{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T13:03:37Z","timestamp":1791032617345,"version":"4.1.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2011,2,24]],"date-time":"2011-02-24T00:00:00Z","timestamp":1298505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,4,8]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Lymphocyte-activation gene-3 (LAG-3, CD223) is a marker for recently activated effector T cells. Activated T lymphocytes are of major importance in many autoimmune diseases and organ transplant rejection. Therefore, specifically depleting LAG-3+ T cells might lead to targeted immunosuppression that would spare resting T cells while eliminating pathogenic activated T cells. We have shown previously that anti-LAG-3 antibodies sharing depleting as well as modulating activities inhibit heart allograft rejection in rats. Here, we have developed and characterized a cytotoxic LAG-3 chimeric antibody (chimeric A9H12), and evaluated its potential as a selective therapeutic depleting agent in a non-human primate model of delayed-type hypersensitivity (DTH). Chimeric A9H12 showed a high affinity to its antigen and depleted both cytomegalovirus (CMV)-activated CD4+ and CD8+ human T lymphocytes in vitro. In vivo, a single intravenous injection at either 1 or 0\u00b71\u2003mg\/kg was sufficient to deplete LAG-3+-activated T cells in lymph nodes and to prevent the T helper type 1 (Th1)-driven skin inflammation in a tuberculin-induced DTH model in baboons. T lymphocyte and macrophage infiltration into the skin was also reduced. The in vivo effect was long-lasting, as several weeks to months were required after injection to restore a positive reaction after antigen challenge. Our data confirm that LAG-3 is a promising therapeutic target for depleting antibodies that might lead to higher therapeutic indexes compared to traditional immunosuppressive agents in autoimmune diseases and transplantation.<\/jats:p>","DOI":"10.1111\/j.1365-2249.2011.04329.x","type":"journal-article","created":{"date-parts":[[2011,2,26]],"date-time":"2011-02-26T14:11:30Z","timestamp":1298729490000},"page":"265-274","source":"Crossref","is-referenced-by-count":34,"title":["Antibody-mediated depletion of lymphocyte-activation gene-3 (LAG-3+)-activated T lymphocytes prevents delayed-type hypersensitivity in non-human primates"],"prefix":"10.1093","volume":"164","author":[{"given":"N","family":"Poirier","sequence":"first","affiliation":[{"name":"INSERM, UMR643; Institut de Transplantation Urologie Nephrologie (ITUN), CHU de Nantes, Facult\u00e9 de M\u00e9decine, Nantes"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Haudebourg","sequence":"additional","affiliation":[{"name":"INSERM, UMR643; Institut de Transplantation Urologie Nephrologie (ITUN), CHU de Nantes, Facult\u00e9 de M\u00e9decine, Nantes"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Brignone","sequence":"additional","affiliation":[{"name":"Immutep SA, Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Dilek","sequence":"additional","affiliation":[{"name":"INSERM, UMR643; Institut de Transplantation Urologie Nephrologie (ITUN), CHU de Nantes, Facult\u00e9 de M\u00e9decine, Nantes"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Hervouet","sequence":"additional","affiliation":[{"name":"INSERM, UMR643; Institut de Transplantation Urologie Nephrologie (ITUN), CHU de Nantes, Facult\u00e9 de M\u00e9decine, Nantes"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Minault","sequence":"additional","affiliation":[{"name":"INSERM, UMR643; Institut de Transplantation Urologie Nephrologie (ITUN), CHU de Nantes, Facult\u00e9 de M\u00e9decine, Nantes"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Coulon","sequence":"additional","affiliation":[{"name":"INSERM, UMR643; Institut de Transplantation Urologie Nephrologie (ITUN), CHU de Nantes, Facult\u00e9 de M\u00e9decine, Nantes"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R V","family":"de Silly","sequence":"additional","affiliation":[{"name":"INSERM, UMR643; Institut de Transplantation Urologie Nephrologie (ITUN), CHU de Nantes, Facult\u00e9 de M\u00e9decine, Nantes"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Triebel","sequence":"additional","affiliation":[{"name":"Immutep SA, Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Blancho","sequence":"additional","affiliation":[{"name":"INSERM, UMR643; Institut de Transplantation Urologie Nephrologie (ITUN), CHU de Nantes, Facult\u00e9 de M\u00e9decine, Nantes"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B","family":"Vanhove","sequence":"additional","affiliation":[{"name":"INSERM, UMR643; Institut de Transplantation Urologie Nephrologie (ITUN), CHU de Nantes, Facult\u00e9 de