Rapamycin/IL-2 Combination Therapy in Patients With Type 1 Diabetes Augments Tregs yet Transiently Impairs [Beta]-Cell Function
Rapamycin/interleukin-2 (IL-2) combination treatment of NOD mice effectively treats autoimmune diabetes. We performed a phase 1 clinical trial to test the safety and immunologic effects of rapamycin/IL-2 combination therapy in type 1 diabetic (T1D) patients. Nine T1D subjects were treated with 2-4 m...
Gespeichert in:
| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2012-09, Vol.61 (9), p.2340 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | |
|---|---|
| container_issue | 9 |
| container_start_page | 2340 |
| container_title | Diabetes (New York, N.Y.) |
| container_volume | 61 |
| creator | Long, S Alice Rieck, Mary Sanda, Srinath Bollyky, Jennifer B Samuels, Peter L Goland, Robin Ahmann, Andrew Rabinovitch, Alex Aggarwal, Sudeepta Phippard, Deborah Turka, Laurence A Ehlers, Mario R Bianchine, Peter J Boyle, Karen D Adah, Steven A Bluestone, Jeffrey A Buckner, Jane H Greenbaum, Carla J |
| description | Rapamycin/interleukin-2 (IL-2) combination treatment of NOD mice effectively treats autoimmune diabetes. We performed a phase 1 clinical trial to test the safety and immunologic effects of rapamycin/IL-2 combination therapy in type 1 diabetic (T1D) patients. Nine T1D subjects were treated with 2-4 mg/day rapamycin orally for 3 months and 4.5 × 10(6) IU IL-2 s.c. three times per week for 1 month. [beta]-Cell function was monitored by measuring C-peptide. Immunologic changes were monitored using flow cytometry and serum analyses. Regulatory T cells (Tregs) increased within the first month of therapy, yet clinical and metabolic data demonstrated a transient worsening in all subjects. The increase in Tregs was transient, paralleling IL-2 treatment, whereas the response of Tregs to IL-2, as measured by STAT5 phosphorylation, increased and persisted after treatment. No differences were observed in effector T-cell subset frequencies, but an increase in natural killer cells and eosinophils occurred with IL-2 therapy. Rapamycin/IL-2 therapy, as given in this phase 1 study, resulted in transient [beta]-cell dysfunction despite an increase in Tregs. Such results highlight the difficulties in translating therapies to the clinic and emphasize the importance of broadly interrogating the immune system to evaluate the effects of therapy. |
| format | Article |
| fullrecord | <record><control><sourceid>proquest</sourceid><recordid>TN_cdi_proquest_journals_1038958390</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2757556061</sourcerecordid><originalsourceid>FETCH-proquest_journals_10389583903</originalsourceid><addsrcrecordid>eNqNTU1LAzEUDGLBVfsfHngOJhvsNkddLRZ6EFlQECmv5bVN2c3GvOwhJ_-6W_EHyBxmmA_mTBTaGitNWb2fi0IpXUpd2epCXDIflVKzEYX4fsWAXd46f7tcyRLqvts4j8n1HpoDRQwZnIeX0SGfGN5cOkCTA4GGR4cbSsRwP-y737SJtGfIlEaFnk-TNsOyC-giw8cDJfyUNbUtLAa_PZ1ci8kOW6bpH1-Jm8VTUz_LEPuvgTitj_0Q_RittTJzezc3Vpn_tX4AWCJQmw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1038958390</pqid></control><display><type>article</type><title>Rapamycin/IL-2 Combination Therapy in Patients With Type 1 Diabetes Augments Tregs yet Transiently Impairs [Beta]-Cell Function</title><source>PubMed Central</source><source>EZB Electronic Journals Library</source><source>Journals@Ovid Complete</source><creator>Long, S Alice ; Rieck, Mary ; Sanda, Srinath ; Bollyky, Jennifer B ; Samuels, Peter L ; Goland, Robin ; Ahmann, Andrew ; Rabinovitch, Alex ; Aggarwal, Sudeepta ; Phippard, Deborah ; Turka, Laurence A ; Ehlers, Mario R ; Bianchine, Peter J ; Boyle, Karen D ; Adah, Steven A ; Bluestone, Jeffrey A ; Buckner, Jane H ; Greenbaum, Carla J</creator><creatorcontrib>Long, S Alice ; Rieck, Mary ; Sanda, Srinath ; Bollyky, Jennifer B ; Samuels, Peter L ; Goland, Robin ; Ahmann, Andrew ; Rabinovitch, Alex ; Aggarwal, Sudeepta ; Phippard, Deborah ; Turka, Laurence A ; Ehlers, Mario R ; Bianchine, Peter J ; Boyle, Karen D ; Adah, Steven A ; Bluestone, Jeffrey A ; Buckner, Jane H ; Greenbaum, Carla J</creatorcontrib><description>Rapamycin/interleukin-2 (IL-2) combination treatment of NOD mice effectively treats autoimmune diabetes. We performed a phase 1 clinical trial to test the safety and immunologic effects of rapamycin/IL-2 combination therapy in type 1 diabetic (T1D) patients. Nine T1D subjects were treated with 2-4 mg/day rapamycin orally for 3 months and 4.5 × 10(6) IU IL-2 s.c. three times per week for 1 month. [beta]-Cell function was monitored by measuring C-peptide. Immunologic changes were monitored using flow cytometry and serum analyses. Regulatory T cells (Tregs) increased within the first month of therapy, yet clinical and metabolic data demonstrated a transient worsening in all subjects. The increase in Tregs was transient, paralleling IL-2 treatment, whereas the response of Tregs to IL-2, as measured by STAT5 phosphorylation, increased and persisted after treatment. No differences were observed in effector T-cell subset frequencies, but an increase in natural killer cells and eosinophils occurred with IL-2 therapy. Rapamycin/IL-2 therapy, as given in this phase 1 study, resulted in transient [beta]-cell dysfunction despite an increase in Tregs. Such results highlight the difficulties in translating therapies to the clinic and emphasize the importance of broadly interrogating the immune system to evaluate the effects of therapy.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>New York: American Diabetes Association</publisher><subject>Clinical trials ; Cytokines ; Diabetes ; Flow cytometry ; Growth factors ; Hyperglycemia ; Laboratories ; Peptides ; Proteins ; Transplants & implants</subject><ispartof>Diabetes (New York, N.Y.), 2012-09, Vol.61 (9), p.2340</ispartof><rights>Copyright American Diabetes Association Sep 2012</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids></links><search><creatorcontrib>Long, S Alice</creatorcontrib><creatorcontrib>Rieck, Mary</creatorcontrib><creatorcontrib>Sanda, Srinath</creatorcontrib><creatorcontrib>Bollyky, Jennifer B</creatorcontrib><creatorcontrib>Samuels, Peter L</creatorcontrib><creatorcontrib>Goland, Robin</creatorcontrib><creatorcontrib>Ahmann, Andrew</creatorcontrib><creatorcontrib>Rabinovitch, Alex</creatorcontrib><creatorcontrib>Aggarwal, Sudeepta</creatorcontrib><creatorcontrib>Phippard, Deborah</creatorcontrib><creatorcontrib>Turka, Laurence A</creatorcontrib><creatorcontrib>Ehlers, Mario R</creatorcontrib><creatorcontrib>Bianchine, Peter J</creatorcontrib><creatorcontrib>Boyle, Karen D</creatorcontrib><creatorcontrib>Adah, Steven A</creatorcontrib><creatorcontrib>Bluestone, Jeffrey A</creatorcontrib><creatorcontrib>Buckner, Jane H</creatorcontrib><creatorcontrib>Greenbaum, Carla J</creatorcontrib><title>Rapamycin/IL-2 Combination Therapy in Patients With Type 1 Diabetes Augments Tregs yet Transiently Impairs [Beta]-Cell Function</title><title>Diabetes (New York, N.Y.)</title><description>Rapamycin/interleukin-2 (IL-2) combination treatment of NOD mice effectively treats autoimmune diabetes. We performed a phase 1 clinical trial to test the safety and immunologic effects of rapamycin/IL-2 combination therapy in type 1 diabetic (T1D) patients. Nine T1D subjects were treated with 2-4 mg/day rapamycin orally for 3 months and 4.5 × 10(6) IU IL-2 s.c. three times per week for 1 month. [beta]-Cell function was monitored by measuring C-peptide. Immunologic changes were monitored using flow cytometry and serum analyses. Regulatory T cells (Tregs) increased within the first month of therapy, yet clinical and metabolic data demonstrated a transient worsening