{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T05:02:13Z","timestamp":1767848533423,"version":"3.49.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T00:00:00Z","timestamp":1726790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000038","name":"HHS | U.S. Food and Drug Administration","doi-asserted-by":"publisher","award":["FD003539-01"],"award-info":[{"award-number":["FD003539-01"]}],"id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI097423"],"award-info":[{"award-number":["AI097423"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001258","name":"Roche Organ Transplant Research Foundation","doi-asserted-by":"publisher","award":["346678023"],"award-info":[{"award-number":["346678023"]}],"id":[{"id":"10.13039\/501100001258","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Alemtuzumab induction with belatacept\/rapamycin-based maintenance immunotherapy (ABR) prevents kidney allograft rejection and specifically limits early costimulation blockade\u2013resistant rejection (CoBRR). To evaluate the mechanisms by which this regimen alters CoBRR, we characterized the phenotype and functional response of preexisting memory cells to allogeneic endothelial cells using intracellular cytokine staining and flow cytometry. IL-7\u2013induced lymphocyte proliferation in the presence or absence of rapamycin was assessed to characterize the phenotype of proliferating cells. Lymphocytes from 40 recipients who underwent transplant using the ABR regimen were studied longitudinally. The rapid immunoresponses of preexisting alloreactive cells to allogeneic endothelial cells were predominantly CD8+TNF-\u03b1+\/IFN-\u03b3+ cells. These cells were effector memory (TEM) and terminally differentiated effector memory cells lacking CD28 expression, and most were CD57+PD1\u2212. Neither rapamycin nor belatacept directly inhibited these cells. IL-7, a cytokine induced during lymphopenia postdepletion, provoked dramatic CD8+ TEM cell proliferation and a low level of CD8+CD57+PD1\u2212 cell expansion in vitro. The IL-7 stimulation induced CD8+ cell mTOR phosphorylation, and rapamycin treatment markedly inhibited IL-7\u2013induced TEM and CD57+PD1\u2212 cell expansion. This effect was evident in patients receiving the ABR in that the repopulation of CD8+CD57+PD1\u2212 TEM cells was substantially suppressed for at least 36 mo after transplant. These findings help define one mechanism by which a costimulation blockade\/rapamycin-based therapy following alemtuzumab induction minimizes CoBRR, namely that in the presence of rapamycin, costimulation-resistant alloreactive cells are disproportionately ineffective at repopulating following post-transplant T cell depletion.<\/jats:p>","DOI":"10.4049\/jimmunol.2400146","type":"journal-article","created":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T12:42:13Z","timestamp":1726836133000},"page":"1305-1317","source":"Crossref","is-referenced-by-count":3,"title":["Rapamycin Prevents Expansion of Costimulation Blockade-resistant CD8+ Alloreactive Memory Cells following Depletional Induction in Renal Transplant Recipients"],"prefix":"10.1093","volume":"213","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7190-2943","authenticated-orcid":false,"given":"Shu","family":"Li","sequence":"first","affiliation":[{"name":"Department of Surgery, Duke University School of Medicine , Durham, NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qimeng","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University School of Medicine , Durham, NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"He","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University School of Medicine , Durham, NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2004-5962","authenticated-orcid":false,"given":"Allan D","family":"Kirk","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University School of Medicine , Durham, NC"},{"name":"Department of Integrative Immunobiology, Duke University School of Medicine , Durham, NC"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,9,20]]},"reference":[{"key":"2025020609280857700_r1","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1111\/ajt.12712","article-title":"Renal transplantation using belatacept without maintenance steroids or calcineurin inhibitors","volume":"14","author":"Kirk","year":"2014","journal-title":"Am. 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