M\u00e9decine, Nantes"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,2,24]]},"reference":[{"key":"2021122708475478500_b1","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1128\/CMR.00040-08","article-title":"Infectious complications associated with monoclonal antibodies and related small molecules","volume":"22","author":"Salvana","year":"2009","journal-title":"Clin Microbiol Rev"},{"key":"2021122708475478500_b2","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1097\/00007890-200005270-00034","article-title":"Prolonged allograft survival through conditional and specific ablation of alloreactive T cells expressing a suicide gene","volume":"69","author":"Thomas-Vaslin","year":"2000","journal-title":"Transplantation"},{"key":"2021122708475478500_b3","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1084\/jem.171.5.1393","article-title":"LAG-3, a novel lymphocyte activation gene closely related to CD4","volume":"171","author":"Triebel","year":"1990","journal-title":"J Exp Med"},{"key":"2021122708475478500_b4","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.it.2003.10.001","article-title":"LAG-3: a regulator of T-cell and DC responses and its use in therapeutic vaccination","volume":"24","author":"Triebel","year":"2003","journal-title":"Trends Immunol"},{"key":"2021122708475478500_b5","doi-asserted-by":"crossref","first-page":"5744","DOI":"10.1073\/pnas.94.11.5744","article-title":"Characterization of the major histocompatibility complex class II binding site on LAG-3 protein","volume":"94","author":"Huard","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021122708475478500_b6","doi-asserted-by":"crossref","first-page":"2748","DOI":"10.4049\/jimmunol.162.5.2748","article-title":"Lymphocyte activation gene-3, a MHC class II ligand expressed on activated T cells, stimulates TNF-alpha and IL-12 production by monocytes and dendritic cells","volume":"162","author":"Avice","year":"1999","journal-title":"J Immunol"},{"key":"2021122708475478500_b7","doi-asserted-by":"crossref","first-page":"3874","DOI":"10.4049\/jimmunol.168.8.3874","article-title":"Maturation and activation of dendritic cells induced by lymphocyte activation gene-3 (CD223)","volume":"168","author":"Andreae","year":"2002","journal-title":"J Immunol"},{"key":"2021122708475478500_b8","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.4049\/jimmunol.0800185","article-title":"LAG-3 regulates plasmacytoid dendritic cell homeostasis","volume":"182","author":"Workman","year":"2009","journal-title":"J Immunol"},{"key":"2021122708475478500_b9","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/BF00241263","article-title":"Cellular expression and tissue distribution of the human LAG-3-encoded protein, an MHC class II ligand","volume":"39","author":"Huard","year":"1994","journal-title":"Immunogenetics"},{"key":"2021122708475478500_b10","doi-asserted-by":"crossref","first-page":"4058","DOI":"10.4049\/jimmunol.161.8.4058","article-title":"CD3\/TCR complex-associated LAG-3 molecules inhibit CD3\/TCR signaling","volume":"161","author":"Hannier","year":"1998","journal-title":"J Immunol"},{"key":"2021122708475478500_b11","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1002\/eji.200323382","article-title":"The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells","volume":"33","author":"Workman","year":"2003","journal-title":"Eur J Immunol"},{"key":"2021122708475478500_b12","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1111\/j.1365-2567.2005.02145.x","article-title":"The negative regulatory function of the lymphocyte-activation gene-3 co-receptor (CD223) on human T cells","volume":"115","author":"Macon-Lemaitre","year":"2005","journal-title":"Immunology"},{"key":"2021122708475478500_b13","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.immuni.2004.08.010","article-title":"Role of LAG-3 in regulatory T cells","volume":"21","author":"Huang","year":"2004","journal-title":"Immunity"},{"key":"2021122708475478500_b14","doi-asserted-by":"crossref","first-page":"13974","DOI":"10.1073\/pnas.0906872106","article-title":"CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2","volume":"106","author":"Okamura","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021122708475478500_b15","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1097\/01.tp.0000282865.84743.9c","article-title":"Depletion of LAG-3 positive cells in cardiac allograft reveals their role in rejection and tolerance","volume":"84","author":"Haudebourg","year":"2007","journal-title":"Transplantation"},{"key":"2021122708475478500_b16","doi-asserted-by":"crossref","first-page":"7","DOI":"10.5070\/D32FW0G1XX","article-title":"Delayed type hypersensitivity: current theories with an historic perspective","volume":"5","author":"Black","year":"1999","journal-title":"Dermatol Online