{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:08:45Z","timestamp":1791410925782,"version":"4.3.3"},"reference-count":46,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2014,12,8]],"date-time":"2014-12-08T00:00:00Z","timestamp":1417996800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000222","name":"Heart and Stroke Foundation of Canada","doi-asserted-by":"publisher","award":["G-13-0002851"],"award-info":[{"award-number":["G-13-0002851"]}],"id":[{"id":"10.13039\/501100000222","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunology"],"published-print":{"date-parts":[[2015,1]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Therapies that promote tolerance in solid organ transplantation will improve patient outcomes by eliminating the need for long\u2010term immunosuppression. To investigate mechanisms of rapamycin\u2010induced tolerance, C3H\/HeJ mice were heterotopically transplanted with MHC\u2010mismatched hearts from BALB\/<jats:styled-content style=\"fixed-case\">cJ<\/jats:styled-content> mice and were monitored for rejection after a short course of rapamycin treatment. Mice that had received rapamycin developed tolerance with indefinite graft survival, whereas untreated mice all rejected their grafts within 9\u00a0days. <jats:italic>In vitro<\/jats:italic>, splenic mononuclear cells from tolerant mice maintained primary CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> immune responses to donor antigens consistent with a mechanism that involves active suppression of immune responses. Furthermore, infection with lymphocytic choriomeningitis virus strain WE led to loss of tolerance suggesting that tolerance could be overcome by infection. Rapamycin\u2010induced, donor\u2010specific tolerance was associated with an expansion of regulatory T (Treg) cells in both the spleen and allograft and elevated plasma levels of fibrinogen\u2010like protein 2 (FGL2). Depletion of Treg cells with anti\u2010CD25 (PC61) and treatment with anti\u2010FGL2 antibody both prevented tolerance induction. Tolerant allografts were populated with Treg cells that co\u2010expressed FGL2 and FoxP3, whereas rejecting allografts and syngeneic grafts were nearly devoid of dual\u2010staining cells. We examined the utility of an immunoregulatory gene panel to discriminate between tolerance and rejection. We observed that Treg\u2010associated genes (<jats:italic>foxp3<\/jats:italic>,<jats:italic> lag3<\/jats:italic>,<jats:italic> tgf\u2010\u03b2<\/jats:italic> and <jats:italic>fgl2)<\/jats:italic> had increased expression and pro\u2010inflammatory genes (<jats:italic>ifn\u2010\u03b3<\/jats:italic> and <jats:italic>gzmb<\/jats:italic>) had decreased expression in tolerant compared with rejecting allografts. Taken together, these data strongly suggest that Treg cells expressing FGL2 mediate rapamycin\u2010induced tolerance. Furthermore, a gene biomarker panel that includes <jats:italic>fgl2<\/jats:italic> can distinguish between rejecting and tolerant grafts.<\/jats:p>","DOI":"10.1111\/imm.12354","type":"journal-article","created":{"date-parts":[[2014,7,3]],"date-time":"2014-07-03T08:15:36Z","timestamp":1404375336000},"page":"91-106","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["The regulatory T cell effector molecule fibrinogen\u2010like protein 2 is necessary for the development of rapamycin\u2010induced tolerance to fully MHC\u2010mismatched murine cardiac allografts"],"prefix":"10.1111","volume":"144","author":[{"given":"Peter","family":"Urbanellis","sequence":"first","affiliation":[{"name":"Multi\u2010Organ Transplant Program University Health Network Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Shyu","sequence":"additional","affiliation":[{"name":"Multi\u2010Organ Transplant Program University Health Network Toronto ON Canada"},{"name":"Department of Immunology University of Toronto Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramzi","family":"Khattar","sequence":"additional","affiliation":[{"name":"Multi\u2010Organ Transplant Program University Health Network Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihong","family":"Wang","sequence":"additional","affiliation":[{"name":"Multi\u2010Organ Transplant Program University Health Network Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Zakharova","sequence":"additional","affiliation":[{"name":"Department of Immunology University of Toronto Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"He","sequence":"additional","affiliation":[{"name":"Multi\u2010Organ Transplant Program University Health Network Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Sadozai","sequence":"additional","affiliation":[{"name":"Multi\u2010Organ Transplant Program University Health Network Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achiya Z.","family":"Amir","sequence":"additional","affiliation":[{"name":"Hospital for Sick Children Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itay","family":"Shalev","sequence":"additional","affiliation":[{"name":"Multi\u2010Organ Transplant Program University Health Network Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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