{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T07:47:21Z","timestamp":1792396041776,"version":"4.4.0"},"reference-count":24,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2017,6,20]],"date-time":"2017-06-20T00:00:00Z","timestamp":1497916800000},"content-version":"vor","delay-in-days":842,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Juvenile Diabetes Research Foundation (JDRF)"},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation (ISF)","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunology"],"published-print":{"date-parts":[[2015,3]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>The autoimmune destruction of pancreatic <jats:italic>\u03b2<\/jats:italic>\u2010cells is the hallmark of type 1 diabetes (T1D). Failure of anti\u2010<jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>3 antibodies to provide long\u2010lasting reversal of T1D and the expression of a natural killer (<jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content>) cell ligand on <jats:italic>\u03b2<\/jats:italic>\u2010cells suggest that <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> cells play a role in disease pathogenesis. Indeed, killing of <jats:italic>\u03b2<\/jats:italic>\u2010cells by <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> cells has been shown to occur, mediated by activation of the <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> cell activating receptor, <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content>p46. <jats:italic>\u03b1<\/jats:italic>1\u2010Antitrypsin (<jats:styled-content style=\"fixed-case\">AAT<\/jats:styled-content>), an anti\u2010inflammatory and immunomodulatory glycoprotein, protects <jats:italic>\u03b2<\/jats:italic>\u2010cells from injurious immune responses and is currently evaluated as a therapeutic for recent onset T1D. Although isolated T lymphocytes are not inhibited by <jats:styled-content style=\"fixed-case\">AAT<\/jats:styled-content>, dendritic cells (<jats:styled-content style=\"fixed-case\">DC<\/jats:styled-content>) become tolerogenic in its presence and other innate immune cells become less inflammatory. Yet a comprehensive profile of <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> cell responses in the presence of <jats:styled-content style=\"fixed-case\">AAT<\/jats:styled-content> has yet to be described. In the present study, we demonstrate that <jats:styled-content style=\"fixed-case\">AAT<\/jats:styled-content> significantly reduces <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> cell degranulation against <jats:italic>\u03b2<\/jats:italic>\u2010cells, albeit in the whole animal and not in isolated <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> cell cultures. <jats:styled-content style=\"fixed-case\">AAT<\/jats:styled-content>\u2010treated mice, and not isolated cultured <jats:italic>\u03b2<\/jats:italic>\u2010cells, exhibited a marked reduction in <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content>p46 ligand levels on <jats:italic>\u03b2<\/jats:italic>\u2010cells. In related experiments, <jats:styled-content style=\"fixed-case\">AAT<\/jats:styled-content>\u2010treated <jats:styled-content style=\"fixed-case\">DC<\/jats:styled-content> exhibited reduced inducible <jats:styled-content style=\"fixed-case\">DC<\/jats:styled-content>\u2010expressed interleukin\u201015 levels and evoked a weaker <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> cell response. <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> cell depletion in a T1D mouse model resulted in improved <jats:italic>\u03b2<\/jats:italic>\u2010cell function and survival, similar to the effects observed by <jats:styled-content style=\"fixed-case\">AAT<\/jats:styled-content> treatment alone; nonetheless, the two approaches were non\u2010synergistic. Our data suggest that <jats:styled-content style=\"fixed-case\">AAT<\/jats:styled-content> is a selective immunomodulator that retains pivotal <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> cell responses, while diverting their activities away from islet <jats:italic>\u03b2<\/jats:italic>\u2010cells.<\/jats:p>","DOI":"10.1111\/imm.12403","type":"journal-article","created":{"date-parts":[[2014,10,13]],"date-time":"2014-10-13T06:14:27Z","timestamp":1413180867000},"page":"530-539","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["<i>\u03b1<\/i>1\u2010Antitrypsin modifies general natural killer cell interactions with dendritic cells and specific interactions with islet <i>\u03b2<\/i>\u2010cells in favour of protection from autoimmune diabetes"],"prefix":"10.1111","volume":"144","author":[{"given":"Ofer","family":"Guttman","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology Faculty of Health Sciences Ben\u2010Gurion University of the Negev Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rami","family":"Yossef","sequence":"additional","affiliation":[{"name":"The Shraga Segal Department for Microbiology, Immunology and Genetics Faculty of Health Sciences Ben\u2010Gurion University of the Negev Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Freixo\u2010Lima","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology Faculty of Health Sciences Ben\u2010Gurion University of the Negev Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peleg","family":"Rider","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology Faculty of Health Sciences Ben\u2010Gurion University of the Negev Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angel","family":"Porgador","sequence":"additional","affiliation":[{"name":"The Shraga Segal Department for Microbiology, Immunology and Genetics Faculty of Health Sciences Ben\u2010Gurion University of the Negev Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eli C.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology Faculty of Health Sciences Ben\u2010Gurion University of the Negev Beer\u2010Sheva 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