Acute Vascular Rejection and Accommodation: Divergent Outcomes of the Humoral Response to Organ Transplantation

Background: The most difficult barrier to organ transplantation is humoral rejection, a condition initiated by binding of antibodies to blood vessels in the graft. Fortunately, humoral rejection is not the only outcome of antibody binding to the graft. In some cases, accommodation, a condition in which the graft does not undergo humoral injury despite the existence of humoral immunity directed against it, occurs and the graft remains seemingly inured. The mechanism underlying accommodation is uncertain, but changes in the function of antibodies, changes in the target antigen, and changes in the graft imparting resistance to injury have been implicated.

Methods: Using the swine-to-baboon cardiac xenograft model, we asked which mechanism(s) may distinguish acute vascular rejection from accommodation.

Results: In both acute vascular rejection and accommodation, antibodies were bound and complement activated in blood vessels of the graft. However, in acute vascular rejection, the full complement cascade was activated; while in accommodation, the complement cascade was interrupted, suggesting complement was inhibited in the latter condition. In acute vascular rejection, heparan sulfate and syndecan-4-phosphate, which can aid in complement control, were nearly absent, whereas in accommodation these were present in heightened amounts.

Conclusion: These findings suggest that control of complement may underlie accommodation, at least in part, and raise the possibility that this control and possibly other protective mechanisms could be exerted by heparan sulfate.