2134/37198
Bettina Wiegmann
Bettina
Wiegmann
Constanca Figueiredo
Constanca
Figueiredo
Christiane Gras
Christiane
Gras
Michael Pflaum
Michael
Pflaum
Sabrina Schmeckebier
Sabrina
Schmeckebier
Sotiris Korossis
Sotiris
Korossis
Axel Haverich
Axel
Haverich
Rainer Blasczyk
Rainer
Blasczyk
Prevention of rejection of allogeneic endothelial cells in a biohybrid lung by silencing HLA-class I expression
Loughborough University
2019
Biohybrid lung
HLA
Biomaterial
Endothelial cells
Mechanical Engineering not elsewhere classified
2019-03-15 11:46:58
Journal contribution
https://repository.lboro.ac.uk/articles/journal_contribution/Prevention_of_rejection_of_allogeneic_endothelial_cells_in_a_biohybrid_lung_by_silencing_HLA-class_I_expression/9547010
Variability in Human Leukocyte Antigens (HLA) remains a hurdle to the application of allogeneic cellular products. Due to insufficient autologous endothelial cell harvesting for the biohybrid lung, allogeneic human cord blood derived endothelial cells (HCBEC) were used for the endothelialization of poly-4-methyl-1-pentene (PMP) gas exchange membranes. Therefore, HLA class I expression was silenced stably in HCBECs to prevent rejection. The capacity of HLA class I-silenced HCBEC to abrogate allogeneic immune responses, their functional properties and suitability for endothelialization of PMP membranes were investigated. Delivery of β2-microglobulin (β2m)-specific shRNAs reduced β2m mRNA levels by up to 90% and caused a knockdown of HLA class I expression by up to 85%. HLA-silenced HCBEC abrogated T-cell responses and escaped antibody-mediated complement-dependent cytotoxicity. The EC phenotype and cytokine secretion profiles between HLA-expressing or -silenced HCBEC remained unaltered. EC specific activation (e.g. ICAM) and thrombogenic markers (e.g. thrombomodulin) remained unaffected by HLA-silencing, but their expression was upregulated by TNFα-stimulation. Furthermore, HLA-silenced HCBECs showed high proliferation rates and built an EC monolayer onto PMP membranes. This study represents a new therapeutic concept in the field of cell and organ transplantation and may bring the bioartificial lung as an alternative to lung transplantation closer to reality.