{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T14:54:39Z","timestamp":1782485679495,"version":"3.54.5"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2016,5,13]],"date-time":"2016-05-13T00:00:00Z","timestamp":1463097600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC127"],"award-info":[{"award-number":["CRC127"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0155676","type":"journal-article","created":{"date-parts":[[2016,5,13]],"date-time":"2016-05-13T17:40:10Z","timestamp":1463161210000},"page":"e0155676","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":39,"title":["Ubiquitous LEA29Y Expression Blocks T Cell Co-Stimulation but Permits Sexual Reproduction in Genetically Modified Pigs"],"prefix":"10.1371","volume":"11","author":[{"given":"Andrea","family":"B\u00e4hr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"K\u00e4ser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Kemter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilhelm","family":"Gerner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayuko","family":"Kurome","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiebke","family":"Baars","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadja","family":"Herbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsti","family":"Witter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annegret","family":"W\u00fcnsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie C.","family":"Talker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Kessler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Nagashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armin","family":"Saalm\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Schwinzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eckhard","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolai","family":"Klymiuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2016,5,13]]},"reference":[{"issue":"5","key":"ref1","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1111\/xen.12129","article-title":"The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of xenocorneal transplantation","volume":"21","author":"MK Kim","year":"2014","journal-title":"Xenotransplantation"},{"issue":"6","key":"ref2","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.1016\/j.transproceed.2014.06.008","article-title":"Clinical porcine islet xenotransplantation under comprehensive regulation","volume":"46","author":"S Matsumoto","year":"2014","journal-title":"Transplantation proceedings"},{"issue":"2","key":"ref3","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1111\/ajt.12562","article-title":"One-year heterotopic cardiac xenograft survival in a pig to baboon model","volume":"14","author":"MM Mohiuddin","year":"2014","journal-title":"American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons"},{"issue":"2","key":"ref4","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1002\/path.4635","article-title":"The role of genetically engineered pigs in xenotransplantation research","volume":"238","author":"DK Cooper","year":"2016","journal-title":"J Pathol"},{"issue":"1","key":"ref5","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1097\/TP.0b013e318191c784","article-title":"HLA-E\/human beta2-microglobulin transgenic pigs: protection against xenogeneic human anti-pig natural killer cell cytotoxicity","volume":"87","author":"EH Weiss","year":"2009","journal-title":"Transplantation"},{"issue":"6","key":"ref6","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.2337\/db11-1325","article-title":"Xenografted islet cell clusters from INSLEA29Y transgenic pigs rescue diabetes and prevent immune rejection in humanized mice","volume":"61","author":"N Klymiuk","year":"2012","journal-title":"Diabetes"},{"issue":"4","key":"ref7","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/s11248-004-7268-4","article-title":"Transgenic expression of CTLA4-Ig by fetal pig neurons for xenotransplantation","volume":"14","author":"C Martin","year":"2005","journal-title":"Transgenic research"},{"issue":"2","key":"ref8","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s11248-014-9833-9","article-title":"Transgenic expression of human cytoxic T-lymphocyte associated antigen4-immunoglobulin (hCTLA4Ig) by porcine skin for xenogeneic skin grafting","volume":"24","author":"Y Wang","year":"2015","journal-title":"Transgenic research"},{"issue":"3","key":"ref9","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1096\/fj.11-185041","article-title":"First inducible transgene expression in porcine large animal models","volume":"26","author":"N Klymiuk","year":"2012","journal-title":"FASEB journal: official publication of the Federation of American Societies for Experimental Biology"},{"issue":"6","key":"ref10","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1111\/j.1399-3089.2009.00533.x","article-title":"Production and characterization of transgenic pigs expressing porcine CTLA4-Ig","volume":"16","author":"CJ Phelps","year":"2009","journal-title":"Xenotransplantation"},{"key":"ref11","first-page":"95","article-title":"BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95\/98\/NT","volume":"41","author":"TA Hall","year":"1999","journal-title":"Nucl Acids Symp Ser"},{"issue":"6828","key":"ref12","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/35069112","article-title":"Structural basis for co-stimulation by the human CTLA-4\/B7-2 complex","volume":"410","author":"JC Schwartz","year":"2001","journal-title":"Nature"},{"issue":"9","key":"ref13","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1369\/jhc.2010.955377","article-title":"Tissue and cellular expression patterns of porcine CFTR: similarities to and differences from human CFTR","volume":"58","author":"S Plog","year":"2010","journal-title":"The journal of histochemistry and cytochemistry: official journal of the Histochemistry Society"},{"issue":"1","key":"ref14","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1073\/pnas.2235688100","article-title":"Electroporation and RNA interference in the rodent retina