Antibodies in transplantation: the effects of HLA and non-HLA antibody binding and mechanisms of injury

Abstract

Until recently, allograft rejection was thought to be mediated primarily by alloreactive T cells. Consequently, immunosuppressive approaches focused on inhibition of T cell activation. While short-term graft survival has significantly improved and rejection rates have dropped, acute rejection has not been eliminated and chronic rejection remains the major threat to long-term graft survival. Increased attention to humoral immunity in experimental systems and in the clinic has revealed that donor specific antibodies (DSA) can mediate and promote acute and chronic rejection. Herein, we detail the effects of alloantibody, particularly HLA antibody, binding to graft vascular and other cells, and briefly summarize the experimental methods used to assess such outcomes.

Fig. 1

The pleiotropic effects of HLA I antibody binding to graft vascular cells. Donor specific HLA I antibodies bind to HLA I molecules expressed on the surface of endothelial cells lining the vasculature of the transplanted organ. In addition to triggering complement activation through their Fcγ fragment, antibodies recognizing HLA I molecules cross-link these receptors at the cell surface, inducing intracellular signaling. HLA I-mediated cell signaling results in increased FGFR at the endothelial cell surface, migration, proliferation, and resistance to apoptosis and complement-induced death. Cellular proliferation requires a molecular association between HLA I molecules and integrin β4. HLA I cross-linking also increases cytosolic calcium (Ca²⁺), which triggers mobilization of Weibel–Palade bodies and increased cell surface P-selectin, leading to adherence of selectin-ligand bearing immune cells