Prevention of recurrent but not spontaneous autoimmune diabetes by transplanted NOD islets adenovirally transduced with immunomodulating molecules
Abstract Pancreatic islet transplantation has the potential to maintain normoglycemia in patients with established type 1 diabetes, thereby obviating the need for frequent insulin injections. Our previous study showed that recombinant IL-12p40-producing islets prevented the recurrence of NOD diabete...
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| Veröffentlicht in: | Diabetes research and clinical practice 2008-06, Vol.80 (3), p.352-359 |
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| creator | Sakata, Muneaki Yasuda, Hisafumi Moriyama, Hiroaki Yamada, Katsumi Kotani, Reiko Kurohara, Midori Okumachi, Yasuyo Kishi, Minoru Arai, Takashi Hara, Kenta Hamada, Hirofumi Yokono, Koichi Nagata, Masao |
| description | Abstract Pancreatic islet transplantation has the potential to maintain normoglycemia in patients with established type 1 diabetes, thereby obviating the need for frequent insulin injections. Our previous study showed that recombinant IL-12p40-producing islets prevented the recurrence of NOD diabetes. First, to see which immunomodulating molecule-secreting islet grafts can most powerfully prevent diabetes development in NOD mice without immunosuppressant, NOD islets were transfected with one of the following adenoviral vectors: Ad.IL-12p40, Ad.TGF-β, Ad.CTLA4-Ig, or Ad.TNF-α after which they were transplanted under the renal capsule of acutely diabetic NOD mice. The immunomodulating molecules produced by these adenovirus-transfected islets in vitro were 74 ± 19 ng, 50 ± 4 ng, 821 ± 31 ng, and 77 ± 18 ng/100 islets, respectively. Transplantation of IL-12p40, TNF-α, and CTLA4-Ig but not TGF-β-secreting islets displayed enhanced survival and delayed diabetes recurrence in recent-onset diabetic recipients. IL-12p40-producing islet grafts most powerfully prevented recurrent diabetes in NOD mice. In addition, local production of TNF-α and CTLA4-Ig significantly prolonged islet graft survival. In second series of experiment, these manipulated islets were transplanted under the renal capsule of 10-week-old NOD recipients and were also transplanted subcutaneously into 2-week-old NOD recipients. Transplantation of these islets into 2- or 10-week-old pre-diabetic mice failed to protect them from developing diabetes; in fact, transplantation of Ad.TNF-α-transfected islets into 2-week-old mice actually accelerated diabetes onset. Taken together, this approach was ineffectual as a prophylactic protocol. In conclusion, this study showed comparisons of the immunomodulating effects of 4 different adenoviral vectors in the same transplantation model and local production of IL-12p40, TNF-α and CTLA4-Ig significantly prevented recurrent diabetes in NOD mice. |
| doi_str_mv | 10.1016/j.diabres.2008.01.030 |
| format | Article |
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Our previous study showed that recombinant IL-12p40-producing islets prevented the recurrence of NOD diabetes. First, to see which immunomodulating molecule-secreting islet grafts can most powerfully prevent diabetes development in NOD mice without immunosuppressant, NOD islets were transfected with one of the following adenoviral vectors: Ad.IL-12p40, Ad.TGF-β, Ad.CTLA4-Ig, or Ad.TNF-α after which they were transplanted under the renal capsule of acutely diabetic NOD mice. The immunomodulating molecules produced by these adenovirus-transfected islets in vitro were 74 ± 19 ng, 50 ± 4 ng, 821 ± 31 ng, and 77 ± 18 ng/100 islets, respectively. Transplantation of IL-12p40, TNF-α, and CTLA4-Ig but not TGF-β-secreting islets displayed enhanced survival and delayed diabetes recurrence in recent-onset diabetic recipients. IL-12p40-producing islet grafts most powerfully prevented recurrent diabetes in NOD mice. In addition, local production of TNF-α and CTLA4-Ig significantly prolonged islet graft survival. In second series of experiment, these manipulated islets were transplanted under the renal capsule