in vivo and in vitro","volume":"101","author":"T Matsuda","year":"2004","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"7","key":"ref15","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/0092-8674(91)90011-M","article-title":"Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene","volume":"65","author":"VL Tybulewicz","year":"1991","journal-title":"Cell"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/978-1-4939-1594-1_4","article-title":"Nuclear transfer and transgenesis in the pig","volume":"1222","author":"M Kurome","year":"2015","journal-title":"Methods in molecular biology"},{"issue":"7","key":"ref17","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1097\/TP.0b013e31819c85e8","article-title":"Suppression of human T-cell activation and expansion of regulatory T cells by pig cells overexpressing PD-ligands","volume":"87","author":"A Plege","year":"2009","journal-title":"Transplantation"},{"issue":"6","key":"ref18","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.4049\/jimmunol.138.6.1852","article-title":"Monoclonal antibodies reactive with swine lymphocytes. II. Detection of an antigen on resting T cells down-regulated after activation","volume":"138","author":"A Saalmuller","year":"1987","journal-title":"Journal of immunology"},{"issue":"14","key":"ref19","doi-asserted-by":"crossref","first-page":"4395","DOI":"10.1073\/pnas.79.14.4395","article-title":"Clonal analysis of human cytotoxic T lymphocytes: T4+ and T8+ effector T cells recognize products of different major histocompatibility complex regions","volume":"79","author":"SC Meuer","year":"1982","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"4","key":"ref20","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/S0093-691X(98)00166-6","article-title":"Cryopreservation and ensuing in vitro fertilization ability of boar spermatozoa from epididymides stored at 4 degrees C","volume":"50","author":"K Kikuchi","year":"1998","journal-title":"Theriogenology"},{"issue":"6","key":"ref21","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.1095\/biolreprod.103.020081","article-title":"Production of piglets derived from in vitro-produced blastocysts fertilized and cultured in chemically defined media: effects of theophylline, adenosine, and cysteine during in vitro fertilization","volume":"69","author":"K Yoshioka","year":"2003","journal-title":"Biology of reproduction"},{"issue":"3","key":"ref22","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1111\/j.1600-6143.2005.00749.x","article-title":"Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties","volume":"5","author":"CP Larsen","year":"2005","journal-title":"American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons"},{"issue":"1","key":"ref23","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.dci.2013.01.003","article-title":"Phenotypic maturation of porcine NK- and T-cell subsets","volume":"40","author":"SC Talker","year":"2013","journal-title":"Developmental and comparative immunology"},{"issue":"3\u20134","key":"ref24","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S0165-2427(02)00045-4","article-title":"T-helper cells from naive to committed","volume":"87","author":"A Saalmuller","year":"2002","journal-title":"Veterinary immunology and immunopathology"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/1297-9716-44-18","article-title":"CD27 expression discriminates porcine T helper cells with functionally distinct properties","volume":"44","author":"K Reutner","year":"2013","journal-title":"Vet Res"},{"issue":"8","key":"ref26","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1016\/j.theriogenology.2008.06.004","article-title":"Boar semen variability and its effects on IVF efficiency","volume":"70","author":"MA Gil","year":"2008","journal-title":"Theriogenology"},{"issue":"6","key":"ref27","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1262\/jrd.2013-069","article-title":"Production of diabetic offspring using cryopreserved epididymal sperm by in vitro fertilization and intrafallopian insemination techniques in transgenic pigs","volume":"59","author":"K Umeyama","year":"2013","journal-title":"J Reprod Dev"},{"issue":"8","key":"ref28","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1111\/ajt.12810","article-title":"Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II randomized study","volume":"14","author":"GB Klintmalm","year":"2014","journal-title":"American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons"},{"issue":"3","key":"ref29","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1111\/ajt.12600","article-title":"High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept","volume":"14","author":"SM Krummey","year":"2014","journal-title":"American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons"},{"issue":"11","key":"ref30","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1517\/14712598.2013.845661","article-title":"T-cell co-stimulatory blockade in transplantation: two steps forward one step back!","volume":"13","author":"LV Riella","year":"2013","journal-title":"Expert opinion on biological therapy"},{"issue":"5","key":"ref31","doi-asserted-by":"crossref","first-page":"274","DOI":"10.2174\/157339910793360897","article-title":"Gene therapy to improve pancreatic islet transplantation for Type 1 diabetes mellitus","volume":"6","author":"A Hughes","year":"2010","journal-title":"Current diabetes reviews"},{"issue":"9816","key":"ref32","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/S0140-6736(11)61091-X","article-title":"Clinical xenotransplantation: the next medical revolution?","volume":"379","author":"B Ekser","year":"2012","journal-title":"Lancet"},{"issue":"6","key":"ref33","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1097\/MOT.0000000000000020","article-title":"Islet xenotransplantation from genetically engineered pigs","volume":"18","author":"S Nagaraju","year":"2013","journal-title":"Current opinion in organ transplantation"},{"issue":"5","key":"ref34","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1111\/xen.12107","article-title":"hCTLA4-Ig