{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:47:55Z","timestamp":1789750075903,"version":"4.0.1"},"reference-count":43,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T00:00:00Z","timestamp":1690502400000},"content-version":"vor","delay-in-days":27,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Xenotransplantation"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Expression of human complement pathway regulatory proteins (hCPRP's) such as CD46 or CD55 has been associated with improved survival of pig organ xenografts in multiple different models. Here we evaluate the hypothesis that an increased human CD46 gene dose, through homozygosity or additional expression of a second hCPRP, is associated with increased protein expression and with improved protection from injury when GTKO lung xenografts are perfused with human blood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twenty three GTKO lungs heterozygous for human CD46 (GTKO.heteroCD46), 10 lungs homozygous for hCD46 (GTKO.homoCD46), and six GTKO.homoCD46 lungs also heterozygous for hCD55 (GTKO.homoCD46.hCD55) were perfused with human blood for up to 4\u00a0h in an <jats:italic>ex vivo<\/jats:italic> circuit.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Relative to GTKO.heteroCD46 (152\u00a0min, range 5\u2013240; 6\/23 surviving at 4\u00a0h), survival was significantly improved for GTKO.homoCD46 (&gt;240\u00a0min, range 45\u2013240, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.034; 7\/10 surviving at 4\u00a0h) or GTKO.homoCD46.hCD55 lungs (&gt;240\u00a0min, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.001; 6\/6 surviving at 4\u00a0h). Homozygosity was associated with increased capillary expression of hCD46 (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.0001). Increased hCD46 expression was associated with significantly prolonged lung survival (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.048),) but surprisingly not with reduction in measured complement factor C3a. Hematocrit, monocyte count, and pulmonary vascular resistance were not significantly altered in association with increased hCD46 gene dose or protein expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Genetic engineering approaches designed to augment hCPRP activity \u2014 increasing the expression of hCD46 through homozygosity or co\u2010expressing hCD55 with hCD46 \u2014 were associated with prolonged GTKO lung xenograft survival. Increased expression of hCD46 was associated with reduced coagulation cascade activation, but did not further reduce complement activation relative to lungs with relatively low CD46 expression. We conclude that coagulation pathway dysregulation contributes to injury in GTKO pig lung xenografts perfused with human blood, and that the survival advantage for lungs with increased hCPRP expression is likely attributable to improved endothelial thromboregulation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/xen.12812","type":"journal-article","created":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T12:37:50Z","timestamp":1690547870000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Increased human complement pathway regulatory protein gene dose is associated with increased endothelial expression and prolonged survival during ex\u2010vivo perfusion of GTKO pig lungs with human blood"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0484-8362","authenticated-orcid":false,"given":"Ryan","family":"Chaban","sequence":"first","affiliation":[{"name":"Center for Transplantation Sciences and Department of Surgery Massachusetts General Hospital and Harvard School of Medicine Boston Massachusetts USA"},{"name":"Department of Cardiac and Vascular Surgery University Hospital of Johannes Gutenberg University Mainz Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gannon","family":"McGrath","sequence":"additional","affiliation":[{"name":"Center for Transplantation Sciences and Department of Surgery Massachusetts General Hospital and Harvard School of Medicine Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3314-3716","authenticated-orcid":false,"given":"Zahra","family":"Habibabady","sequence":"additional","affiliation":[{"name":"Center for Transplantation Sciences and Department of Surgery Massachusetts General Hospital and Harvard School of Medicine Boston Massachusetts USA"},{"name":"Department of Surgery University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivy","family":"Rosales","sequence":"additional","affiliation":[{"name":"Center for Transplantation Sciences and Department of Surgery Massachusetts General Hospital and Harvard School of Medicine Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8943-4750","authenticated-orcid":false,"given":"Lars","family":"Burdorf","sequence":"additional","affiliation":[{"name":"Center for Transplantation Sciences and Department of Surgery Massachusetts General Hospital and Harvard School of Medicine Boston Massachusetts USA"},{"name":"Department of Surgery University of Maryland School of Medicine Baltimore Maryland USA"},{"name":"Revivicor, Inc. Blacksburg Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Ayares","sequence":"additional","affiliation":[{"name":"Revivicor, Inc. Blacksburg Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elana","family":"Rybak","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianshu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald G.","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siamak","family":"Dahi","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franchesca","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn M.","family":"Parsell","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gheorghe","family":"Braileanu","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangfei","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn","family":"Sievert","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Phelps","sequence":"additional","affiliation":[{"name":"Revivicor, Inc. 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