{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T07:57:46Z","timestamp":1785484666610,"version":"3.56.0"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1175470"],"award-info":[{"award-number":["1175470"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["GNT1150425"],"award-info":[{"award-number":["GNT1150425"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Breakthrough T1D","award":["3-PDF-2024-1505-A-N"],"award-info":[{"award-number":["3-PDF-2024-1505-A-N"]}]},{"DOI":"10.13039\/501100001782","name":"University of Melbourne","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001782","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims\/hypothesis<\/jats:title>\n                    <jats:p>\n                      CD8\u207a T cells are key mediators of beta cell destruction in type 1 diabetes, employing the perforin\/granzyme and Fas\/Fas ligand pathways. Evidence from our studies and others indicates that perforin plays a dominant role in CD8\u207a T cell mediated beta cell destruction in non-obese diabetic (NOD) mice. As perforin is indispensable for delivering pro-apoptotic granzymes into the cytosol of target cells, pharmacological inhibition of perforin may potentially protect beta cells against CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell cytotoxicity. Such a strategy will slow down beta cell loss and the progression to autoimmune diabetes. Small molecule perforin inhibitors recently becoming available provided an opportunity to test this hypothesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The new small molecule perforin inhibitor SN34960 was evaluated for its ability to protect the beta cells of non-obese diabetic mice upon attack by autoreactive cytotoxic T lymphocytes, both in vitro and in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In vitro, perforin inhibitor SN34960 protected isolated pancreatic islets from CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell-mediated destruction (\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.001). In vivo, a single dose of SN34960 reduced the death of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) peptide-loaded target cells by ~50% over 16 h compared with non-peptide-loaded control cells (\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.05). Furthermore, prediabetic NOD mice treated with perforin inhibitor for 7 days had a reduced incidence of diabetes when autoimmune attack was accelerated by anti-PDL1 blockade (91.2% vs 58.4%,\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.05). Pharmacological perforin inhibition with SN34960 did not alter the activation or differentiation status of pathogenic cytotoxic T lymphocyte infiltrating the pancreas; instead, its mode of action is specifically to block the membrane-disruptive and pro-apoptotic effects of perforin following its secretion into the synaptic cleft.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>\n                      Our results suggest that pharmacological perforin inhibition may represent a novel approach to protect beta cells from destruction by autoreactive CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06773-8","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T16:56:39Z","timestamp":1781196999000},"page":"2599-2606","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological inhibition of perforin dampens CD8+ T cell-mediated beta cell destruction in autoimmune diabetes in mice"],"prefix":"10.1007","volume":"69","author":[{"given":"Prerak M.","family":"Trivedi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tara","family":"Catterall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivien R.","family":"Sutton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viki","family":"Moshovakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorraine","family":"Elkerbout","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hedieh","family":"Akhlaghi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Spicer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Boon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas W. H.","family":"Kay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph A.","family":"Trapani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen E.","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"issue":"6","key":"6773_CR1","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1038\/nri3839","volume":"15","author":"I Voskoboinik","year":"2015","unstructured":"Voskoboinik I, Whisstock JC, Trapani JA (2015) Perforin and granzymes: function, dysfunction and human pathology. 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Blood 118(3):618\u2013626. https:\/\/doi.org\/10.1182\/blood-2010-12-324533","journal-title":"Blood"}],"container-title":["Diabetologia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06773-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00125-026-06773-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06773-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T07:03:49Z","timestamp":1785481429000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00125-026-06773-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,11]]},"references-count":19,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["6773"],"URL":"https:\/\/doi.org\/10.1007\/s00125-026-06773-8","relation":{},"ISSN":["0012-186X","1432-0428"],"issn-type":[{"value":"0012-186X","type":"print"},{"value":"1432-0428","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,11]]},"assertion":[{"value":"25 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The work in this manuscript is dedicated to the memory of our dear co-author, long-standing colleague and friend Professor Helen E. Thomas, an inspiration to us all. We thank L. Kloboucnik and R. Chan (Bioresources Centre, BRC, St Vincent\u2019s Hospital, Melbourne) for excellent technical assistance and animal husbandry.","order":1,"name":"Ethics","label":"Acknowledgements","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"All data supporting the conclusions of this study are stored at St Vincent\u2019s Institute of Medical Research or the Peter MacCallum Cancer Centre and are available on request to PMT or JAT.","order":2,"name":"Ethics","label":"Data availability","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The work was supported by investigator grant (L3) no. 1175470 from the National Health and Medical Research Council of Australia (NHMRC) to JAT and NHMRC programme grant no. GNT1150425 to HET and TWHK. Breakthrough T1D fellowship 3-PDF-2024-1505-A-N supported PMT during completion of this work.","order":3,"name":"Ethics","label":"Funding","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","label":"Authors\u2019 relationships and activities","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"All of the authors have: (1) made substantial contributions to conceptualising, designing and carrying out the research; (2) revised the manuscript; and (3) consented to being included as an author and approved the final version to be published. JAT and PMT are guarantors for this study.","order":5,"name":"Ethics","label":"Contribution statement","group":{"name":"EthicsHeading","label":"Ethics"}}]}}