, ANGELA WEAVER, STACI A. THOMAIDOU, SOFIA DEMINE, STÉPHANE COOMANS DE BRACHÈNE, ALEXANDRA ALVELOS, MARIA I. CHANG, GARRICK ORR, KARA YAMADA, KENTARO LIU, JING ZALDUMBIDE, ARNAUD SCHEUNER, DONALYN EIZIRIK, DECIO L. EVANS-MOLINA, CARMELLA |
| description | Interferon-α (IFNα) plays a prominent role in type 1 diabetes (T1D) pathogenesis and mediates its effects through the IFN receptor (IFNAR) and the protein tyrosine kinases JAK1 and TYK2. Polymorphisms that decrease TYK2 activity are protective against T1D, and TYK2 inhibitors (TYKi) are being evaluated for therapeutic benefit in other autoimmune conditions. To test whether TYK2 inhibitors BMS-986202 and BMS-986165 have similar efficacy in diverse models of T1D, we evaluated their effect in vitro on human islets, EndoC-βH1 cells, and iPSC-derived islet-like aggregates and monitored diabetes incidence in RIP-LCMV and NOD mice following in vivo treatment with BMS-986202. TYK2i prevented IFNα-mediated upregulation of CXCL10, MX1, and HLA-ABC in human islets, iPSCs, and EndoC-βH1 and decreased IFNα-mediated STAT1/2 phosphorylation and apoptosis in human islets. Importantly, BMS-986202 reduced diabetes incidence in RIP-LCMV mice by 80% (n=18 vehicle/18 TYK2i; p |
| doi_str_mv | 10.2337/db23-25-OR |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2849359816</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2849359816</sourcerecordid><originalsourceid>FETCH-LOGICAL-c1046-eeb02299569c92d462cd83e7e00be3dbf7834b57bc253f3b10bb4556d97790813</originalsourceid><addsrcrecordid>eNotkE1LAzEYhIMoWKsXf0HAgyBE87HZbHpb2vqBhUqtoKewyb6LKetuTVKh_97WyhzmMA8zMAhdMnrLhVB3teWCcEnmiyM0YFpoIrh6P0YDShknTGl1is5iXFFK850GqP6DR7iclPglQPQ1dCle41dowSVc2phC5dJoH7rWd95VLZ7-VO2mSr7vcN_g5cczx0_dp7c-9SFi3-Hldg2Y4YmvLCSI5-ikqdoIF_8-RG_30-X4kczmD0_jckYco1lOACzlXGuZa6d5neXc1YUABZRaELVtVCEyK5V1XIpGWEatzaTMa62UpgUTQ3R16F2H_nsDMZlVvwndbtLwItNC6oLlO-rmQLnQxxigMevgv6qwNYya_Ytm_6Lh0swX4hcJeWJZ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2849359816</pqid></control><display><type>article</type><title>25-OR: ADA Presidents' Select Abstract: Preclinical Evaluation of TYK2 Inhibitors in Type 1 Diabetes</title><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>SYED, FAROOQ ; BALLEW, OLIVIA ; LEE, CHIH-CHUN ; RANA, JYOTI ; CASTELA, ANGELA ; WEAVER, STACI A. ; THOMAIDOU, SOFIA ; DEMINE, STÉPHANE ; COOMANS DE BRACHÈNE, ALEXANDRA ; ALVELOS, MARIA I. ; CHANG, GARRICK ; ORR, KARA ; YAMADA, KENTARO ; LIU, JING ; ZALDUMBIDE, ARNAUD ; SCHEUNER, DONALYN ; EIZIRIK, DECIO L. ; EVANS-MOLINA, CARMELLA</creator><creatorcontrib>SYED, FAROOQ ; BALLEW, OLIVIA ; LEE, CHIH-CHUN ; RANA, JYOTI ; CASTELA, ANGELA ; WEAVER, STACI A. ; THOMAIDOU, SOFIA ; DEMINE, STÉPHANE ; COOMANS DE BRACHÈNE, ALEXANDRA ; ALVELOS, MARIA I. ; CHANG, GARRICK ; ORR, KARA ; YAMADA, KENTARO ; LIU, JING ; ZALDUMBIDE, ARNAUD ; SCHEUNER, DONALYN ; EIZIRIK, DECIO L. ; EVANS-MOLINA, CARMELLA</creatorcontrib><description>Interferon-α (IFNα) plays a prominent role in type 1 diabetes (T1D) pathogenesis and mediates its effects through the IFN receptor (IFNAR) and the protein tyrosine kinases JAK1 and TYK2. Polymorphisms that decrease TYK2 activity are protective against T1D, and TYK2 inhibitors (TYKi) are being evaluated for therapeutic benefit in other autoimmune conditions. To test whether TYK2 inhibitors BMS-986202 and BMS-986165 have similar efficacy