{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T07:27:56Z","timestamp":1784618876602,"version":"3.55.0"},"reference-count":32,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,4,20]],"date-time":"2025-04-20T00:00:00Z","timestamp":1745107200000},"content-version":"vor","delay-in-days":50,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Xenotransplantation"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Significant progress has been made in the long\u2010term survival of non\u2010human primates after orthotopic gene\u2010edited pig cardiac xenotransplantation. However, to our knowledge, there are no reports of the successful reversal of an acute rejection episode in such an experiment. We present evidence suggesting that rejection can be reversed with corticosteroids and complement inhibition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Orthotopic transplantation of a pig heart (with 69 gene\u2010edits) was carried out in a baboon. The immunosuppressive regimen was based on CD40\/CD154 T cell co\u2010stimulation pathway blockade and rapamycin. Cardiac function remained excellent until Day 162, when there were increases in heart rate, ventricular septal wall thickness, left ventricular end\u2010diastolic pressures (LVEDP), and troponin level, which were associated with a low serum level of rapamycin (&lt;4\u00a0ng\/mL). Anti\u2010rejection treatment was begun with an increase in rapamycin dosage, steroid bolus therapy, two doses of a C1\u2010esterase inhibitor, and an extra dose of the anti\u2010CD154mAb.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>There was a rapid correction of all hemodynamic parameters, and the troponin T level (which had risen to 139\u00a0ng\/L) returned to pre\u2010rejection levels. Ventricular septal thickness and LVEDP returned to pre\u2010rejection levels after treatment. The baboon remains well with normal graft function. Baseline heart rate remains faster than before the rejection episode.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>As we transition to the clinical application of gene\u2010edited pig cardiac xenotransplantation, the ability to treat rejection is of vital importance. The optimal treatment for rejection remains uncertain but we suggest that systemic complement inhibition is important.<\/jats:p><\/jats:sec>","DOI":"10.1111\/xen.70044","type":"journal-article","created":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T04:40:38Z","timestamp":1745642438000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Treatment of Presumptive Rejection After Orthotopic Pig\u2010to\u2010Baboon Cardiac Xenotransplantation"],"prefix":"10.1111","volume":"32","author":[{"given":"Chace B.","family":"Mitchell","sequence":"first","affiliation":[{"name":"Division of Cardiothoracic Surgery Department of Surgery Heart Institute Children's Hospital of Los Angeles (CHLA), University of Southern California (USC)  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J.","family":"Neal","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine The University of Texas MD Anderson Cancer Center, Michale E. Keeling Center for Comparative Medicine and Research  Bastrop Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe H.","family":"Simmons","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine The University of Texas MD Anderson Cancer Center, Michale E. Keeling Center for Comparative Medicine and Research  Bastrop Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sriram","family":"Chitta","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine The University of Texas MD Anderson Cancer Center, Michale E. Keeling Center for Comparative Medicine and Research  Bastrop Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David K. C.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Center for Transplantation Sciences Massachusetts General Hospital \/ Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Cleveland","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery Department of Surgery Heart Institute Children's Hospital of Los Angeles (CHLA), University of Southern California (USC)  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Cleveland","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery Department of Surgery Heart Institute Children's Hospital of Los Angeles (CHLA), University of Southern California (USC)  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,20]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/xen.12516"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajt.2022.12.023"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010018\u20100765\u2010z"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.athoracsur.2021.05.025"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.21037\/tp\u201022\u2010664"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/xen.12744"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2201422"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(23)00775\u20104"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41586\u2010024\u201000879\u2010y"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/xen.12816"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00246\u2010018\u20101998\u20101"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/petr.14260"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/xen.70009"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.114.001553"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.118.011890"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.athoracsur.2023.07.039"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2022.04.032"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.12659\/AOT.935338"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijsu.2019.08.024"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/xen.12771"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010024\u201003429\u20101"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.carpath.2019.06.004"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajt.2024.01.016"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.16994"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.4070\/kcj.2018.0189"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201068505\u20101"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02380"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/xen.12517"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1600\u20106135.2003.00258.x"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/xen.12133"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2021.07.051"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000004765"}],"container-title":["Xenotransplantation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/xen.70044","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T05:31:33Z","timestamp":1754631093000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/xen.70044"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3]]},"references-count":32,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1111\/xen.70044"],"URL":"https:\/\/doi.org\/10.1111\/xen.70044","archive":["Portico"],"relation":{},"ISSN":["0908-665X","1399-3089"],"issn-type":[{"value":"0908-665X","type":"print"},{"value":"1399-3089","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3]]},"assertion":[{"value":"2025-04-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70044"}}