BACKGROUND: Presence of donor-specific antibodies (Abs) is detrimental to posttransplant allograft function. Some sensitized recipients have successfully undergone transplantation after pretransplant conditioning regimen using plasmapheresis and/or intravenous immunoglobulin therapy, but underlying mechanisms that confer such allograft protection are undefined. METHODS: We developed a single human leukocyte antigen (HLA)-mismatched heterotopic murine heart transplant model (HLA-A2 into HLA-A2-sensitized-C57BL/6) to determine whether pretreatment of donors with low concentration of HLA class I (W6/32) or control Ab (C1.18.4) will confer protection. Expression levels of survival genes, Bcl-2 and heme oxygenase-1, were analyzed by gene array analysis and quantitative real-time polymerase chain reaction. Expression levels of cytokine panel were analyzed by Luminex. Role of Bcl-2 in the induction of allograft protection was analyzed by silencing the Bcl-2 expression in the donor hearts using a small hairpin (shRNA) specific for Bcl-2. RESULTS: Control Ab-pretreated hearts were rejected in less than 5 days demonstrating hemorrhage, Ab, and C4 deposition. In contrast, W6/32-pretreated hearts were rejected at 15 days (P<0.05) that was prolonged to 25 days with antilymphocyte serum treatment. W6/32-pretreated hearts on day 5 exhibited increased expression of Bcl-2 (5.5-folds), Bcl-xl (5.5-folds), and heme oxygenase-1 (4.4-folds); decreased expression of ICAM-1, VCAM-1 (3.2-fold), along with reduced levels of cytokines interleukin (IL)-1β (4.4-folds), tumor necrosis factor α (3.7-folds), IL-6 (7.5-folds), IL-12 (2.3-folds) and chemokines monocyte chemotactic protein 1 (4.5-folds), MIG (4.4-folds), MIP-1α (3.4-folds), and IL-8 (3.1-folds). Silencing of Bcl-2 in accommodated hearts before transplant resulted in loss of protection with rejection (9±3 vs. 15±2days, P<0.05). CONCLUSION: Pretreatment of hearts with low levels of anti-HLA Abs increases expression of antiapoptotic genes that inhibits caspases, leading to decreased inflammatory cytokines and chemokines, which promote allograft survival.
BACKGROUND: Presence of donor-specific antibodies (Abs) is detrimental to posttransplant allograft function. Some sensitized recipients have successfully undergone transplantation after pretransplant conditioning regimen using plasmapheresis and/or intravenous immunoglobulin therapy, but underlying mechanisms that confer such allograft protection are undefined. METHODS: We developed a single human leukocyte antigen (HLA)-mismatched heterotopicmurine heart transplant model (HLA-A2 into HLA-A2-sensitized-C57BL/6) to determine whether pretreatment of donors with low concentration of HLAclass I (W6/32) or control Ab (C1.18.4) will confer protection. Expression levels of survival genes, Bcl-2 and heme oxygenase-1, were analyzed by gene array analysis and quantitative real-time polymerase chain reaction. Expression levels of cytokine panel were analyzed by Luminex. Role of Bcl-2 in the induction of allograft protection was analyzed by silencing the Bcl-2 expression in the donor hearts using a small hairpin (shRNA) specific for Bcl-2. RESULTS:Control Ab-pretreated hearts were rejected in less than 5 days demonstrating hemorrhage, Ab, and C4 deposition. In contrast, W6/32-pretreated hearts were rejected at 15 days (P<0.05) that was prolonged to 25 days with antilymphocyte serum treatment. W6/32-pretreated hearts on day 5 exhibited increased expression of Bcl-2 (5.5-folds), Bcl-xl (5.5-folds), and heme oxygenase-1 (4.4-folds); decreased expression of ICAM-1, VCAM-1 (3.2-fold), along with reduced levels of cytokines interleukin (IL)-1β (4.4-folds), tumor necrosis factor α (3.7-folds), IL-6 (7.5-folds), IL-12 (2.3-folds) and chemokines monocyte chemotactic protein 1 (4.5-folds), MIG (4.4-folds), MIP-1α (3.4-folds), and IL-8 (3.1-folds). Silencing of Bcl-2 in accommodated hearts before transplant resulted in loss of protection with rejection (9±3 vs. 15±2days, P<0.05). CONCLUSION: Pretreatment of hearts with low levels of anti-HLAAbs increases expression of antiapoptotic genes that inhibits caspases, leading to decreased inflammatory cytokines and chemokines, which promote allograft survival.
Authors: G P Alexandre; J P Squifflet; M De Bruyère; D Latinne; R Reding; P Gianello; M Carlier; Y Pirson Journal: Transplant Proc Date: 1987-12 Impact factor: 1.066
Authors: A V Reisaeter; T Leivestad; D Albrechtsen; H Holdaas; A Hartmann; G Sødal; A Flatmark; P Fauchald Journal: Transplantation Date: 1995-08-15 Impact factor: 4.939
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Authors: Anita S Chong; Maria-Luisa Alegre; Michelle L Miller; Robert L Fairchild Journal: Cold Spring Harb Perspect Med Date: 2013-12-01 Impact factor: 6.915
Authors: Laura Kummer; Marcin Zaradzki; Vijith Vijayan; Rawa Arif; Markus A Weigand; Stephan Immenschuh; Andreas H Wagner; Jan Larmann Journal: Front Physiol Date: 2020-05-08 Impact factor: 4.566