{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:55:04Z","timestamp":1790834104045,"version":"4.1.0"},"reference-count":50,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>T-cell anergy is a tolerance mechanism defined as a hyporesponsive status of antigen-specific T cells upon prior antigen encounter and is believed to play a critical role in the evasion of tumor immunity and the amelioration of allogeneic transplant rejection. Molecular mechanisms in controlling T-cell anergy are less known. We show here that administration of an agonistic monoclonal antibody (mAb) to CD137, a member of the tumor necrosis factor receptor superfamily, prevents the induction of CD8+ cytolytic T-lymphocyte (CTL) anergy by soluble antigens. More importantly, CD137 mAb restores the functions of established anergic CTLs upon reencountering their cognate antigen. As a result, infusion of CD137 mAb inhibits progressive tumor growth that is caused by soluble tumor antigen-induced tolerance in a P815R model. CD137 mAb also restores proliferation and effector functions of anergic alloreactive 2C T cells in a bone marrow transplantation model. Our results indicate that ligation of CD137 receptor delivers a regulatory signal for T-cell anergy and implicate manipulation of the CD137 pathway as a new approach to break T-cell tolerance.<\/jats:p>","DOI":"10.1182\/blood-2003-06-2184","type":"journal-article","created":{"date-parts":[[2003,9,16]],"date-time":"2003-09-16T00:48:15Z","timestamp":1063673295000},"page":"177-184","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":92,"title":["Ligation of CD137 receptor prevents and reverses established anergy of CD8+ cytolytic T lymphocytes in vivo"],"prefix":"10.1182","volume":"103","author":[{"given":"Ryan A.","family":"Wilcox","sequence":"first","affiliation":[{"name":"From the Department of Immunology, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, MN; Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis; and Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Tamada","sequence":"additional","affiliation":[{"name":"From the Department of Immunology, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, MN; Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis; and Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dallas B.","family":"Flies","sequence":"additional","affiliation":[{"name":"From the Department of Immunology, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, MN; Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis; and Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gefeng","family":"Zhu","sequence":"additional","affiliation":[{"name":"From the Department of Immunology, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, MN; Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis; and Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei I.","family":"Chapoval","sequence":"additional","affiliation":[{"name":"From the Department of Immunology, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, MN; Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis; and Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce R.","family":"Blazar","sequence":"additional","affiliation":[{"name":"From the Department of Immunology, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, MN; Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis; and Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Martin","family":"Kast","sequence":"additional","affiliation":[{"name":"From the Department of Immunology, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, MN; Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis; and Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lieping","family":"Chen","sequence":"additional","affiliation":[{"name":"From the Department of Immunology, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, MN; Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis; and Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2020021223155137900_REF1","doi-asserted-by":"crossref","unstructured":"Schwartz RH. T cell anergy. 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Role of TNF receptor-associated factor 2 and p38 mitogen-activated protein kinase activation during 4-1BB-dependent immune response. J Immunol. 2000; 165: 6193-6204.","DOI":"10.4049\/jimmunol.165.11.6193"},{"key":"2020021223155137900_REF43","unstructured":"Tan JT, Ha J, Cho HR, et al. Analysis of expression and function of the costimulatory molecule 4-1BB in alloimmune responses. Transplantation. 2000;70: 175-183."},{"key":"2020021223155137900_REF44","doi-asserted-by":"crossref","unstructured":"Wekerle T, Kurtz J, Bigenzahn S, Takeuchi Y, Sykes M. Mechanisms of transplant tolerance induction using costimulatory blockade. Curr Opin Immunol. 2002;14: 592-600.","DOI":"10.1016\/S0952-7915(02)00378-3"},{"key":"2020021223155137900_REF45","doi-asserted-by":"crossref","unstructured":"Taylor PA, Noelle RJ, Blazar BR. CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. 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