Chris Laird1, Lars Burdorf, Richard N Pierson. 1. aDivision of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine bVA Maryland Healthcare System, Baltimore, Maryland, USA.
Abstract
PURPOSE OF REVIEW: This article reviews recent progress in the field of lung xenotransplantation, including mechanisms of xenograft injury, and the influence of mechanism-directed genetic modifications and other interventions that may soon enable therapeutic use of pig lungs in humans. RECENT FINDINGS: An extensive series of lung xenotransplantation experiments demonstrates that multiple genetic modifications targeting known xenogeneic lung injury mechanisms are associated with incremental improvements in lung survival or function. Addition of human complement (hCD46, hCD55), coagulation (hEPCR, hTBM, hTFPI, hCD39), or anti-inflammatory pathway regulatory genes (HO-1, HLA-E), and GalT and Neu5Gc gene knockout has each demonstrated protective effects on lung survival or function. In addition, drug treatments targeting key inflammatory and clotting pathways have been shown to attenuate residual mechanisms of lung injury. Work with other pig organs in primate models show that regimens based on costimulatory pathway blocking antibodies prolong xenograft function for months to years, suggesting that once initial lung inflammation mechanisms are fully controlled, clinically useful application of pig lung xenografts may soon be feasible. SUMMARY: Genetic modification of pigs coupled with drugs targeting complement activation, coagulation, and inflammation have significantly increased duration of pig lung function in ex-vivo human blood perfusion models, and life-supporting lung xenograft survival in vivo.
PURPOSE OF REVIEW: This article reviews recent progress in the field of lung xenotransplantation, including mechanisms of xenograft injury, and the influence of mechanism-directed genetic modifications and other interventions that may soon enable therapeutic use of pig lungs in humans. RECENT FINDINGS: An extensive series of lung xenotransplantation experiments demonstrates that multiple genetic modifications targeting known xenogeneic lung injury mechanisms are associated with incremental improvements in lung survival or function. Addition of human complement (hCD46, hCD55), coagulation (hEPCR, hTBM, hTFPI, hCD39), or anti-inflammatory pathway regulatory genes (HO-1, HLA-E), and GalT and Neu5Gc gene knockout has each demonstrated protective effects on lung survival or function. In addition, drug treatments targeting key inflammatory and clotting pathways have been shown to attenuate residual mechanisms of lung injury. Work with other pig organs in primate models show that regimens based on costimulatory pathway blocking antibodies prolong xenograft function for months to years, suggesting that once initial lung inflammation mechanisms are fully controlled, clinically useful application of pig lung xenografts may soon be feasible. SUMMARY: Genetic modification of pigs coupled with drugs targeting complement activation, coagulation, and inflammation have significantly increased duration of pig lung function in ex-vivo human blood perfusion models, and life-supporting lung xenograft survival in vivo.
Authors: Benjamin G Lilienfeld; Mark D Crew; Pietro Forte; Bettina C Baumann; Jörg D Seebach Journal: Xenotransplantation Date: 2007-03 Impact factor: 3.907
Authors: Edward Cantu; Jeffrey G Gaca; Daniel Palestrant; Kamran Baig; Daniel J Lukes; Sarah E Gibson; Gonzalo V Gonzalez-Stawinski; Michael Olausson; William Parker; R Duane Davis Journal: Transplantation Date: 2006-04-27 Impact factor: 4.939
Authors: Marcelo Cypel; Mingyao Liu; Matt Rubacha; Jonathan C Yeung; Shin Hirayama; Masaki Anraku; Masaaki Sato; Jeffrey Medin; Beverly L Davidson; Marc de Perrot; Thomas K Waddell; Arthur S Slutsky; Shaf Keshavjee Journal: Sci Transl Med Date: 2009-10-28 Impact factor: 17.956
Authors: Guerard W Byrne; Paul G Stalboerger; Eduardo Davila; Carrie J Heppelmann; Mozammel H Gazi; Hugh C J McGregor; Peter T LaBreche; William R Davies; Vinay P Rao; Keiji Oi; Henry D Tazelaar; John S Logan; Christopher G A McGregor Journal: Xenotransplantation Date: 2008 Jul-Aug Impact factor: 3.907
Authors: Young Tae Kim; Hyun Joo Lee; Sang Woo Lee; Ji Yeon Kim; Hyun Cho Wi; Sun Jung Park; Sung Jin Bae; Hee Jung Kang Journal: Xenotransplantation Date: 2008-02 Impact factor: 3.907
Authors: Bao-Ngoc H Nguyen; Agnes M Azimzadeh; Tianshu Zhang; Guosheng Wu; Henk-Jan Schuurman; Henk-Jan Shuurman; David H Sachs; David Ayares; James S Allan; Richard N Pierson Journal: J Thorac Cardiovasc Surg Date: 2007-04-02 Impact factor: 5.209
Authors: Richard N Pierson; Anthony Dorling; David Ayares; Michael A Rees; Jörg D Seebach; Jay A Fishman; Bernhard J Hering; David K C Cooper Journal: Xenotransplantation Date: 2009 Sep-Oct Impact factor: 3.907
Authors: D K C Cooper; R Gaston; D Eckhoff; J Ladowski; T Yamamoto; L Wang; H Iwase; H Hara; M Tector; A J Tector Journal: Br Med Bull Date: 2018-03-01 Impact factor: 4.291
Authors: Natalia F Smirnova; Thomas M Conlon; Carmela Morrone; Peter Dorfmuller; Marc Humbert; Georgios T Stathopoulos; Stephan Umkehrer; Franz Pfeiffer; Ali Ö Yildirim; Oliver Eickelberg Journal: JCI Insight Date: 2019-02-07
Authors: Maria C Basil; Jeremy Katzen; Anna E Engler; Minzhe Guo; Michael J Herriges; Jaymin J Kathiriya; Rebecca Windmueller; Alexandra B Ysasi; William J Zacharias; Hal A Chapman; Darrell N Kotton; Jason R Rock; Hans-Willem Snoeck; Gordana Vunjak-Novakovic; Jeffrey A Whitsett; Edward E Morrisey Journal: Cell Stem Cell Date: 2020-04-02 Impact factor: 24.633