{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:52:27Z","timestamp":1790628747113,"version":"4.1.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T00:00:00Z","timestamp":1611100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    The Nocardia rubra cell wall skeleton (Nr-CWS) for external use is an immune enhancer, which has been widely used in human cervix diseases such as cervical erosion, but the mechanism of Nr-CWS enhancing immunity is still unclear. The purpose of this study was to explore the effect and mechanism of Nr-CWS on the local immune status of cervical tissue in patients with high-risk human papillomavirus (HR-HPV) infection and cervical precancerous lesion, cervical intraepithelial neoplasia (CIN). The recruited patients with HR-HPV infection and CIN were treated with Nr-CWS. The specimens were taken from these patients before and after local application of Nr-CWS respectively. The normal control specimens were tested simultaneously. Serial section analysis of immunohistochemistry and co-expression analysis were performed to characterize populations of T cells and the expressions of programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1). The levels of cytokines in local cervical tissue were also detected. Nr-CWS significantly increased T cells including CD4\n                    <jats:sup>+<\/jats:sup>\n                    , CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, and reduced the expression of PD-L1 in the patients\u2019 local cervical tissues. Co-expression analyses showed that the proportions of PD-1\n                    <jats:sup>+<\/jats:sup>\n                    CD4\n                    <jats:sup>+<\/jats:sup>\n                    cells in CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and PD-1\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    cells in CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells decreased after Nr-CWS application. Furthermore, the increase in the number of immune cells was accompanied by increased pro-inflammatory cytokines interleukin-12 (IL-12), interferon-\u03b3 (IFN-\u03b3), tumor necrosis factor-\u03b1 (TNF-\u03b1), and decreased suppressive cytokine IL-10. The results indicate that Nr-CWS, as an immunotherapeutic agent for HR-HPV infection and CIN, plays an immune promoting role related to the upregulation of T cell subsets and the inhibition of PD-1\/PD-L1 pathway.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2020.612547","type":"journal-article","created":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T02:12:36Z","timestamp":1611108756000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Nocardia Rubra Cell Wall Skeleton Up-Regulates T Cell Subsets and Inhibits PD-1\/PD-L1 Pathway to Promote Local Immune Status of Patients With High-Risk Human Papillomavirus Infection and Cervical Intraepithelial Neoplasia"],"prefix":"10.3389","volume":"11","author":[{"given":"Wei","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunfang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suxia","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuehui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianyu","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianwen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junmin","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(19)30482-6","article-title":"Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis","volume":"8","author":"Arbyn","year":"2020","journal-title":"Lancet Glob Health"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2011.02.003","article-title":"Human papillomavirus (HPV) type distribution in cervical carcinoma, low-grade, and high-grade squamous intraepithelial lesions in Venezuelan women","volume":"121","author":"Correnti","year":"2011","journal-title":"Gynecol Oncol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e190405","DOI":"10.1590\/0074-02760190405","article-title":"Human papillomavirus type 18 E5 oncoprotein cooperates with E6 and E7 in promoting cell viability and invasion and in modulating the cellular redox state","volume":"115","author":"Hochmann","year":"2020","journal-title":"Mem Inst Oswaldo Cruz"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1086\/516784","article-title":"A 2-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion","volume":"195","author":"Plummer","year":"2007","journal-title":"J Infect Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-10-140","article-title":"Papillomavirus E5: the smallest oncoprotein with many functions","volume":"10","author":"Venuti","year":"2011","journal-title":"Mol Cancer"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e0213062","DOI":"10.1371\/journal.pone.0213062","article-title":"Detoxification therapy of traditional Chinese medicine for genital tract high-risk human papillomavirus infection: A systematic review and meta-analysis","volume":"14","author":"Luo","year":"2019","journal-title":"PloS One"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0b013e3182883a34","article-title":"updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors","author":"Massad","year":"2012","journal-title":"Obstet Gynecol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-0528.2008.01936.x","article-title":"Characterising the local immune responses in cervical intraepithelial neoplasia: a cross-sectional and longitudinal analysis","volume":"115","author":"Woo","year":"2008","journal-title":"BJOG"},{"key":"B9","article-title":"Adjuvant and antitumor activities of Nocardia cell-wall skeletons","volume":"67","author":"Azuma","year":"1976","journal-title":"Gan"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/BF01669429","article-title":"Effects of periodic administration of Nocardia rubra cell-wall skeleton on immunoglobulin production and B-cell-stimulatory factor activity in vitro in workers at a poison gas factory","volume":"30","author":"Hozawa","year":"1989","journal-title":"Cancer Immunol Immunother"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1177\/0300060518764210","article-title":"Nocardia rubra cell wall skeleton accelerates cutaneous wound healing by enhancing macrophage activation and angiogenesis","volume":"46","author":"Wang","year":"2018","journal-title":"J Int