in diverse models of T1D, we evaluated their effect in vitro on human islets, EndoC-βH1 cells, and iPSC-derived islet-like aggregates and monitored diabetes incidence in RIP-LCMV and NOD mice following in vivo treatment with BMS-986202. TYK2i prevented IFNα-mediated upregulation of CXCL10, MX1, and HLA-ABC in human islets, iPSCs, and EndoC-βH1 and decreased IFNα-mediated STAT1/2 phosphorylation and apoptosis in human islets. Importantly, BMS-986202 reduced diabetes incidence in RIP-LCMV mice by 80% (n=18 vehicle/18 TYK2i; p<0.001). Flow cytometry analysis 3 days post LCMV injection revealed a decrease in the percentage of CD11b+F4/80+ macrophages (M1) and CD11b+CD49+ NK cells in pancreatic lymph nodes (PLN) and blood and an increase in circulating CD11b-CD49+ tolerogenic-NK cells in TYK2i-treated RIP-LCMV mice. At days 7 and 14 post LCMV, PDI+CD8+T-cells in the blood, spleen, and PLN and PDI+FOXP3+ Treg cells in the spleen were increased in TYK2i-treated RIP-LCMV mice, indicating T-cell exhaustion. Similarly, treatment with BMS-986202 resulted in a 44% decrease in diabetes incidence in NOD mice (n=32 vehicle/34 TYK2i; p=0.0075) and a significant reduction in insulitis (p<0.05). smFISH analysis revealed decreased β cell expression of STAT1 and MX1 in TYK2i-treated RIP-LCMV mice and NOD mice compared to vehicle-treated mice, while T-cell activation upon co-incubation with target human β cells was inhibited by TYK2i treatment. Taken together, our findings demonstrate that TYK2 inhibition protects against β cell inflammation and T1D development in multiple preclinical models.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db23-25-OR</identifier><language>eng</language><publisher>New York: American Diabetes Association</publisher><subject>Apoptosis ; Beta cells ; CD11b antigen ; CD8 antigen ; Cell activation ; CXCL10 protein ; Diabetes ; Diabetes mellitus (insulin dependent) ; Flow cytometry ; Foxp3 protein ; Inhibitory postsynaptic potentials ; Insulitis ; Janus kinase ; Kinases ; Lymph nodes ; Lymphocytes T ; Macrophages ; Myxovirus resistance proteins ; Phosphorylation ; Spleen ; Stat1 protein ; Tyk2 protein ; α-Interferon</subject><ispartof>Diabetes (New York, N.Y.), 2023-06, Vol.72 (Supplement_1), p.1</ispartof><rights>Copyright American Diabetes Association Jun 2023</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1046-eeb02299569c92d462cd83e7e00be3dbf7834b57bc253f3b10bb4556d97790813</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,27931,27932</link.rule.ids></links><search><creatorcontrib>SYED, FAROOQ</creatorcontrib><creatorcontrib>BALLEW, OLIVIA</creatorcontrib><creatorcontrib>LEE, CHIH-CHUN</creatorcontrib><creatorcontrib>RANA, JYOTI</creatorcontrib><creatorcontrib>CASTELA, ANGELA</creatorcontrib><creatorcontrib>WEAVER, STACI A.</creatorcontrib><creatorcontrib>THOMAIDOU, SOFIA</creatorcontrib><creatorcontrib>DEMINE, STÉPHANE</creatorcontrib><creatorcontrib>COOMANS DE BRACHÈNE, ALEXANDRA</creatorcontrib><creatorcontrib>ALVELOS, MARIA I.</creatorcontrib><creatorcontrib>CHANG, GARRICK</creatorcontrib><creatorcontrib>ORR, KARA</creatorcontrib><creatorcontrib>YAMADA, KENTARO</creatorcontrib><creatorcontrib>LIU, JING</creatorcontrib><creatorcontrib>ZALDUMBIDE, ARNAUD</creatorcontrib><creatorcontrib>SCHEUNER, DONALYN</creatorcontrib><creatorcontrib>EIZIRIK, DECIO L.