transgene expression in keratocytes modulates rejection of corneal xenografts in a pig to non-human primate anterior lamellar keratoplasty model","volume":"21","author":"B Vabres","year":"2014","journal-title":"Xenotransplantation"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/1472-6750-13-43","article-title":"Factors influencing the efficiency of generating genetically engineered pigs by nuclear transfer: multi-factorial analysis of a large data set","volume":"13","author":"M Kurome","year":"2013","journal-title":"BMC biotechnology"},{"issue":"11","key":"ref36","doi-asserted-by":"crossref","first-page":"5249","DOI":"10.4049\/jimmunol.155.11.5249","article-title":"Human anti-porcine xenogeneic T cell response. Evidence for allelic specificity of mixed leukocyte reaction and for both direct and indirect pathways of recognition","volume":"155","author":"K Yamada","year":"1995","journal-title":"Journal of immunology"},{"issue":"6","key":"ref37","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a015545","article-title":"Regulatory cells and transplantation tolerance","volume":"3","author":"SP Cobbold","year":"2013","journal-title":"Cold Spring Harbor perspectives in medicine"},{"issue":"4","key":"ref38","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1097\/TP.0000000000000243","article-title":"Regulatory T-cell therapy in the induction of transplant tolerance: the issue of subpopulations","volume":"98","author":"FC Edozie","year":"2014","journal-title":"Transplantation"},{"issue":"4","key":"ref39","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.smim.2011.06.007","article-title":"Tolerogenic dendritic cells and their role in transplantation","volume":"23","author":"M Ezzelarab","year":"2011","journal-title":"Seminars in immunology"},{"issue":"8","key":"ref40","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/nri2132","article-title":"Tolerogenic dendritic cells and the quest for transplant tolerance","volume":"7","author":"AE Morelli","year":"2007","journal-title":"Nature reviews Immunology"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.jaut.2013.06.006","article-title":"Treg and CTLA-4: two intertwining pathways to immune tolerance","volume":"45","author":"LS Walker","year":"2013","journal-title":"Journal of autoimmunity"},{"issue":"1","key":"ref42","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1111\/j.1600-065X.2011.01011.x","article-title":"Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28\/ B7 family","volume":"241","author":"H Bour-Jordan","year":"2011","journal-title":"Immunological reviews"},{"issue":"12","key":"ref43","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1038\/nri3108","article-title":"The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses","volume":"11","author":"LS Walker","year":"2011","journal-title":"Nature reviews Immunology"},{"issue":"6029","key":"ref44","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1126\/science.1202947","article-title":"Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4","volume":"332","author":"OS Qureshi","year":"2011","journal-title":"Science"},{"issue":"3","key":"ref45","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.intimp.2013.02.007","article-title":"CTLA4-Ig immunosuppressive activity at the level of dendritic cell\/T cell crosstalk","volume":"15","author":"E Mayer","year":"2013","journal-title":"International immunopharmacology"},{"issue":"7","key":"ref46","doi-asserted-by":"crossref","first-page":"e69640","DOI":"10.1371\/journal.pone.0069640","article-title":"Alternative immunomodulatory strategies for xenotransplantation: CD80\/CD86-CTLA4 pathway-modified immature dendritic cells promote xenograft survival","volume":"8","author":"M Tian","year":"2013","journal-title":"PloS one"},{"issue":"11","key":"ref47","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1038\/ni846","article-title":"CTLA-4-Ig regulates tryptophan catabolism in vivo","volume":"3","author":"U Grohmann","year":"2002","journal-title":"Nature immunology"},{"issue":"7","key":"ref48","doi-asserted-by":"crossref","first-page":"4100","DOI":"10.4049\/jimmunol.172.7.4100","article-title":"Ligation of B7-1\/B7-2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells","volume":"172","author":"DH Munn","year":"2004","journal-title":"Journal of immunology"},{"key":"ref49","article-title":"Abatacept inhibits T cell priming by inducing of a unique transcriptional profile that reduces their ability to activate antigen presenting cells","author":"A Patakas","year":"2015","journal-title":"Arthritis & rheumatology"},{"issue":"4","key":"ref50","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1111\/j.1432-2277.2012.01441.x","article-title":"Decreased frequency of peripheral CD4(+) CD161(+) Th(17) -precursor cells in kidney transplant recipients on long-term therapy with Belatacept","volume":"25","author":"FW Vondran","year":"2012","journal-title":"Transplant international: official journal of the European Society for Organ Transplantation"},{"issue":"2","key":"ref51","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/ni1160","article-title":"CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2","volume":"6","author":"X Tai","year":"2005","journal-title":"Nature immunology"},{"issue":"2","key":"ref52","first-page":"580","article-title":"An obligate cell-intrinsic function for CD28 in Tregs","volume":"123","author":"R Zhang","year":"2013","journal-title":"The Journal of clinical investigation"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0155676","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T06:11:46Z","timestamp":1692339106000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0155676"}},"subtitle":[],"editor":[{"given":"Niels Olsen Saraiva","family":"C\u00e2mara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2016,5,13]]},"references-count":52,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2016,5,13]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0155676","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,5,13]]}}}