title: Human α1-antitrypsin modifies B-lymphocyte responses during allograft transplantation.
abstract: 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.
authors.affiliation: Faculty of Health Sciences, Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Mark
authors.initials: M
authors.lastname: Mizrahi
authors.forename: Pablo
authors.initials: P
authors.lastname: Cal
authors.forename: Martin
authors.initials: M
authors.lastname: Rosenthal
authors.forename: David
authors.initials: D
authors.lastname: Ochayon
authors.forename: Galit
authors.initials: G
authors.lastname: Shahaf
authors.forename: Ziv
authors.initials: Z
authors.lastname: Kaner
authors.forename: Peter
authors.initials: P
authors.lastname: Kachker
authors.forename: Eli C
authors.initials: EC
authors.lastname: Lewis
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D053264:B-Cell Activating Factor / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects; D007075:Immunoglobulin M / Q000097:blood; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014184:Transplantation, Homologous; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D053264:B-Cell Activating Factor; D007075:Immunoglobulin M; D000515:alpha 1-Antitrypsin; D016753:Interleukin-10
keywords: B-cell activating factor (BAFF); interleukin-10; regulatory B cells; regulatory T cells; tolerance