</creatorcontrib><creatorcontrib>EVANS-MOLINA, CARMELLA</creatorcontrib><title>25-OR: ADA Presidents' Select Abstract: Preclinical Evaluation of TYK2 Inhibitors in Type 1 Diabetes</title><title>Diabetes (New York, N.Y.)</title><description>Interferon-α (IFNα) plays a prominent role in type 1 diabetes (T1D) pathogenesis and mediates its effects through the IFN receptor (IFNAR) and the protein tyrosine kinases JAK1 and TYK2. Polymorphisms that decrease TYK2 activity are protective against T1D, and TYK2 inhibitors (TYKi) are being evaluated for therapeutic benefit in other autoimmune conditions. To test whether TYK2 inhibitors BMS-986202 and BMS-986165 have similar efficacy in diverse models of T1D, we evaluated their effect in vitro on human islets, EndoC-βH1 cells, and iPSC-derived islet-like aggregates and monitored diabetes incidence in RIP-LCMV and NOD mice following in vivo treatment with BMS-986202. TYK2i prevented IFNα-mediated upregulation of CXCL10, MX1, and HLA-ABC in human islets, iPSCs, and EndoC-βH1 and decreased IFNα-mediated STAT1/2 phosphorylation and apoptosis in human islets. Importantly, BMS-986202 reduced diabetes incidence in RIP-LCMV mice by 80% (n=18 vehicle/18 TYK2i; p<0.001). Flow cytometry analysis 3 days post LCMV injection revealed a decrease in the percentage of CD11b+F4/80+ macrophages (M1) and CD11b+CD49+ NK cells in pancreatic lymph nodes (PLN) and blood and an increase in circulating CD11b-CD49+ tolerogenic-NK cells in TYK2i-treated RIP-LCMV mice. At days 7 and 14 post LCMV, PDI+CD8+T-cells in the blood, spleen, and PLN and PDI+FOXP3+ Treg cells in the spleen were increased in TYK2i-treated RIP-LCMV mice, indicating T-cell exhaustion. Similarly, treatment with BMS-986202 resulted in a 44% decrease in diabetes incidence in NOD mice (n=32 vehicle/34 TYK2i; p=0.0075) and a significant reduction in insulitis (p<0.05). smFISH analysis revealed decreased β cell expression of STAT1 and MX1 in TYK2i-treated RIP-LCMV mice and NOD mice compared to vehicle-treated mice, while T-cell activation upon co-incubation with target human β cells was inhibited by TYK2i treatment. Taken together, our findings demonstrate that TYK2 inhibition protects against β cell inflammation and T1D development in multiple preclinical models.</description><subject>Apoptosis</subject><subject>Beta cells</subject><subject>CD11b antigen</subject><subject>CD8 antigen</subject><subject>Cell activation</subject><subject>CXCL10 protein</subject><subject>Diabetes</subject><subject>Diabetes mellitus (insulin dependent)</subject><subject>Flow cytometry</subject><subject>Foxp3 protein</subject><subject>Inhibitory postsynaptic potentials</subject><subject>Insulitis</subject><subject>Janus kinase</subject><subject>Kinases</subject><subject>Lymph nodes</subject><subject>Lymphocytes T</subject><subject>Macrophages</subject><subject>Myxovirus resistance proteins</subject><subject>Phosphorylation</subject><subject>Spleen</subject><subject>Stat1 protein</subject><subject>Tyk2 protein</subject><subject>α-Interferon</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNotkE1LAzEYhIMoWKsXf0HAgyBE87HZbHpb2vqBhUqtoKewyb6LKetuTVKh_97WyhzmMA8zMAhdMnrLhVB3teWCcEnmiyM0YFpoIrh6P0YDShknTGl1is5iXFFK850GqP6DR7iclPglQPQ1dCle41dowSVc2phC5dJoH7rWd95VLZ7-VO2mSr7vcN_g5cczx0_dp7c-9SFi3-Hldg2Y4YmvLCSI5-ikqdoIF_8-RG_30-X4kczmD0_jckYco1lOACzlXGuZa6d5neXc1YUABZRaELVtVCEyK5V1XIpGWEatzaTMa62UpgUTQ3R16F2H_nsDMZlVvwndbtLwItNC6oLlO-rmQLnQxxigMevgv6qwNYya_Ytm_6Lh0swX4hcJeWJZ</recordid><startdate>20230620</startdate><enddate>20230620</enddate><creator>SYED, FAROOQ</creator><creator>BALLEW, OLIVIA</creator><creator>LEE, CHIH-CHUN</creator><creator>RANA, JYOTI</creator><creator>CASTELA, ANGELA</creator><creator>WEAVER, STACI A.