{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T04:09:17Z","timestamp":1768795757754,"version":"3.49.0"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,10,16]],"date-time":"2015-10-16T00:00:00Z","timestamp":1444953600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,10,16]],"date-time":"2015-10-16T00:00:00Z","timestamp":1444953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Belatacept blocks CD28-mediated T-cell costimulation and prevents renal transplant rejection. Understanding T-cell subset sensitivity to belatacept may identify cellular markers for immunosuppression failure to better guide treatment selection. Here, we evaluate the belatacept sensitivity of allo-antigen-specific CD154-expressing-T-cells, whose T-cytotoxic memory (TcM) subset predicts rejection with high sensitivity after non-renal transplantation. The belatacept concentration associated with half-maximal reduction (EC<jats:sub>50<\/jats:sub>) of CD154 expression was calculated for 36 T-cell subsets defined by combinations of T-helper (Th), Tc, T-memory and CD28 receptors, following allostimulation of peripheral blood leukocytes from 20 normal healthy subjects. Subsets were ranked by median EC<jats:sub>50<\/jats:sub> and by whether subset EC<jats:sub>50<\/jats:sub> was correlated with and therefore could be represented by the frequency of other subsets. No single subset frequency emerged as the significant correlate of EC<jats:sub>50<\/jats:sub> for a given subset. Most (n\u2009=\u200925) T-cell subsets were sensitive to belatacept. Less sensitive subsets demonstrated a memory phenotype and absence of CD28 receptor. Potential drug-resistance markers for future validation include the low frequency highly differentiated, Th-memory-CD28-negative T-cells with the highest median EC<jats:sub>50<\/jats:sub> and the least differentiated, high-frequency Tc subset, with the most CD28-negative T-cells, the third highest median EC<jats:sub>50<\/jats:sub> and significant correlations with frequencies of the highest number of CD28-negative and memory subsets.<\/jats:p>","DOI":"10.1038\/srep15218","type":"journal-article","created":{"date-parts":[[2015,10,16]],"date-time":"2015-10-16T09:33:40Z","timestamp":1444988020000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Alloreactive CD154-expressing T-cell subsets with differential sensitivity to the immunosuppressant, belatacept: potential targets of novel belatacept-based regimens"],"prefix":"10.1038","volume":"5","author":[{"given":"Chethan","family":"Ashokkumar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bishu","family":"Ganguly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Townsend","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaimie","family":"White","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha","family":"Levy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Moritz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Mazariegos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rakesh","family":"Sindhi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,10,16]]},"reference":[{"key":"BFsrep15218_CR1","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1111\/j.1600-6143.2009.03005.x","volume":"10","author":"F Vincenti","year":"2010","unstructured":"Vincenti, F. et al. A Phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT Study). Am. J. Transplant. 10, 535\u2013546 (2010).","journal-title":"Am. J. Transplant."},{"key":"BFsrep15218_CR2","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1111\/j.1600-6143.2005.00749.x","volume":"5","author":"CP Larsen","year":"2005","unstructured":"Larsen, C. P. et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am. J. Transplant. 5, 443\u2013453 (2005).","journal-title":"Am. J. Transplant."},{"key":"BFsrep15218_CR3","doi-asserted-by":"publisher","first-page":"2007","DOI":"10.1084\/jem.182.6.2007","volume":"182","author":"SM Behar","year":"1995","unstructured":"Behar, S. M., Porcelli, S. A., Beckman, E. M. & Brenner, M. B. A pathway of costimulation that prevents anergy in CD28-T-cells: B7-independent costimulation of CD1-restricted T cells. J. Exp. 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Transplantation 99, 164\u2013170 (2015).","journal-title":"Transplantation"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep15218.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep15218","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep15218.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T15:20:39Z","timestamp":1672932039000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep15218"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10,16]]},"references-count":24,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,12,7]]}},"alternative-id":["BFsrep15218"],"URL":"https:\/\/doi.org\/10.1038\/srep15218","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,10,16]]},"assertion":[{"value":"12 March 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 September 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 October 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Test systems are based on technology described in US Patent 8759016. Inventor: Rakesh Sindhi. Assignee: University of Pittsburgh-of the Commonwealth System of Higher Education, Pittsburgh, PA. and licensed to Plexision, Inc., Pittsburgh, PA 15224, in which the University holds equity. Rakesh Sindhi serves as an unpaid consultant and Chethan Ashokkumar as a paid consultant to licensee without other financial relationships. Disclosed conflicts of interest have been managed in accordance with the University of Pittsburgh\u2019s policies and procedures.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"15218"}}