Med Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.28182","article-title":"The biological macromolecule Nocardia rubra cell-wall skeleton as an avenue for cell-based immunotherapy","author":"Meng","year":"2019","journal-title":"J Cell Physiol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.ijbiomac.2017.03.060","article-title":"Nocardia rubra cell-wall skeleton promotes CD4(+) T cell activation and drives Th1 immune response","volume":"101","author":"Wang","year":"2017","journal-title":"Int J Biol Macromol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2019.106023","article-title":"Functional modulation of CD8+ T cell by approved novel immune enhancer: Nocardia rubra Cell-Wall Skeletons (Nr-CWS)","volume":"78","author":"Tao","year":"2020","journal-title":"Int Immunopharmacol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.14670\/HH-11-644","article-title":"Transcription factors GATA4 and TBX5 promote cardiomyogenic differentiation of rat bone marrow mesenchymal stromal cells","volume":"30","author":"Chen","year":"2015","journal-title":"Histol Histopathol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.7860\/JCDR\/2015\/12432.5628","article-title":"A comparison of manual and automated methods of quantitation of oestrogen\/progesterone receptor expression in breast carcinoma","volume":"9","author":"Vijayashree","year":"2015","journal-title":"J Clin Diagn Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.gore.2020.100608","article-title":"Topical therapies for the treatment of cervical intraepithelial neoplasia (CIN) 2-3: A narrative review","volume":"33","author":"Desravines","year":"2020","journal-title":"Gynecol Oncol Rep"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.issn.0529-567X.2017.11.005","article-title":"[Natural changes of high-risk HPV in women with negative for intraepithelial lesion or malignancy: a prospective 1 year study]","volume":"52","author":"He","year":"2017","journal-title":"Zhonghua Fu Chan Ke Za Zhi"},{"key":"B19","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.imlet.2015.10.016","article-title":"Evaluation of T, B and natural killer lymphocyte in the cervical stroma of HIV-positive and negative patients with cervical intraepithelial neoplasia","volume":"169","author":"Lucena","year":"2016","journal-title":"Immunol Lett"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S217264","article-title":"Infiltrating CD4 and CD8 lymphocytes in HPV infected uterine cervical milieu","volume":"11","author":"Maskey","year":"2019","journal-title":"Cancer Manag Res"},{"key":"B21","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1034\/j.1600-0897.2003.01109.x","article-title":"Distinct T cell subsets and cytokine production in cultures derived from transformation zone and squamous intraepithelial lesion biopsies of the uterine cervix","volume":"49","author":"Jacobs","year":"2003","journal-title":"Am J Reprod Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2012.09.010","article-title":"Interaction of epithelial biomarkers, local immune response and condom use in cervical intraepithelial neoplasia 2-3 regression","volume":"127","author":"Munk","year":"2012","journal-title":"Gynecol Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2010.109","article-title":"Local immune response in the microenvironment of CIN2-3 with and without spontaneous regression","volume":"23","author":"Ovestad","year":"2010","journal-title":"Mod Pathol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-3388","article-title":"High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer","volume":"67","author":"Piersma","year":"2007","journal-title":"Cancer Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2017.7105","article-title":"Expression and clinical significance of programmed death-1 on lymphocytes and programmed death ligand-1 on monocytes in the peripheral blood of patients with cervical cancer","volume":"14","author":"Zhang","year":"2017","journal-title":"Oncol Lett"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetimm.2009.10.006","article-title":"Structure and function of programmed death (PD) molecules","volume":"134","author":"Folkl","year":"2010","journal-title":"Vet Immunol Immunopathol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2015.108","article-title":"Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers","volume":"28","author":"Mezache","year":"2015","journal-title":"Mod Pathol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12101","article-title":"Increased expression of programmed death (PD)-1 and its ligand PD-L1 correlates with impaired cell-mediated immunity in high-risk human papillomavirus-related cervical intraepithelial neoplasia","volume":"139","author":"Yang","year":"2013","journal-title":"Immunology"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/jog.13411","article-title":"Expressions of programmed death (PD)-1 and PD-1 ligand (PD-L1) in cervical intraepithelial neoplasia and cervical squamous cell carcinomas are of prognostic value and associated with human papillomavirus status","volume":"43","author":"Yang","year":"2017","journal-title":"J Obstet Gynaecol Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2015.02.008","article-title":"Overcoming T cell exhaustion in infection and cancer","volume":"36","author":"Pauken","year":"2015","journal-title":"Trends Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-041015-055318","article-title":"CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer","volume":"37","author":"McLane","year":"2019","journal-title":"Annu Rev Immunol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.immuni.2014.01.005","article-title":"Molecular and transcriptional basis of CD4(+) T cell dysfunction during chronic infection","volume":"40","author":"Crawford","year":"2014","journal-title":"Immunity"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.612547\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T02:12:38Z","timestamp":1611108758000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.612547\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,20]]},"references-count":33,"alternative-id":["10.3389\/fimmu.2020.612547"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2020.612547","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,20]]},"article-number":"612547"}}