of 10-week-old NOD recipients and were also transplanted subcutaneously into 2-week-old NOD recipients. Transplantation of these islets into 2- or 10-week-old pre-diabetic mice failed to protect them from developing diabetes; in fact, transplantation of Ad.TNF-α-transfected islets into 2-week-old mice actually accelerated diabetes onset. Taken together, this approach was ineffectual as a prophylactic protocol. In conclusion, this study showed comparisons of the immunomodulating effects of 4 different adenoviral vectors in the same transplantation model and local production of IL-12p40, TNF-α and CTLA4-Ig significantly prevented recurrent diabetes in NOD mice.</description><identifier>ISSN: 0168-8227</identifier><identifier>EISSN: 1872-8227</identifier><identifier>DOI: 10.1016/j.diabres.2008.01.030</identifier><identifier>PMID: 18400329</identifier><language>eng</language><publisher>Ireland: Elsevier Ireland Ltd</publisher><subject>Adenoviral vector ; Adenoviridae - genetics ; Animals ; Autoimmune diabetes ; Diabetes Mellitus, Type 1 - prevention & control ; Endocrinology & Metabolism ; Female ; Genetic Vectors ; Humans ; Immunomodulating molecule ; Islet transplantation ; Islets of Langerhans Transplantation ; Male ; Mice ; Mice, Inbred NOD ; Recurrence ; TNF-α ; Transfection ; Tumor Necrosis Factor-alpha - genetics</subject><ispartof>Diabetes research and clinical practice, 2008-06, Vol.80 (3), p.352-359</ispartof><rights>Elsevier Ireland Ltd</rights><rights>2008 Elsevier Ireland Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c418t-71e7cbb05c8cad30b8c81114ff02c0043418a51f59b06333926865ae5204c2a73</citedby><cites>FETCH-LOGICAL-c418t-71e7cbb05c8cad30b8c81114ff02c0043418a51f59b06333926865ae5204c2a73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.diabres.2008.01.030$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,778,782,3539,27913,27914,45984</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18400329$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sakata, Muneaki</creatorcontrib><creatorcontrib>Yasuda, Hisafumi</creatorcontrib><creatorcontrib>Moriyama, Hiroaki</creatorcontrib><creatorcontrib>Yamada, Katsumi</creatorcontrib><creatorcontrib>Kotani, Reiko</creatorcontrib><creatorcontrib>Kurohara, Midori</creatorcontrib><creatorcontrib>Okumachi, Yasuyo</creatorcontrib><creatorcontrib>Kishi, Minoru</creatorcontrib><creatorcontrib>Arai, Takashi</creatorcontrib><creatorcontrib>Hara, Kenta</creatorcontrib><creatorcontrib>Hamada, Hirofumi</creatorcontrib><creatorcontrib>Yokono, Koichi</creatorcontrib><creatorcontrib>Nagata, Masao</creatorcontrib><title>Prevention of recurrent but not spontaneous autoimmune diabetes by transplanted NOD islets adenovirally transduced with immunomodulating molecules</title><title>Diabetes research and clinical practice</title><addtitle>Diabetes Res Clin Pract</addtitle><description>Abstract Pancreatic islet transplantation has the potential to maintain normoglycemia in patients with established type 1 diabetes, thereby obviating the need for frequent insulin injections. Our previous study showed that recombinant IL-12p40-producing islets prevented the recurrence of NOD diabetes. First, to see which immunomodulating molecule-secreting islet grafts can most powerfully prevent diabetes development in NOD mice without immunosuppressant, NOD islets were transfected with one of the following adenoviral vectors: Ad.IL-12p40, Ad.TGF-β, Ad.CTLA4-Ig, or Ad.TNF-α after which they were transplanted under the renal capsule of acutely diabetic NOD mice. The immunomodulating molecules produced by these adenovirus-transfected islets in vitro were 74 ± 19 ng, 50 ± 4 ng, 821 ± 31 ng, and 77 ± 18 ng/100 islets, respectively. Transplantation of IL-12p40, TNF-α, and CTLA4-Ig but not TGF-β-secreting islets displayed enhanced survival and delayed diabetes recurrence in recent-onset diabetic recipients. IL-12p40-producing islet grafts most powerfully prevented recurrent diabetes in NOD mice. In addition, local production of TNF-α and CTLA4-Ig significantly prolonged islet graft survival. In second