Human α1‐antitrypsin modifies B ‐lymphocyte responses during allograft transplantation

Summary B‐lymphocyte activities are associated with allograft rejection. Interleukin‐10 (IL‐10) ‐expressing B cells, however, exhibit regulatory attributes. Human α1‐antitrypsin (h AAT ), a clinically available anti‐inflammatory circulating glycoprotein that rises during acute‐phase responses, promotes semi‐mature dendritic cells and regulatory T (Treg) cells during alloimmune responses. Whether B lymphocytes are also targets of h AAT activity has yet to be determined. Here, we examine whether h AAT modulates B ‐cell responses. In culture, h AAT reduced the lipopolysaccharide‐stimulated K i‐67 + B ‐cell population, I g M release and surface CD 40 levels, but elevated IL ‐10‐producing cells 1.5‐fold. In CD 40 ligand‐stimulated cultures, h AAT promoted a similar trend; reduction in the K i‐ 6 7 + B ‐cell population and in surface expression of CD 86, CD 80 and MHCII . hAAT increased interferon‐γ‐stimulated macrophage B ‐cell activating factor ( BAFF ) secretion, and reduced BAFF ‐receptor levels. Draining lymph nodes of transgenic mice that express circulating h AAT ( C 57 BL /6 background) and that received skin allografts exhibited reduced B‐lymphocyte activation compared with wild‐type recipients. BSA ‐vaccinated h AAT transgenic mice exhibited 2.9‐fold lower BSA‐specific I g G levels, but 2.3‐fold greater IgM levels, compared with wild‐type mice. C irculating T reg cells were 1.3‐fold greater in transgenic h AAT mice, but lower in B‐cell knockout ( BKO ) and chimeric h AAT – BKO mice, compared with wild‐type mice. In conclusion, B cells are cellular targets of h AAT . hAAT ‐induced T reg cell expansion appears to be B ‐cell‐dependent. These changes support the tolerogenic properties of h AAT during immune responses, and suggest that h AAT may be beneficial in pathologies that involve excessive B ‐cell responses.