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 (hAAT), 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 hAAT activity has yet to be determined. Here, we examine whether hAAT modulates B-cell responses. In culture, hAAT reduced the lipopolysaccharide-stimulated Ki-67⁺ B-cell population, IgM release and surface CD40 levels, but elevated IL-10-producing cells 1.5-fold. In CD40 ligand-stimulated cultures, hAAT promoted a similar trend; reduction in the Ki-67⁺ B-cell population and in surface expression of CD86, CD80 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 hAAT (C57BL/6 background) and that received skin allografts exhibited reduced B-lymphocyte activation compared with wild-type recipients. BSA-vaccinated hAAT transgenic mice exhibited 2.9-fold lower BSA-specific IgG levels, but 2.3-fold greater IgM levels, compared with wild-type mice. Circulating Treg cells were 1.3-fold greater in transgenic hAAT mice, but lower in B-cell knockout (BKO) and chimeric hAAT-BKO mice, compared with wild-type mice. In conclusion, B cells are cellular targets of hAAT. hAAT-induced Treg cell expansion appears to be B-cell-dependent. These changes support the tolerogenic properties of hAAT during immune responses, and suggest that hAAT may be beneficial in pathologies that involve excessive B-cell responses.