Mechanisms by which cell surface engineering of the endothelial glycocalyx with a sialic acid-containing polymer prevents organ transplant rejection

Organ transplant rejection is prevented by immunosuppressants, but these drugs do not always work and are associated with many side effects. To circumvent the use of these immunosuppressants, a cell surface engineering (CSE) approach that enzymatically adheres a sialic acid-containing polymer, LPG-Sia, to endothelial cells in blood vessels prior to transplantation was developed. I investigated the mechanisms by which this protocol inhibits immune cell activation. Co-culture assays showed that LPG-Sia decreased immune-mediated endothelial cell death. Blocking sialic acid receptors, siglec-7 and -9, prevented the protective effect of LPG-Sia indicating that they were required for immune inhibition. Transplantation of CSE modified allogeneic arteries reduced co-stimulatory molecule CD86 expression on recipient conventional dendritic cells. Also, accumulation of macrophages, CD4 and CD8 T cells were reduced in CSE modified allograft arteries. Together, these findings indicate that LPG-Sia deactivates immune cells by acting on siglec-7 and -9, and that it reduces early activation of antigen presenting cells that may prevent T cell activation and resultant rejection.