Threshold Alpha-gal Immunogenicity For In-vitro Assays And Implications For Early Valvular Degradation
Joseph R. Nellis1, Jacob C. Scherba1, Max J. Muller1, Scott P. Commins2, Shailesh K. Choudhary2, John R. Bianchi3, Joseph W. Turek1.
1Duke University, Durham, NC, USA, 2University of North Carolina, Chapel Hill, NC, USA, 3Revivicor Inc, Blacksburg, VA, USA.
OBJECTIVE: Alpha-gal is one of the three major antigens associated with acute rejection in xenotransplantation and continues to be present on commercially available bioprosthetic heart valves. Although generally well tolerated, there are case reports of patients with alpha-gal syndrome (AGS) experiencing early valve degradation (EVD). AGS is a chronic allergic reaction against alpha-gal, occurs following a sensitization event and IgE seroconversion, and affects 20% of people in the Southeastern United States. The diagnosis of AGS is made with serum alpha-gal IgE >0.1 IU/mL and clinical symptoms. The goal of our project was to quantify residual alpha-gal on commercial heart valves, establish reactivity thresholds between these valves and alpha-gal IgE titers, and evaluate for the presence of serum alpha-gal IgE in patients experiencing EVD.
METHODS: Indirect ELISA was used to quantify residual alpha-gal on commercially available heart valves from Abbott and Edwards. Immunohistochemistry was then performed on these materials using serum from AGS patients with known alpha-gal IgE titers. Lastly, alpha-gal IgE titers were calculated for patients experiencing EVD at a single heart center in the Southeastern United States. Native pig pericardium and human pulmonary allograft served as positive and negative controls. Alpha-gal knockout porcine pericardium also served as a negative control.
RESULTS: Bioprosthetic heart valves from Abbott and Edwards contained 30 and 40 billion alpha-gal epitopes per mg of tissue respectively. Threshold reactivity was observed at 0.45 IU/ml alpha-gal IgE for native pig pericardium and the porcine-derived Abbott valve. Threshold reactivity was higher for the Edwards, bovine-derived, bioprosthetic valve (6.75 IU/ml). Early trends suggest alpha-gal IgE may be associated with EVD.
CONCLUSIONS: AGS may contribute to EVD particularly for patients with alpha-gal IgE titers >6.75 IU/mL. Bioprosthetic valves engineered from genetically-modified, alpha-gal knockout pigs may avoid EVD in select patients.
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