Background: A spontaneous tolerance of B cells responding to blood group antigens frequently develops in ABO-incompatible pediatric liver transplantation (LT). Liver sinusoidal endothelial cells (LSECs), which exclusively express blood group antigens in the liver, possess a capacity to induce alloantigen-specific tolerance. In this study, we elucidated the role of LSECs in the tolerance induction of blood group antigen-reactive B cells after ABO-incompatible LT using mice that lack galactose-α(1,3)galactose (Gal) epitopes resembling blood group carbohydrate antigens.
Methods: Using adoptive transfer of LSECs from wild type (WT) C57BL/6J mice to congenic α1,3-galactosyltransferase gene knockout (GalT) mice, we established orthotropic GalT → GalT LSEC chimera mice. Anti-Gal Ab (antibody) production was evaluated after immunization of GalT → GalT LSEC chimera mice with Gal rabbit RBC.
Results: Adoptive transfer of LSECs isolated from WT GalT mice via the portal vein resulted in persistent engraftment of Gal LSECs in congenic GalT mouse livers. Only when GalT mice were splenectomized before LSEC inoculation, the GalT → GalT LSEC chimera lost the ability to produce anti-Gal Abs. The administration of blocking monoclonal Abs (mAbs) against programmed death ligand 1 to the splenectomized GalT → GalT LSEC chimera resulted in the recovery of anti-Gal Ab production.
Conclusions: These findings suggest that LSECs take a part in tolerization of immature but not mature B cells specifically for Gal. Furthermore, the programmed death 1/programmed death ligand 1 pathway likely plays a crucial role in the mechanisms underlying spontaneous tolerization of B cells responding to ABO-blood group antigens in LT.