{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T07:56:23Z","timestamp":1769759783602,"version":"3.49.0"},"reference-count":32,"publisher":"BMJ","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gut"],"accepted":{"date-parts":[[2000,12,12]]},"published-print":{"date-parts":[[2001,7,1]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Primary sclerosing cholangitis (PSC) is considered to be a chronic autoimmune disease where infiltrating T lymphocytes have been implicated in the destruction of bile ducts. Altered function of these T cells may reflect abnormalities in the immune response leading to tissue damage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>AIM<\/jats:title>\n                    <jats:p>We investigated the proliferative and functional capacity of freshly isolated liver derived T lymphocytes (LDLs) and natural killer (NK) cells from PSC patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec sec-type=\"methods\">\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      The proliferative responses to common mitogens such as phytohaemagglutinin (PHA), concanavalin A (Con A), and lipopolysaccharide (LPS) were studied, and the cytotoxic function of T lymphocytes was measured using allogeneic target cells. NK (CD56\n                      <jats:sup>+<\/jats:sup>\n                      \/16\n                      <jats:sup>+<\/jats:sup>\n                      ) cytotoxic function was measured using the two cell lines K562 (NK sensitive) and Raji lymphoma cells (NK resistant).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Compared with patients with primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and normal controls (without liver disease), in PSC: (1) LDLs contained a low percentage of T cells; (2) there was significantly decreased expression of interleukin (IL)-2 receptor (p&lt;0.001) on activated T cells (HLA-DR\n                      <jats:sup>+<\/jats:sup>\n                      ); (3) LDLs but not peripheral blood lymphocytes had significantly impaired proliferative responses to mitogens such as PHA, Con A, and LPS (p&lt; 0.001); (4) no cytotoxic activity of PSC liver T and NK cells was recorded; (5) significantly higher levels of tumour necrosis factor \u03b1 (TNF-\u03b1) and IL-1\u03b2 but lower levels of IL-2, IL-10, and interferon \u03b3 were found in the supernatants of mitogen stimulated LDL cultures (p&lt;0.001); (6) higher percentages of freshly isolated PSC LDLs contained intracytoplasmic TNF-\u03b1 and IL-1\u03b2; and (7) pretreatment of PSC LDLs in vitro with neutralising TNF antibodies significantly enhanced proliferative responses and allowed IL-2 receptor expression following stimulation. In addition, the impaired cytolytic activity of both NK and T cells was partially restored. Impaired proliferative or functional capacity of liver derived T cells was not observed in either PBC or AIH patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>We suggest that reduced T cell reactivity in liver infiltrating cells obtained from patients with PSC is due to high local production of TNF-\u03b1. Our findings indicate that the use of anti-TNF antibodies as an alternative treatment for PSC patients should be evaluated.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/gut.49.1.131","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T06:37:59Z","timestamp":1027751879000},"page":"131-141","source":"Crossref","is-referenced-by-count":106,"title":["Tumour necrosis factor \u03b1 impairs function of liver derived T lymphocytes and natural killer cells in patients with primary sclerosing cholangitis"],"prefix":"10.1136","volume":"49","author":[{"given":"X","family":"Bo","sequence":"first","affiliation":[{"name":"aDivision of Clinical Immunology F-79, Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden, \n\nbDivision of Gastroenterology K-63, Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"U","family":"Broome","sequence":"additional","affiliation":[{"name":"aDivision of Clinical Immunology F-79, Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden, \n\nbDivision of Gastroenterology K-63, Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Remberger","sequence":"additional","affiliation":[{"name":"aDivision of Clinical Immunology F-79, Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden, \n\nbDivision of Gastroenterology K-63, Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Sumitran-Holgersson","sequence":"additional","affiliation":[{"name":"aDivision of Clinical Immunology F-79, Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden, \n\nbDivision of Gastroenterology K-63, Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2001,7,1]]},"reference":[{"key":"2025112108363432000_49.1.131.1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/hep.1840040711","article-title":"Primary sclerosing cholangitis.","volume":"4 (suppl 1)","author":"Dickson","year":"1984","journal-title":"Hepatology"},{"key":"2025112108363432000_49.1.131.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198404053101407"},{"key":"2025112108363432000_49.1.131.