IMMUNOLOGICAL CARBOHYDRATE ANTIGEN IN BIOPROSTHETIC HEART VALVES

Cardiovascular diseases are the number one cause of death worldwide and heart valve diseases are prominent. Currently there is no medicinal therapy for treatment of valve stenosis and replacement surgery is required. Bioprosthetic heart valves (BHV) are mainly used in aging patients because those do not require daily life-long anti-coagulant support therapy. However, BHV relative short durability (10-15 years) promotes use of mechanical heart valves in patients below age 50. Immune responses against the BHV are thought to play a major role in premature failure of BHV. BHV are manufactured from cardiac valve or pericardium tissues from animal sources (porcine, bovine and equine). We hypothesized that immune responses to carbohydrate antigens in those non-human tissues might contribute to BHV reduced durability. In vertebrates, cell surface carbohydrate chains (glycans) end with sialic acids (Sia). The two most common types of Sia are Neu5Ac and its hydroxylated form Neu5Gc. However, humans cannot synthesize Neu5Gc due to loss of CMAH gene. Thus, Neu5Gc is foreign to humans that induce an immune response against it. Here, we characterize the Sia content on porcine and bovine cardiac tissues and in seven most commonly used commercial BHV. We demonstrate that both animal-derived cardiac tissues and commercial BHV express Neu5Ac and Neu5Gc, and serum from healthy human donors recognize Neu5Gc-containing antigens on these tissues. Furthermore, affinity-purified anti-Neu5Gc IgG from polyclonal human IgG specifically binds Neu5Gc-glycoantigens on commercial BHV. Finally, using novel glyco-nanoparticles we developed a mouse model with induced expression of polyclonal anti-Neu5Gc IgG response that similarly recognized Neu5Gc-containing antigens on the BHV. In this model we further investigate the immune response effects on premature deterioration of BHV in-vivo.