in all subjects. The increase in Tregs was transient, paralleling IL-2 treatment, whereas the response of Tregs to IL-2, as measured by STAT5 phosphorylation, increased and persisted after treatment. No differences were observed in effector T-cell subset frequencies, but an increase in natural killer cells and eosinophils occurred with IL-2 therapy. Rapamycin/IL-2 therapy, as given in this phase 1 study, resulted in transient [beta]-cell dysfunction despite an increase in Tregs. Such results highlight the difficulties in translating therapies to the clinic and emphasize the importance of broadly interrogating the immune system to evaluate the effects of therapy.</description><subject>Clinical trials</subject><subject>Cytokines</subject><subject>Diabetes</subject><subject>Flow cytometry</subject><subject>Growth factors</subject><subject>Hyperglycemia</subject><subject>Laboratories</subject><subject>Peptides</subject><subject>Proteins</subject><subject>Transplants & implants</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNTU1LAzEUDGLBVfsfHngOJhvsNkddLRZ6EFlQECmv5bVN2c3GvOwhJ_-6W_EHyBxmmA_mTBTaGitNWb2fi0IpXUpd2epCXDIflVKzEYX4fsWAXd46f7tcyRLqvts4j8n1HpoDRQwZnIeX0SGfGN5cOkCTA4GGR4cbSsRwP-y737SJtGfIlEaFnk-TNsOyC-giw8cDJfyUNbUtLAa_PZ1ci8kOW6bpH1-Jm8VTUz_LEPuvgTitj_0Q_RittTJzezc3Vpn_tX4AWCJQmw</recordid><startdate>20120901</startdate><enddate>20120901</enddate><creator>Long, S Alice</creator><creator>Rieck, Mary</creator><creator>Sanda, Srinath</creator><creator>Bollyky, Jennifer B</creator><creator>Samuels, Peter L</creator><creator>Goland, Robin</creator><creator>Ahmann, Andrew</creator><creator>Rabinovitch, Alex</creator><creator>Aggarwal, Sudeepta</creator><creator>Phippard, Deborah</creator><creator>Turka, Laurence A</creator><creator>Ehlers, Mario R</creator><creator>Bianchine, Peter J</creator><creator>Boyle, Karen D</creator><creator>Adah, Steven A</creator><creator>Bluestone, Jeffrey A</creator><creator>Buckner, Jane H</creator><creator>Greenbaum, Carla J</creator><general>American Diabetes Association</general><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>S0X</scope></search><sort><creationdate>20120901</creationdate><title>Rapamycin/IL-2 Combination Therapy in Patients With Type 1 Diabetes Augments Tregs yet Transiently Impairs [Beta]-Cell Function</title><author>Long, S Alice ; Rieck, Mary ; Sanda, Srinath ; Bollyky, Jennifer B ; Samuels, Peter L ; Goland, Robin ; Ahmann, Andrew ; Rabinovitch, Alex ; Aggarwal, Sudeepta ; Phippard, Deborah ; Turka, Laurence A ; Ehlers, Mario R ; Bianchine, Peter J ; Boyle, Karen D ; Adah, Steven A ; Bluestone, Jeffrey A ; Buckner, Jane H ; Greenbaum, Carla J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_journals_10389583903</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Clinical trials</topic><topic>Cytokines</topic><topic>Diabetes</topic><topic>Flow cytometry</topic><topic>Growth factors</topic><topic>Hyperglycemia</topic><topic>Laboratories</topic><topic>Peptides</topic><topic>Proteins</topic><topic>Transplants & implants</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Long, S Alice</creatorcontrib><creatorcontrib>Rieck, Mary</creatorcontrib><creatorcontrib>Sanda, Srinath</creatorcontrib><creatorcontrib>Bollyky, Jennifer B</creatorcontrib><creatorcontrib>Samuels, Peter L</creatorcontrib><creatorcontrib>Goland, Robin</creatorcontrib><creatorcontrib>Ahmann, Andrew</creatorcontrib><creatorcontrib>Rabinovitch, Alex</creatorcontrib><creatorcontrib>Aggarwal, Sudeepta</creatorcontrib><creatorcontrib>Phippard, Deborah</creatorcontrib><creatorcontrib>Turka, Laurence A</creatorcontrib><creatorcontrib>Ehlers, Mario R</creatorcontrib><creatorcontrib>Bianchine, Peter J</creatorcontrib><creatorcontrib>Boyle, Karen D</creatorcontrib><creatorcontrib>Adah, Steven A</creatorcontrib><creatorcontrib>Bluestone, Jeffrey