series of experiment, these manipulated islets were transplanted under the renal capsule of 10-week-old NOD recipients and were also transplanted subcutaneously into 2-week-old NOD recipients. Transplantation of these islets into 2- or 10-week-old pre-diabetic mice failed to protect them from developing diabetes; in fact, transplantation of Ad.TNF-α-transfected islets into 2-week-old mice actually accelerated diabetes onset. Taken together, this approach was ineffectual as a prophylactic protocol. In conclusion, this study showed comparisons of the immunomodulating effects of 4 different adenoviral vectors in the same transplantation model and local production of IL-12p40, TNF-α and CTLA4-Ig significantly prevented recurrent diabetes in NOD mice.</description><subject>Adenoviral vector</subject><subject>Adenoviridae - genetics</subject><subject>Animals</subject><subject>Autoimmune diabetes</subject><subject>Diabetes Mellitus, Type 1 - prevention & control</subject><subject>Endocrinology & Metabolism</subject><subject>Female</subject><subject>Genetic Vectors</subject><subject>Humans</subject><subject>Immunomodulating molecule</subject><subject>Islet transplantation</subject><subject>Islets of Langerhans Transplantation</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Recurrence</subject><subject>TNF-α</subject><subject>Transfection</subject><subject>Tumor Necrosis Factor-alpha - genetics</subject><issn>0168-8227</issn><issn>1872-8227</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFktuKFDEQhoMo7rj6CEquvJu2kj5lbhTZ9QSLK6jXIZ2u1ozpZMxhZF7DJza90yB441Uq8FX9_PUXIU8ZVAxY92JfjUYNAWPFAUQFrIIa7pENEz3fCs77-2RTOHFXX5BHMe4BoKub9iG5YKIBqPluQ35_CnhEl4x31E80oM4hlD8dcqLOJxoP3iXl0OdIVU7ezHN2SBdxTBjpcKIpKBcPVrmEI_14e01NtJgKPqLzRxOUtSs0Zl2QXyZ9p3dz_OzHbFUy7hudvS3iFuNj8mBSNuKT9b0kX9---XL1fntz--7D1eubrW6YSNueYa-HAVottBprGIQWjLFmmoBrgKYulGrZ1O6GYruud7wTXauw5dBorvr6kjw_zz0E_zNjTHI2UaO1Z7ey2xWyqbsCtmdQBx9jwEkegplVOEkGcglD7uUahlzCkMBkCaP0PVsF8jDj-Ldr3X4BXp0BLDaPBoOM2qArOzIliCRHb_4r8fKfCdoaZ7SyP_CEce9zcGWHksnIJcjPy0UsBwGiHINgov4DY2C2ew</recordid><startdate>20080601</startdate><enddate>20080601</enddate><creator>Sakata, Muneaki</creator><creator>Yasuda, Hisafumi</creator><creator>Moriyama, Hiroaki</creator><creator>Yamada, Katsumi</creator><creator>Kotani, Reiko</creator><creator>Kurohara, Midori</creator><creator>Okumachi, Yasuyo</creator><creator>Kishi, Minoru</creator><creator>Arai, Takashi</creator><creator>Hara, Kenta</creator><creator>Hamada, Hirofumi</creator><creator>Yokono, Koichi</creator><creator>Nagata, Masao</creator><general>Elsevier Ireland Ltd</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>20080601</creationdate><title>Prevention of recurrent but not spontaneous autoimmune diabetes by transplanted NOD islets adenovirally transduced with immunomodulating molecules</title><author>Sakata, Muneaki ; Yasuda, Hisafumi ; Moriyama, Hiroaki ; Yamada, Katsumi ; Kotani, Reiko ; Kurohara, Midori ; Okumachi, Yasuyo ; Kishi, Minoru ; Arai, Takashi ; Hara, Kenta ; Hamada, Hirofumi ; Yokono, Koichi ; Nagata, Masao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c418t-71e7cbb05c8cad30b8c81114ff02c0043418a51f59b06333926865ae5204c2a73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adenoviral vector</topic><topic>Adenoviridae - genetics</topic><topic>Animals</topic><topic>Autoimmune diabetes</topic><topic>Diabetes Mellitus, Type 1 - prevention & control</topic><topic>Endocrinology & Metabolism</topic><topic>Female</topic><topic>Genetic Vectors</topic><topic>Humans</topic><topic>Immunomodulating molecule</topic><topic>Islet transplantation</topic><topic>Islets of Langerhans Transplantation</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred NOD</topic><topic>Recurrence</topic><topic>TNF-α</topic><topic>Transfection</topic><topic>Tumor Necrosis Factor-alpha - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sakata, Muneaki</creatorcontrib><creatorcontrib>Yasuda, Hisafumi</creatorcontrib><creatorcontrib>Moriyama, Hiroaki</creatorcontrib><creatorcontrib>Yamada, Katsumi</creatorcontrib><creatorcontrib>Kotani, Reiko</creatorcontrib><creatorcontrib>Kurohara, Midori</creatorcontrib><creatorcontrib>Okumachi, Yasuyo</creatorcontrib><creatorcontrib>Kishi, Minoru</creatorcontrib><creatorcontrib>Arai, Takashi</creatorcontrib><creatorcontrib>Hara, Kenta</creatorcontrib><creatorcontrib>Hamada, Hirofumi</creatorcontrib><creatorcontrib>Yokono, Koichi</creatorcontrib><creatorcontrib>Nagata, Masao</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>Diabetes research and clinical practice</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sakata, Muneaki</au><au>Yasuda, Hisafumi</au><au>Moriyama, Hiroaki</au><au>Yamada, Katsumi</au><au>Kotani, Reiko</au><au>Kurohara, Midori</au><au>Okumachi, Yasuyo</au><au>Kishi, Minoru</au><au>Arai, Takashi</au><au>Hara, Kenta</au><au>Hamada, Hirofumi</au><au>Yokono, Koichi</au><au>Nagata, Masao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prevention of recurrent but not spontaneous autoimmune diabetes by transplanted NOD islets adenovirally transduced with immunomodulating molecules</atitle><jtitle>Diabetes research and clinical practice</jtitle><addtitle>Diabetes Res Clin Pract</addtitle><date>2008-06-01</date><risdate>2008</risdate><volume>80</volume><issue>3</issue><spage>352</spage><epage>359</epage><pages>352-359</pages><issn>0168-8227</issn><eissn>1872-8227</eissn><abstract>Abstract Pancreatic islet transplantation has the potential to maintain normoglycemia in patients with established type 1 diabetes, thereby obviating the need for frequent insulin injections. Our previous study showed that recombinant IL-12p40-producing islets prevented the recurrence of NOD diabetes. First, to see which immunomodulating molecule-secreting islet grafts can most powerfully prevent diabetes development in NOD mice without immunosuppressant, NOD islets were transfected with one of the following adenoviral vectors: Ad.IL-12p40, Ad.TGF-β, Ad.CTLA4-Ig, or Ad.TNF-α after which they were transplanted under the renal capsule of acutely diabetic NOD mice. The immunomodulating molecules produced by these adenovirus-transfected islets in vitro were 74 ± 19 ng, 50 ± 4 ng, 821 ± 31 ng, and 77 ± 18 ng/100 islets, respectively. Transplantation of IL-12p40, TNF-α, and CTLA4-Ig but not TGF-β-secreting islets displayed enhanced survival and delayed diabetes recurrence in recent-onset diabetic recipients. IL-12p40-producing islet grafts most powerfully prevented recurrent diabetes in NOD mice. In addition, local production of TNF-α and CTLA4-Ig significantly prolonged islet graft survival. In second series of experiment, these manipulated islets were transplanted under the renal capsule of 10-week-old NOD recipients and were also transplanted subcutaneously into 2-week-old NOD recipients. Transplantation of these islets into 2- or 10-week-old pre-diabetic mice failed to protect them from developing diabetes; in fact, transplantation of Ad.TNF-α-transfected islets into 2-week-old mice actually accelerated diabetes onset. Taken together, this approach was ineffectual as a prophylactic protocol. In conclusion, this study showed comparisons of the immunomodulating effects of 4 different adenoviral vectors in the same transplantation model and local production of IL-12p40, TNF-α and CTLA4-Ig significantly prevented recurrent diabetes in NOD mice.</abstract><cop>Ireland</cop><pub>Elsevier Ireland Ltd</pub><pmid>18400329</pmid><doi>10.1016/j.diabres.2008.01.030</doi><tpages>8</tpages></addata></record> |
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| subjects | Adenoviral vector Adenoviridae - genetics Animals Autoimmune diabetes Diabetes Mellitus, Type 1 - prevention & control Endocrinology & Metabolism Female Genetic Vectors Humans Immunomodulating molecule Islet transplantation Islets of Langerhans Transplantation Male Mice Mice, Inbred NOD Recurrence TNF-α Transfection Tumor Necrosis Factor-alpha - genetics |
| title | Prevention of recurrent but not spontaneous autoimmune diabetes by transplanted NOD islets adenovirally transduced with immunomodulating molecules |
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