{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:27:37Z","timestamp":1790224057940,"version":"4.1.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":2769,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,2]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>CD4+CD25+ regulatory T cells (T-regs) are central to the maintenance of immune tolerance and represent an immune intervention candidate in autoimmune hepatitis (AIH), a condition characterized by impaired T-reg number and function. We investigated whether T-regs can be expanded from the existing CD4+CD25+ T cell pool and generated<\/jats:bold>\n                                 <jats:bold>\n                                    de novo\n                                 <\/jats:bold>\n                                 <jats:bold>from CD4+CD25\u2212 T cells in AIH patients and healthy controls. Purified CD4+CD25+ and CD4+CD25\u2212 T cells from 24 patients with type 1 AIH and 22 healthy controls were cultured for up to 5 weeks with anti-CD3\/anti-CD28 T cell expander and high-dose interleukin-2 (IL-2). Cell phenotypes, suppressor ability, forkhead winged\/helix transcription factor box P3 (FOXP3) gene, and protein expression were assessed weekly by cytofluorimetry, proliferation assay, real-time polymerase chain reaction (PCR), and immunoblot. During culture, the number of CD4+CD25+ T cells derived from the existing T-reg pool (expanded T-regs) and generated<\/jats:bold>\n                                 <jats:bold>\n                                    de novo\n                                 <\/jats:bold>\n                                 <jats:bold>from CD4+CD25\u2212 T cells (newly generated T-regs) increased constantly up to week 4 in both healthy controls and, to a lesser extent, in AIH patients. Expanded T-regs retained conventional T-reg phenotype and, compared with baseline, demonstrated more vigorous suppressive function and increased FOXP3 gene and protein expression. Newly generated T-regs not only acquired T-reg phenotype but underwent greater growth and were more resistant to apoptosis than expanded T-regs. Their suppressive function augmented throughout culture, reaching a peak at week 4, preceded by a peak FOXP3 gene and protein expression at week 2. Suppressor function and FOXP3 expression of both expanded and newly generated T-regs were higher in normal controls than in AIH patients.<\/jats:bold>\n                                 <jats:bold>\n                                    Conclusion:\n                                 <\/jats:bold>\n                                 <jats:bold>Functionally enhanced T-regs can be expanded and generated<\/jats:bold>\n                                 <jats:bold>\n                                    de novo\n                                 <\/jats:bold>\n                                 <jats:bold>in patients with AIH. This finding may assist in reconstituting impaired immune regulation and restoring peripheral tolerance through T-reg infusion in this condition. (Hepatology 2008;47:581\u2013591.)<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.22071","type":"journal-article","created":{"date-parts":[[2008,1,26]],"date-time":"2008-01-26T00:17:25Z","timestamp":1201306645000},"page":"581-591","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":107,"title":["Expansion and de novo generation of potentially therapeutic regulatory T cells in patients with autoimmune hepatitis"],"prefix":"10.1097","volume":"47","author":[{"given":"Maria Serena","family":"Longhi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Meda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Samyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgina","family":"Mieli-Vergani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Vergani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-27-20241201","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.immuni.2006.08.003","article-title":"From vanilla to 28 flavors: multiple varieties of T regulatory cells.","volume":"25","author":"Shevach","year":"2006","journal-title":"Immunity"},{"key":"R2-27-20241201","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1034\/j.1600-065X.2001.1820102.x","article-title":"Immunologic tolerance maintained by CD25 CD4 regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance.","volume":"182","author":"Sakaguchi","year":"2001","journal-title":"Immunol Rev"},{"key":"R3-27-20241201","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.it.2004.04.009","article-title":"Cornerstone of peripheral tolerance: naturally occurring CD4CD25 regulatory T cells.","volume":"25","author":"Piccirillo","year":"2004","journal-title":"Trends Immunol"},{"key":"R4-27-20241201","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/ni904","article-title":"Foxp3 programs the development and function of CD4CD25 regulatory T cells.","volume":"4","author":"Fontenot","year":"2003","journal-title":"Nat Immunol"},{"key":"R5-27-20241201","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/ni909","article-title":"An essential role for Scurfin in CD4CD25 T regulatory cells.","volume":"4","author":"Khattri","year":"2003","journal-title":"Nat Immunol"},{"key":"R6-27-20241201","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/ni1455","article-title":"Foxp3 in control of the regulatory T cell lineage.","volume":"8","author":"Zheng","year":"2007","journal-title":"Nat Immunol"},{"key":"R7-27-20241201","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1084\/jem.161.1.72","article-title":"Organspecific autoimmune diseases induced in mice by elimination of T cell subset. 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