The immunogenicity of the extracellular matrix in arterial xenografts

Determinants of xenograft immunogenicity are poorly characterized. We showed previously that decellularized arterial xenografts (DAXs) dilate, whereas decellularized arterial isografts (DAIs) and allografts do not, suggesting an interspecies, rather than an intraspecies, immunogenicity of the arterial extracellular matrix leading to chronic rejection. Now we have investigated the immunogenicity of the arterial extracellular matrix in xenografts and its impact on chronic injury (elastin lysis) and remodeling (graft dilation).

Diameter and elastin content were measured in DAIs and DAXs from hamster to rat (concordant combination) and guinea pig to rat (discordant combinations) at 8 weeks. We also characterized the immune effectors infiltrating DAIs and DAXs by immunohistochemistry after 6 hours to 4 weeks of implantation. Results were compared with nondecellularized isografts and xenografts. Last, the impact of the donor-recipient phylogenetic distance on monocyte-macrophage penetration into the media was assessed in three xenograft combinations.

DAXs from guinea pig, but not from hamster, were aneurysmal at 8 weeks. Elastin lysis paralleled graft dilation. DAXs, but not DAIs, were infiltrated by monocytes, macrophages, T lymphocytes, and immunoglobulins. The donor-recipient combination did not affect the phenotype of the inflammatory infiltrate in DAXs, but it modified the kinetics of monocyte-macrophage penetration into the media. The absence of decellularization changed the inflammatory infiltrate phenotype (absence of macrophages) but had little impact on DAX injury and remodeling.

DAX immunogenicity accounts for most of chronic arterial xenograft injury, which is modulated by the donor-recipient combination. The immunogenicity of arterial xenografts, unlike allografts, is supported by the extracellular matrix in addition to the cells and could influence the long-term fate of xenografts.