title: B-cell activation and allosensitization after left ventricular assist device implantation is due to T-cell activation and CD40 ligand expression.
abstract: Left ventricular assist device (LVAD) implantation is frequently complicated by B-cell activation and allosensitization, posing a significant risk to successful transplant outcome. This study investigated whether B-cell hyperreactivity and alloantibody production in LVAD recipients involves T-cell dependent pathways. T-cell calcium flux and nuclear translocation of NFATc were used to determine states of T-cell activation. Flow cytometry was used to assess human T- and B-cell activation after culture with LVAD-derived biomaterial particles. Sera from LVAD recipients and controls were tested for the presence of anti-HLA antibodies, and for soluble CD40 ligand. LVAD-derived biomaterial induced rapid and sustained calcium flux into normal T cells, resulting in calcineurin-dependent nuclear translocation of NFATc. This resulted in increased T-cell expression of CD40 ligand and subsequent B-cell activation, which was reduced by inhibitors of T-cell activation (CsA or anti-CD25 mAb) or by anti-CD40 ligand mAb. LVAD recipients demonstrated higher frequencies of anti-HLA antibodies and serum levels of soluble CD40 ligand compared with heart failure controls. The results indicate that exposure of human mononuclear cells to LVAD-derived biomaterial leads to T-cell dependent B-cell activation via CD40--CD40 ligand interaction, and suggest that treatment with calcineurin inhibitors or monoclonal antibodies against either CD25 or CD40 ligand could be effective at preventing B-cell hyperreactivity and allosensitization after LVAD implantation.
authors.affiliation: College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Schuster
authors.forename: Alfred
authors.initials: A
authors.lastname: Kocher
authors.forename: Ranjit
authors.initials: R
authors.lastname: John
authors.forename: Marion
authors.initials: M
authors.lastname: Hoffman
authors.forename: Jan
authors.initials: J
authors.lastname: Ankersmit
authors.forename: Katherine
authors.initials: K
authors.lastname: Lietz
authors.forename: Niloo
authors.initials: N
authors.lastname: Edwards
authors.forename: Mehmet
authors.initials: M
authors.lastname: Oz
authors.forename: Silviu
authors.initials: S
authors.lastname: Itescu
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006680:HLA Antigens / Q000276:immunology; D006333:Heart Failure / Q000276:immunology / Q000601:surgery; D006353:Heart-Assist Devices; D006801:Humans; D007518:Isoantibodies / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D011140:Polyurethanes / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D006680:HLA Antigens; D007518:Isoantibodies; D011140:Polyurethanes; D023201:CD40 Ligand; D019703:Calcineurin; D002118:Calcium