A</creatorcontrib><creatorcontrib>Buckner, Jane H</creatorcontrib><creatorcontrib>Greenbaum, Carla J</creatorcontrib><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest research library</collection><collection>Science Database</collection><collection>ProQuest Biological Science Journals</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Long, S Alice</au><au>Rieck, Mary</au><au>Sanda, Srinath</au><au>Bollyky, Jennifer B</au><au>Samuels, Peter L</au><au>Goland, Robin</au><au>Ahmann, Andrew</au><au>Rabinovitch, Alex</au><au>Aggarwal, Sudeepta</au><au>Phippard, Deborah</au><au>Turka, Laurence A</au><au>Ehlers, Mario R</au><au>Bianchine, Peter J</au><au>Boyle, Karen D</au><au>Adah, Steven A</au><au>Bluestone, Jeffrey A</au><au>Buckner, Jane H</au><au>Greenbaum, Carla J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rapamycin/IL-2 Combination Therapy in Patients With Type 1 Diabetes Augments Tregs yet Transiently Impairs [Beta]-Cell Function</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><date>2012-09-01</date><risdate>2012</risdate><volume>61</volume><issue>9</issue><spage>2340</spage><pages>2340-</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Rapamycin/interleukin-2 (IL-2) combination treatment of NOD mice effectively treats autoimmune diabetes. We performed a phase 1 clinical trial to test the safety and immunologic effects of rapamycin/IL-2 combination therapy in type 1 diabetic (T1D) patients. Nine T1D subjects were treated with 2-4 mg/day rapamycin orally for 3 months and 4.5 × 10(6) IU IL-2 s.c. three times per week for 1 month. [beta]-Cell function was monitored by measuring C-peptide. Immunologic changes were monitored using flow cytometry and serum analyses. Regulatory T cells (Tregs) increased within the first month of therapy, yet clinical and metabolic data demonstrated a transient worsening in all subjects. The increase in Tregs was transient, paralleling IL-2 treatment, whereas the response of Tregs to IL-2, as measured by STAT5 phosphorylation, increased and persisted after treatment. No differences were observed in effector T-cell subset frequencies, but an increase in natural killer cells and eosinophils occurred with IL-2 therapy. Rapamycin/IL-2 therapy, as given in this phase 1 study, resulted in transient [beta]-cell dysfunction despite an increase in Tregs. Such results highlight the difficulties in translating therapies to the clinic and emphasize the importance of broadly interrogating the immune system to evaluate the effects of therapy.</abstract><cop>New York</cop><pub>American Diabetes Association</pub></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2012-09, Vol.61 (9), p.2340 |
| issn | 0012-1797 1939-327X |
| language | eng |
| recordid | cdi_proquest_journals_1038958390 |
| source | PubMed Central; EZB Electronic Journals Library; Journals@Ovid Complete |
| subjects | Clinical trials Cytokines Diabetes Flow cytometry Growth factors Hyperglycemia Laboratories Peptides Proteins Transplants & implants |
| title | Rapamycin/IL-2 Combination Therapy in Patients With Type 1 Diabetes Augments Tregs yet Transiently Impairs [Beta]-Cell Function |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-28T11%3A44%3A30IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Rapamycin/IL-2%20Combination%20Therapy%20in%20Patients%20With%20Type%201%20Diabetes%20Augments%20Tregs%20yet%20Transiently%20Impairs%20%5BBeta%5D-Cell%20Function&rft.jtitle=Diabetes%20(New%20York,%20N.Y.)&rft.au=Long,%20S%20Alice&rft.date=2012-09-01&rft.volume=61&rft.issue=9&rft.spage=2340&rft.pages=2340-&rft.issn=0012-1797&rft.eissn=1939-327X&rft.coden=DIAEAZ&rft_id=info:doi/&rft_dat=%3Cproquest%3E2757556061%3C/proquest%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1038958390&rft_id=info:pmid/&rfr_iscdi=true |