BACKGROUND: Achieving tolerance of vascularized composite allografts (VCAs) would improve the risk-to-benefit ratio in patients who undergo this life-enhancing, though not lifesaving, transplant. Kidney cotransplantation along with a short course of high-dose immunosuppression enables tolerance of heart allografts across a full major histocompatibility complex (MHC) mismatch. In this study, we investigated whether tolerance of VCAs across full MHC disparities could be achieved in animals already tolerant of heart and kidney allografts. METHODS: Miniature swine that were tolerant of heart and/or kidney allografts long term underwent transplantation of myocutaneous VCA across the same MHC barrier. Before VCA transplant, group 1 (n = 3) underwent class I-mismatched kidney transplantation; group 2 (n = 3) underwent 2 sequential class I-mismatched kidney transplantations; group 3 (n = 2) underwent haploidentical MHC-mismatched heart/kidney transplantation; and group 4 (n = 2) underwent full MHC-mismatched heart/kidney transplantation. RESULTS: All 3 animals in group 1 and 2 of 3 animals in group 2 showed skin rejection within 85 days; 1 animal in group 2 showed prolonged skin survival longer than 200 days. Animals in groups 3 and 4 showed skin rejection within 30 days and regained in vitro evidence of donor responsiveness. CONCLUSIONS: This is the first preclinical study in which hearts, kidneys, and VCAs have been transplanted into the same recipient. Despite VCA rejection, tolerance of heart and kidney allografts was maintained. These results suggest that regulatory tolerance of skin is possible but not generally achieved by the same level of immunomodulation that is capable of inducing tolerance of heart and kidney allografts. Achieving tolerance of skin may require additional immunomodulatory therapies.
BACKGROUND: Achieving tolerance of vascularized composite allografts (VCAs) would improve the risk-to-benefit ratio in patients who undergo this life-enhancing, though not lifesaving, transplant. Kidney cotransplantation along with a short course of high-dose immunosuppression enables tolerance of heart allografts across a full major histocompatibility complex (MHC) mismatch. In this study, we investigated whether tolerance of VCAs across full MHC disparities could be achieved in animals already tolerant of heart and kidney allografts. METHODS: Miniature swine that were tolerant of heart and/or kidney allografts long term underwent transplantation of myocutaneous VCA across the same MHC barrier. Before VCA transplant, group 1 (n = 3) underwent class I-mismatched kidney transplantation; group 2 (n = 3) underwent 2 sequential class I-mismatched kidney transplantations; group 3 (n = 2) underwent haploidentical MHC-mismatched heart/kidney transplantation; and group 4 (n = 2) underwent full MHC-mismatched heart/kidney transplantation. RESULTS: All 3 animals in group 1 and 2 of 3 animals in group 2 showed skin rejection within 85 days; 1 animal in group 2 showed prolonged skin survival longer than 200 days. Animals in groups 3 and 4 showed skin rejection within 30 days and regained in vitro evidence of donor responsiveness. CONCLUSIONS: This is the first preclinical study in which hearts, kidneys, and VCAs have been transplanted into the same recipient. Despite VCA rejection, tolerance of heart and kidney allografts was maintained. These results suggest that regulatory tolerance of skin is possible but not generally achieved by the same level of immunomodulation that is capable of inducing tolerance of heart and kidney allografts. Achieving tolerance of skin may require additional immunomodulatory therapies.
Authors: Anette Wu; Kazuhiko Yamada; Francesco L Ierino; Parsia A Vagefi; David H Sachs Journal: Transpl Immunol Date: 2003 Jul-Sep Impact factor: 1.708
Authors: R L Kirkman; R B Colvin; M W Flye; G S Leight; S A Rosenberg; G M Williams; D H Sachs Journal: Transplantation Date: 1979-07 Impact factor: 4.939
Authors: D A Leonard; J M Kurtz; C Mallard; A Albritton; R Duran-Struuck; E A Farkash; R Crepeau; A Matar; B M Horner; M A Randolph; D H Sachs; C A Huang; C L Cetrulo Journal: Am J Transplant Date: 2014-01-09 Impact factor: 8.086
Authors: Saami Khalifian; Philip S Brazio; Raja Mohan; Cynthia Shaffer; Gerald Brandacher; Rolf N Barth; Eduardo D Rodriguez Journal: Lancet Date: 2014-04-27 Impact factor: 79.321
Authors: Curtis L Cetrulo; Radbeh Torabi; Joseph R Scalea; Akira Shimizu; Angelo A Leto Barone; Bradford C Gillon; Masayuki Tasaki; David A Leonard; Taylor A Cormack; Vincenzo Villani; Mark A Randolph; David H Sachs; Kazuhiko Yamada Journal: Transplantation Date: 2013-12-15 Impact factor: 4.939
Authors: R Utsugi; R N Barth; R S Lee; H Kitamura; J C LaMattina; J Ambroz; D H Sachs; K Yamada Journal: Transplantation Date: 2001-05-27 Impact factor: 4.939
Authors: François Petit; Alicia B Minns; Jean-Michel Dubernard; Shehan Hettiaratchy; W P Andrew Lee Journal: Ann Surg Date: 2003-01 Impact factor: 12.969
Authors: J R Scalea; M Okumi; V Villani; A Shimizu; H Nishimura; B C Gillon; R Torabi; T Cormack; S Moran; C LeGuern; D H Sachs; K Yamada Journal: Am J Transplant Date: 2014-08-06 Impact factor: 8.086
Authors: Christian Andreas Radu; Sebastian Fischer; Yannick Diehm; Otto Hetzel; Florian Neubrech; Laura Dittmar; Christian Kleist; Martha Maria Gebhard; Peter Terness; Ulrich Kneser; Jurij Kiefer Journal: Langenbecks Arch Surg Date: 2017-08-19 Impact factor: 3.445
Authors: Jeffrey L Platt; Christina L Kaufman; Mayara Garcia de Mattos Barbosa; Marilia Cascalho Journal: Curr Opin Organ Transplant Date: 2017-10 Impact factor: 2.640