{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T07:06:59Z","timestamp":1777619219837,"version":"3.51.4"},"reference-count":37,"publisher":"SAGE Publications","issue":"12","license":[{"start":{"date-parts":[[2013,12,1]],"date-time":"2013-12-01T00:00:00Z","timestamp":1385856000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Cell Transplant"],"published-print":{"date-parts":[[2013,12]]},"abstract":"<jats:p>\n                    Islet grafts can contribute to their own destruction via the elaboration of proinflammatory genes, many of which are transcriptionally regulated by nuclear factor \u03ba-light-chain-enhancer of activated B-cells (NF-\u03baB). Thus, NF-\u03baB constitutes an enticing gene therapy candidate to improve the success of islet transplantation. To test this hypothesis in vivo, we blocked NF-\u03baB in BALB\/c (H2\n                    <jats:sup>d<\/jats:sup>\n                    ) to C57\/BL6 (H2\n                    <jats:sup>b<\/jats:sup>\n                    ) mouse islet allografts by genetically engineering islets to express the NF-\u03baB superrepressor, I\u03baB\u03b1. Here we show by microarray and RTqPCR that islets exhibit an intrinsic early immediate proinflammatory response, with the most highly upregulated proinflammatory genes comprising the chemokines Cxcl1, Cxcl2, Cxcl10, and Ccl2; the cytokines Tnf-\u03b1 and Il-6; and the adhesion molecule Icam1. Overexpression of I\u03baB\u03b1 inhibited the expression of these genes by 50\u201395% in islets and MIN6 \u03b2-cells in vitro, by inhibiting NF-\u03baB-dependent gene transcription. Histological and RTqPCR analysis at postoperative day (POD) 10 revealed that I\u03baB\u03b1-transduced islet allografts exhibited improved islet architecture and strong insulin-labeling with decreased Ccl2 and Il-6 mRNA levels compared to the GFP-transduced control grafts. Despite these protective effects, NF-\u03baB-blocked islet allografts were promptly rejected in our MHC-mismatched mouse model. However, I\u03baB\u03b1-expressing grafts did harbor localized \u201cpockets\u201d of Foxp3\n                    <jats:sup>+<\/jats:sup>\n                    mononuclear cells not evident in the control grafts. This result suggested that the effect of the NF-\u03baB blockade might synergize with regulatory T-cell-sparing rapamycin. Indeed, combining intragraft I\u03baB\u03b1 expression with low-dose rapamycin increased the mean survival time of islet allografts from 20 to 81 days, with 20% of the grafts surviving for greater than 100 days. In conclusion, rapamycin unmasks the protective potential of intragraft NF-\u03baB blockade, which can, in some cases, permit permanent allograft survival without continuous systemic immunosuppression.\n                  <\/jats:p>","DOI":"10.3727\/096368912x658737","type":"journal-article","created":{"date-parts":[[2013,4,9]],"date-time":"2013-04-09T10:48:16Z","timestamp":1365504496000},"page":"2355-2366","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":17,"title":["Low-Dose Rapamycin Unmasks the Protective Potential of Targeting Intragraft NF-\u03baB for Islet Transplants"],"prefix":"10.1177","volume":"22","author":[{"given":"Nathan W.","family":"Zammit","sequence":"first","affiliation":[{"name":"Gene Therapy and Autoimmunity Group, Immunology Program, Garvan Institute, Darlinghurst, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernice M.","family":"Tan","sequence":"additional","affiliation":[{"name":"Gene Therapy and Autoimmunity Group, Immunology Program, Garvan Institute, Darlinghurst, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stacey N.","family":"Walters","sequence":"additional","affiliation":[{"name":"Gene Therapy and Autoimmunity Group, Immunology Program, Garvan Institute, Darlinghurst, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Liuwantara","sequence":"additional","affiliation":[{"name":"Gene Therapy and Autoimmunity Group, Immunology Program, Garvan Institute, Darlinghurst, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeanette E.","family":"Villanueva","sequence":"additional","affiliation":[{"name":"Gene Therapy and Autoimmunity Group, Immunology Program, Garvan Institute, Darlinghurst, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth K.","family":"Malle","sequence":"additional","affiliation":[{"name":"Gene Therapy and Autoimmunity Group, Immunology Program, Garvan Institute, Darlinghurst, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shane T.","family":"Grey","sequence":"additional","affiliation":[{"name":"Gene Therapy and Autoimmunity Group, Immunology Program, Garvan Institute, Darlinghurst, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2013,12,1]]},"reference":[{"key":"bibr1-096368912X658737","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.11.2815"},{"key":"bibr2-096368912X658737","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.6.3663"},{"key":"bibr3-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1126\/science.3140380"},{"key":"bibr4-096368912X658737","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.55.01.06.db05-0613"},{"key":"bibr5-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1038\/nature04753"},{"key":"bibr6-096368912X658737","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.51.1.66"},{"key":"bibr7-096368912X658737","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.10.2559"},{"key":"bibr8-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M108658200"},{"key":"bibr9-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80178-6"},{"key":"bibr10-096368912X658737","doi-asserted-by":"publisher","DOI":"10.3727\/096368911X627372"},{"key":"bibr11-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0508166103"},{"key":"bibr12-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V91.7.2249"},{"key":"bibr13-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1038\/nm1202-792"},{"key":"bibr14-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M005943200"},{"key":"bibr15-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2008.21"},{"key":"bibr16-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1084\/jem.190.8.1135"},{"key":"bibr17-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1016\/S0041-1345(98)01769-2"},{"key":"bibr18-096368912X658737","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.12.6250"},{"key":"bibr19-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.13.5721-5732.2004"},{"key":"bibr20-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1038\/ni0302-221"},{"key":"bibr21-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1038\/nri2215"},{"key":"bibr22-096368912X658737","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.52.2.348"},{"key":"bibr23-096368912X658737","doi-asserted-by":"publisher","DOI":"10.2337\/db06-0142"},{"key":"bibr24-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"bibr25-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1210\/endo-127-1-126"},{"key":"bibr26-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116297"},{"key":"bibr27-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0b013e31824d11d7"},{"key":"bibr28-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207700200"},{"key":"bibr29-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1038\/nri1332"},{"key":"bibr30-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2011.07.011"},{"key":"bibr31-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200007273430401"},{"key":"bibr32-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.4.1788"},{"key":"bibr33-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2010.04.044"},{"key":"bibr34-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1038\/nri2546"},{"key":"bibr35-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1097\/01.tp.0000250548.13063.44"},{"key":"bibr36-096368912X658737","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.182.2.793"},{"key":"bibr37-096368912X658737","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0b013e31823cab44"}],"container-title":["Cell 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