Donor Brain Death Inhibits Tolerance Induction in Miniature Swine Recipients of Fully MHC‐Disparate Pulmonary Allografts

• Published in: American journal of transplantation Vol. 12; no. 5; pp. 1290 - 1295
• Main Authors: Meltzer, A. J., Veillette, G. R., Aoyama, A., Kim, K. M., Cochrane, M. E., Wain, J. C., Madsen, J. C., Sachs, D. H., Rosengard, B. R., Allan, J. S.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01.05.2012; Wiley
• Subjects: Allografts; Animal models; Animals; Biological and medical sciences; Brain; Brain death; Brain Death - immunology; Donors; Enzyme-Linked Immunosorbent Assay; Gene expression; Graft Rejection - immunology; Immune Tolerance - immunology; Immunological tolerance; Inflammation; Interleukin 1; Interleukin 10; Interleukin 6; Interleukin-1 - genetics; Interleukin-1 - metabolism; Interleukin-10 - genetics; Interleukin-10 - metabolism; Interleukin-6 - genetics; Interleukin-6 - metabolism; Lung; lung transplantation; Lung Transplantation - immunology; Major histocompatibility complex; Major Histocompatibility Complex - immunology; Medical sciences; Models, Animal; Real-Time Polymerase Chain Reaction; RNA, Messenger - genetics; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Swine; Swine, Miniature; Tacrolimus; Tissue Donors; tolerance induction; Transplantation, Homologous; Tumor necrosis factor- alpha; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Ventilation; Suboptimal donor; Human; Lung; Major histocompatibility system; Brain death; Recipient; Transplantation; tolerance induction; Homotransplantation; Respiratory system; Vertebrata; Mammalia; Treatment; Swine; Surgery; Animal; Immune tolerance; Graft; Inhibitor; lung transplantation; Artiodactyla; Ungulata
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2011.03949.x

We have previously shown that a short course of high‐dose tacrolimus induces long‐term tolerance to fully mismatched lung allografts procured from healthy MHC‐inbred miniature swine. Here, we investigate whether donor brain death affects tolerance induction. Four recipient swine were transplanted with fully mismatched lung grafts from donors that were rendered brain dead and mechanically ventilated for 4 h before procurement (Group 1). These recipients were compared to two control groups (Group 2: 4 h of donor ventilation without brain death [n = 5]; and Group 3: no donor brain death with <1 h of ventilation [n = 6]). All recipients were treated with a 12‐day course of tacrolimus. In contrast to both groups of control animals, the swine transplanted with lung allografts from brain dead donors all rejected their grafts by postoperative day 45 and showed persistent responsiveness to donor antigen by MLR. Several additional swine underwent brain death induction and/or mechanical ventilation alone to determine the effects of these procedures on the expression of proinflammatory molecules. Significant increases in serum concentrations of IL‐1, TNF‐α and IL‐10 were seen after brain death. Upregulation of IL‐1 and IL‐6 gene expression was also observed. Donor brain death abrogates tolerance induction in a preclinical lung transplant model.