J"},{"key":"2021122708475478500_b17","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/0022-1759(87)90507-2","article-title":"Injection of physiological saline facilitates recovery of ascitic fluids for monoclonal antibody production","volume":"104","author":"Coll","year":"1987","journal-title":"J Immunol Methods"},{"key":"2021122708475478500_b18","doi-asserted-by":"crossref","first-page":"8789","DOI":"10.1073\/pnas.94.16.8789","article-title":"CTLA4Ig and anti-CD40 ligand prevent renal allograft rejection in primates","volume":"94","author":"Kirk","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021122708475478500_b19","doi-asserted-by":"crossref","first-page":"8164","DOI":"10.4049\/jimmunol.179.12.8164","article-title":"Anti-CD28 antibodies modify regulatory mechanisms and reinforce tolerance in CD40Ig-treated heart allograft recipients","volume":"179","author":"Guillonneau","year":"2007","journal-title":"J Immunol"},{"key":"2021122708475478500_b20","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1038\/nm931","article-title":"Fc-dependent depletion of activated T cells occurs through CD40L-specific antibody rather than costimulation blockade","volume":"9","author":"Monk","year":"2003","journal-title":"Nat Med"},{"key":"2021122708475478500_b21","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1093\/intimm\/dxh162","article-title":"The contribution of Fc effector mechanisms in the efficacy of anti-CD154 immunotherapy depends on the nature of the immune challenge","volume":"16","author":"Ferrant","year":"2004","journal-title":"Int Immunol"},{"key":"2021122708475478500_b22","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.molimm.2007.08.006","article-title":"Platelet pro-aggregatory effects of CD40L monoclonal antibody","volume":"45","author":"Mirabet","year":"2008","journal-title":"Mol Immunol"},{"key":"2021122708475478500_b23","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/j.1600-065X.1992.tb01422.x","article-title":"Interleukin-2 receptor-directed immunosuppressive therapies: antibody- or cytokine-based targeting molecules","volume":"129","author":"Strom","year":"1992","journal-title":"Immunol Rev"},{"key":"2021122708475478500_b24","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1097\/01.TP.0000155179.61445.78","article-title":"Critical influence of natural regulatory CD25+ T cells on the fate of allografts in the absence of immunosuppression","volume":"79","author":"Benghiat","year":"2005","journal-title":"Transplantation"},{"key":"2021122708475478500_b25","doi-asserted-by":"crossref","first-page":"6545","DOI":"10.4049\/jimmunol.0903879","article-title":"LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites","volume":"184","author":"Camisaschi","year":"2010","journal-title":"J Immunol"},{"key":"2021122708475478500_b26","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1172\/JCI40926","article-title":"Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice","volume":"120","author":"Tomura","year":"2010","journal-title":"J Clin Invest"},{"key":"2021122708475478500_b27","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1126\/science.178.4062.757","article-title":"Transfer factor: delayed hypersensitivity to Schistosoma mansoni and tuberculin in Macaca mulatta","volume":"178","author":"Maddison","year":"1972","journal-title":"Science"},{"key":"2021122708475478500_b28","first-page":"63","article-title":"Modeling of delayed type hypersensitivity (DTH) in the non-human primate (NHP)","volume":"5","author":"Cordoba","year":"2008","journal-title":"Drug Discov Today"},{"key":"2021122708475478500_b29","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/jemt.1090","article-title":"Immunopathogenesis of delayed-type hypersensitivity","volume":"53","author":"Kobayashi","year":"2001","journal-title":"Microsc Res Tech"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1365-2249.2011.04329.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/164\/2\/265\/41909351\/j.1365-2249.2011.04329.x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/164\/2\/265\/41909351\/j.1365-2249.2011.04329.x.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,5]],"date-time":"2023-06-05T12:11:01Z","timestamp":1685967061000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/164\/2\/265\/6429042"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,2,24]]},"references-count":29,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2011,2,24]]},"published-print":{"date-parts":[[2011,4,8]]}},"URL":"https:\/\/doi.org\/10.1111\/j.1365-2249.2011.04329.x","relation":{},"ISSN":["0009-9104","1365-2249"],"issn-type":[{"value":"0009-9104","type":"print"},{"value":"1365-2249","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2011,5]]},"published":{"date-parts":[[2011,2,24]]}}}