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(97)80417-5"},{"key":"2025112108363432000_49.1.131.4","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840010612"},{"key":"2025112108363432000_49.1.131.5","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1002\/hep.1840050321","article-title":"Immunologic analysis of mononucelar cells in liver tissue and blood of patients with primary sclerosing cholangitis.","volume":"5","author":"Whiteside","year":"1985","journal-title":"Hepatology"},{"key":"2025112108363432000_49.1.131.6","doi-asserted-by":"publisher","DOI":"10.1136\/gut.38.4.610"},{"key":"2025112108363432000_49.1.131.7","doi-asserted-by":"publisher","DOI":"10.1136\/gut.21.10.870"},{"key":"2025112108363432000_49.1.131.8","doi-asserted-by":"crossref","first-page":"3675","DOI":"10.4049\/jimmunol.161.7.3675","article-title":"The regulation and functional consequence of proinflammatory cytokine binding on human intestinal epithelial cells.","volume":"161","author":"Panja","year":"1998","journal-title":"J Immunol"},{"key":"2025112108363432000_49.1.131.9","doi-asserted-by":"publisher","DOI":"10.1016\/0049-0172(89)90081-4"},{"key":"2025112108363432000_49.1.131.10","doi-asserted-by":"publisher","DOI":"10.1136\/gut.32.4.403"},{"key":"2025112108363432000_49.1.131.11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.16.6367"},{"key":"2025112108363432000_49.1.131.12","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/BF00191429","article-title":"Cellular localization of inflammatory cytokines in human glomerulonephritis.","volume":"424","author":"Takemura","year":"1994","journal-title":"Virchows Archiv"},{"key":"2025112108363432000_49.1.131.13","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.1990.tb03334.x"},{"key":"2025112108363432000_49.1.131.14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.1995.tb03130.x"},{"key":"2025112108363432000_49.1.131.15","doi-asserted-by":"publisher","DOI":"10.1016\/1074-7613(95)90086-1"},{"key":"2025112108363432000_49.1.131.16","doi-asserted-by":"crossref","first-page":"47","DOI":"10.3109\/00365529409103625","article-title":"Etiology and pathogenesis in primary sclerosing cholangitis.","volume":"204","author":"Boberg","year":"1994","journal-title":"Scand J Gastroenterol Suppl"},{"key":"2025112108363432000_49.1.131.17","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840070515"},{"key":"2025112108363432000_49.1.131.18","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(97)05419-6"},{"key":"2025112108363432000_49.1.131.19","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(99)80297-9"},{"key":"2025112108363432000_49.1.131.20","doi-asserted-by":"publisher","DOI":"10.1007\/BF02621273"},{"key":"2025112108363432000_49.1.131.21","doi-asserted-by":"publisher","DOI":"10.1002\/lt.500020107"},{"key":"2025112108363432000_49.1.131.22","doi-asserted-by":"publisher","DOI":"10.1016\/0168-8278(92)90024-J"},{"key":"2025112108363432000_49.1.131.23","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-1007189"},{"key":"2025112108363432000_49.1.131.24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.7.3195"},{"key":"2025112108363432000_49.1.131.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(99)80068-3"},{"key":"2025112108363432000_49.1.131.26","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1172\/JCI117394","article-title":"Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor\/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis.","volume":"94","author":"Cope","year":"1994","journal-title":"J Clin Invest"},{"key":"2025112108363432000_49.1.131.27","first-page":"21","article-title":"Soluble TNF receptor production by activated T lymphocytes: differential effects of acute and chronic exposure to TNF.","volume":"84","author":"Cope","year":"1995","journal-title":"Immunology"},{"key":"2025112108363432000_49.1.131.28","doi-asserted-by":"publisher","DOI":"10.1084\/jem.185.9.1573"},{"key":"2025112108363432000_49.1.131.29","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(98)80087-3"},{"key":"2025112108363432000_49.1.131.30","doi-asserted-by":"publisher","DOI":"10.1006\/cimm.1998.1307"},{"key":"2025112108363432000_49.1.131.31","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)80067-O"},{"key":"2025112108363432000_49.1.131.32","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1172\/JCI116598","article-title":"Functional interleukin-2 receptors on intestinal epithelial cells.","volume":"92","author":"Ciacci","year":"1993","journal-title":"J Clin Invest"}],"container-title":["Gut"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/gut.49.1.131","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T16:36:42Z","timestamp":1763743002000},"score":1,"resource":{"primary":{"URL":"https:\/\/gut.bmj.com\/lookup\/doi\/10.1136\/gut.49.1.131"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,7,1]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2001,7,1]]},"published-print":{"date-parts":[[2001,7,1]]}},"alternative-id":["10.1136\/gut.49.1.131"],"URL":"https:\/\/doi.org\/10.1136\/gut.49.1.131","relation":{},"ISSN":["0017-5749","1468-3288"],"issn-type":[{"value":"0017-5749","type":"print"},{"value":"1468-3288","type":"electronic"}],"subject":[],"published":{"date-parts":[[2001,7,1]]}}}