{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T08:18:06Z","timestamp":1780733886852,"version":"3.54.1"},"reference-count":29,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2021,1,1]],"date-time":"2021-01-01T00:00:00Z","timestamp":1609459200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of Shaanxi Province","award":["No.2021SF-228, 2017JM8092, 2020JM-406, 2017SF-123"],"award-info":[{"award-number":["No.2021SF-228, 2017JM8092, 2020JM-406, 2017SF-123"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No.30901268, 81300322"],"award-info":[{"award-number":["No.30901268, 81300322"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Int J Immunopathol Pharmacol"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:p>\n                    Introduction: The spleen plays an important role in regulating the immune response to infectious pathogens. T-cells dysfunction and exhaustion have been reported in patients with hepatitis B\/C virus (HBV\/HCV) infection, which contributes to persistent virus infection. The aims of this study were to investigate spleen-related evidence of immunosuppression and immune tolerance in HCV cirrhotic patients with portal hypertension (PH). Methods: The expression of programmed cell death 1 (PD-1), T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) and its ligand PD-L1\/2, and Galectin-9 in the spleens and livers of HCV cirrhotic patients ( n = 15) was analyzed using real-time PCR and immunohistochemistry. Flow cytometry was used to evaluate the expression of PD-1 and Tim-3 on splenic T-cells and the peripheral blood T-cells before and after splenectomy ( n = 8). Results: Spleens from patients with PH showed significantly increased mRNA levels of PD-L2, Tim-3, Galectin-9, CD80, and CD86, and decreased levels of CD28 compared to control spleens (spleens removed due to traumatic injury) (all p &lt; 0.05). Additionally, protein expression of inhibitory signaling molecules was significantly increased in both the spleens and livers of cirrhotic patients compared with controls (all p &lt; 0.05). Peripheral blood and splenic CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T-cells also expressed higher protein levels of PD-1, Tim-3, and CTLA-4 in cirrhotic patients as compared with healthy controls (all p &lt; 0.05). The proportion of PD-1\n                    <jats:sup>+<\/jats:sup>\n                    CD4\n                    <jats:sup>+<\/jats:sup>\n                    T lymphocytes (26.2% \u00b1 7.12% vs. 21.0% \u00b1 9.14%, p = 0.0293) and Tim-3\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T lymphocytes (9.4% \u00b1 3.04% vs. 6.0% \u00b1 2.24%, p = 0.0175) in peripheral blood decreased followed splenectomy. Conclusion: The CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T-cells in spleen and peripheral blood highly expressed PD-1 and Tim-3 in HCV-infected and cirrhotic patients with portal hypertension. Highly expressed PD-1 and Tim-3 in peripheral blood T-lymphocytes can be partly reversed following splenectomy.\n                  <\/jats:p>","DOI":"10.1177\/20587384211061051","type":"journal-article","created":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T01:18:45Z","timestamp":1640049525000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["Splenic CD4\n                    <sup>+<\/sup>\n                    and CD8\n                    <sup>+<\/sup>\n                    T-cells highly expressed PD-1 and Tim-3 in cirrhotic patients with HCV infection and portal hypertension"],"prefix":"10.1177","volume":"35","author":[{"given":"Na","family":"Huang","sequence":"first","affiliation":[{"name":"National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zhou","sequence":"additional","affiliation":[{"name":"National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Chen","sequence":"additional","affiliation":[{"name":"National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Zhang","sequence":"additional","affiliation":[{"name":"National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[{"name":"National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"Department of Oncology Surgery, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Sun","sequence":"additional","affiliation":[{"name":"National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Ren","sequence":"additional","affiliation":[{"name":"National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baohua","family":"Li","sequence":"additional","affiliation":[{"name":"National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yang","sequence":"additional","affiliation":[{"name":"National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"Department of Pathology, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1463-8035","authenticated-orcid":false,"given":"Fanpu","family":"Ji","sequence":"additional","affiliation":[{"name":"National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"Department of Infectious Diseases, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"Key Laboratory of Environment and Genes Related to Diseases, Xi\u2019an Jiaotong University, Ministry of Education of China, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongfang","family":"Li","sequence":"additional","affiliation":[{"name":"National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"Key Laboratory of Environment and Genes Related to Diseases, Xi\u2019an Jiaotong University, Ministry of Education of China, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2021,12,20]]},"reference":[{"key":"bibr1-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2016.176"},{"key":"bibr2-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.06.035"},{"key":"bibr3-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.15192"},{"key":"bibr4-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1111\/apt.14507"},{"key":"bibr5-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-00817-w"},{"key":"bibr6-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31160"},{"key":"bibr7-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.06.025"},{"key":"bibr8-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.13370"},{"key":"bibr9-20587384211061051","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00129"},{"key":"bibr10-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-73137-6"},{"key":"bibr11-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.08.008"},{"key":"bibr12-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.13108"},{"key":"bibr13-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-017-1214-8"},{"key":"bibr14-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2018.0121"},{"key":"bibr15-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1089\/vim.2017.0176"},{"key":"bibr16-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.12234"},{"key":"bibr17-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2015.05.008"},{"key":"bibr18-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-014-9586-9"},{"key":"bibr19-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1016\/j.bjid.2013.02.004"},{"key":"bibr20-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2011.04393.x"},{"key":"bibr21-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12158"},{"key":"bibr22-20587384211061051","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v12.i13.2089"},{"key":"bibr23-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20121416"},{"key":"bibr24-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20112741"},{"key":"bibr25-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23173"},{"key":"bibr26-20587384211061051","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2017.00098"},{"key":"bibr27-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00639-09"},{"key":"bibr28-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101513"},{"key":"bibr29-20587384211061051","doi-asserted-by":"publisher","DOI":"10.1007\/s13277-015-4764-5"}],"container-title":["International Journal of Immunopathology and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/20587384211061051","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/20587384211061051","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/20587384211061051","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T10:00:07Z","timestamp":1777456807000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/20587384211061051"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1]]},"references-count":29,"alternative-id":["10.1177\/20587384211061051"],"URL":"https:\/\/doi.org\/10.1177\/20587384211061051","relation":{},"ISSN":["0394-6320","2058-7384"],"issn-type":[{"value":"0394-6320","type":"print"},{"value":"2058-7384","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1]]},"article-number":"20587384211061051"}}