</creator><creator>THOMAIDOU, SOFIA</creator><creator>DEMINE, STÉPHANE</creator><creator>COOMANS DE BRACHÈNE, ALEXANDRA</creator><creator>ALVELOS, MARIA I.</creator><creator>CHANG, GARRICK</creator><creator>ORR, KARA</creator><creator>YAMADA, KENTARO</creator><creator>LIU, JING</creator><creator>ZALDUMBIDE, ARNAUD</creator><creator>SCHEUNER, DONALYN</creator><creator>EIZIRIK, DECIO L.</creator><creator>EVANS-MOLINA, CARMELLA</creator><general>American Diabetes Association</general><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope></search><sort><creationdate>20230620</creationdate><title>25-OR: ADA Presidents' Select Abstract: Preclinical Evaluation of TYK2 Inhibitors in Type 1 Diabetes</title><author>SYED, FAROOQ ; BALLEW, OLIVIA ; LEE, CHIH-CHUN ; RANA, JYOTI ; CASTELA, ANGELA ; WEAVER, STACI A. ; THOMAIDOU, SOFIA ; DEMINE, STÉPHANE ; COOMANS DE BRACHÈNE, ALEXANDRA ; ALVELOS, MARIA I. ; CHANG, GARRICK ; ORR, KARA ; YAMADA, KENTARO ; LIU, JING ; ZALDUMBIDE, ARNAUD ; SCHEUNER, DONALYN ; EIZIRIK, DECIO L. ; EVANS-MOLINA, CARMELLA</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1046-eeb02299569c92d462cd83e7e00be3dbf7834b57bc253f3b10bb4556d97790813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Apoptosis</topic><topic>Beta cells</topic><topic>CD11b antigen</topic><topic>CD8 antigen</topic><topic>Cell activation</topic><topic>CXCL10 protein</topic><topic>Diabetes</topic><topic>Diabetes mellitus (insulin dependent)</topic><topic>Flow cytometry</topic><topic>Foxp3 protein</topic><topic>Inhibitory postsynaptic potentials</topic><topic>Insulitis</topic><topic>Janus kinase</topic><topic>Kinases</topic><topic>Lymph nodes</topic><topic>Lymphocytes T</topic><topic>Macrophages</topic><topic>Myxovirus resistance proteins</topic><topic>Phosphorylation</topic><topic>Spleen</topic><topic>Stat1 protein</topic><topic>Tyk2 protein</topic><topic>α-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>SYED, FAROOQ</creatorcontrib><creatorcontrib>BALLEW, OLIVIA</creatorcontrib><creatorcontrib>LEE, CHIH-CHUN</creatorcontrib><creatorcontrib>RANA, JYOTI</creatorcontrib><creatorcontrib>CASTELA, ANGELA</creatorcontrib><creatorcontrib>WEAVER, STACI A.</creatorcontrib><creatorcontrib>THOMAIDOU, SOFIA</creatorcontrib><creatorcontrib>DEMINE, STÉPHANE</creatorcontrib><creatorcontrib>COOMANS DE BRACHÈNE, ALEXANDRA</creatorcontrib><creatorcontrib>ALVELOS, MARIA I.</creatorcontrib><creatorcontrib>CHANG, GARRICK</creatorcontrib><creatorcontrib>ORR, KARA</creatorcontrib><creatorcontrib>YAMADA, KENTARO</creatorcontrib><creatorcontrib>LIU, JING</creatorcontrib><creatorcontrib>ZALDUMBIDE, ARNAUD</creatorcontrib><creatorcontrib>SCHEUNER, DONALYN</creatorcontrib><creatorcontrib>EIZIRIK, DECIO L.</creatorcontrib><creatorcontrib>EVANS-MOLINA, CARMELLA</creatorcontrib><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>SYED, FAROOQ</au><au>BALLEW, OLIVIA</au><au>LEE, CHIH-CHUN</au><au>RANA, JYOTI</au><au>CASTELA, ANGELA</au><au>WEAVER, STACI A.</au><au>THOMAIDOU, SOFIA</au><au>DEMINE, STÉPHANE</au><au>COOMANS DE BRACHÈNE, ALEXANDRA</au><au>ALVELOS, MARIA I.</au><au>CHANG, GARRICK</au><au>ORR, KARA</au><au>YAMADA, KENTARO</au><au>LIU, JING</au><au>ZALDUMBIDE, ARNAUD</au><au>SCHEUNER, DONALYN</au><au>EIZIRIK, DECIO L.</au><au>EVANS-MOLINA, CARMELLA</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>25-OR: ADA Presidents' Select Abstract: Preclinical Evaluation of TYK2 Inhibitors in Type 1 Diabetes</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><date>2023-06-20</date><risdate>2023</risdate><volume>72</volume><issue>Supplement_1</issue><spage>1</spage><pages>1-</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><abstract>Interferon-α (IFNα) plays a prominent role in type 1 diabetes (T1D) pathogenesis and mediates its effects through the IFN receptor (IFNAR) and the protein tyrosine kinases JAK1 and TYK2. Polymorphisms that decrease TYK2 activity are protective against T1D, and TYK2 inhibitors (TYKi) are being evaluated for therapeutic benefit in other autoimmune conditions. To test whether TYK2 inhibitors BMS-986202 and BMS-986165 have similar efficacy in diverse models of T1D, we evaluated their effect in vitro on human islets, EndoC-βH1 cells, and iPSC-derived islet-like aggregates and monitored diabetes incidence in RIP-LCMV and NOD mice following in vivo treatment with BMS-986202. TYK2i prevented IFNα-mediated upregulation of CXCL10, MX1, and HLA-ABC in human islets, iPSCs, and EndoC-βH1 and decreased IFNα-mediated STAT1/2 phosphorylation and apoptosis in human islets. Importantly, BMS-986202 reduced diabetes incidence in RIP-LCMV mice by 80% (n=18 vehicle/18 TYK2i; p<0.001). Flow cytometry analysis 3 days post LCMV injection revealed a decrease in the percentage of CD11b+F4/80+ macrophages (M1) and CD11b+CD49+ NK cells in pancreatic lymph nodes (PLN) and blood and an increase in circulating CD11b-CD49+ tolerogenic-NK cells in TYK2i-treated RIP-LCMV mice. At days 7 and 14 post LCMV, PDI+CD8+T-cells in the blood, spleen, and PLN and PDI+FOXP3+ Treg cells in the spleen were increased in TYK2i-treated RIP-LCMV mice, indicating T-cell exhaustion. Similarly, treatment with BMS-986202 resulted in a 44% decrease in diabetes incidence in NOD mice (n=32 vehicle/34 TYK2i; p=0.0075) and a significant reduction in insulitis (p<0.05). smFISH analysis revealed decreased β cell expression of STAT1 and MX1 in TYK2i-treated RIP-LCMV mice and NOD mice compared to vehicle-treated mice, while T-cell activation upon co-incubation with target human β cells was inhibited by TYK2i treatment. Taken together, our findings demonstrate that TYK2 inhibition protects against β cell inflammation and T1D development in multiple preclinical models.</abstract><cop>New York</cop><pub>American Diabetes Association</pub><doi>10.2337/db23-25-OR</doi></addata></record> |
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| subjects | Apoptosis Beta cells CD11b antigen CD8 antigen Cell activation CXCL10 protein Diabetes Diabetes mellitus (insulin dependent) Flow cytometry Foxp3 protein Inhibitory postsynaptic potentials Insulitis Janus kinase Kinases Lymph nodes Lymphocytes T Macrophages Myxovirus resistance proteins Phosphorylation Spleen Stat1 protein Tyk2 protein α-Interferon |
| title | 25-OR: ADA Presidents' Select Abstract: Preclinical Evaluation of TYK2 Inhibitors in Type 1 Diabetes |
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