Donor specific antibody mediates chronic allograft vasculopathy through NK cells in an Fc-dependent manner, independent of complement.
Does donor specific antibody mediate chronic allograft vasculopathy through NK cells in murine heart allografts?
Donor specific antibody mediates chronic allograft vasculopathy through an Fc-dependent, NK cell-mediated pathway, providing a potential mechanism for C4d-negative chronic antibody-mediated rejection.
Chronic allograft vasculopathy (CAV) in murine heart allografts can be elicited by adoptive transfer of donor specific antibody (DSA) to class I MHC antigens and is independent of complement. Here we address the mechanism by which DSA causes CAV. B6.RAG1(-/-) or B6.RAG1(-/-)C3(-/-) (H-2(b)) mice received B10.BR (H-2(k)) heart allografts and repeated doses of IgG2a, IgG1 or F(ab')(2) fragments of IgG2a DSA (anti-H-2(k)). Intact DSA regularly elicited markedly stenotic CAV in recipients over 28 days. In contrast, depletion of NK cells with anti-NK1.1 reduced significantly DSA-induced CAV, as judged morphometrically. Recipients genetically deficient in mature NK cells (γ-chain knock out) also showed decreased severity of DSA-induced CAV. Direct NK reactivity to the graft was not necessary. F(ab')(2) DSA fragments, even at doses twofold higher than intact DSA, were inactive. Graft microvascular endothelial cells responded to DSA in vivo by increased expression of phospho-extracellular signal-regulated kinase (pERK), a response not elicited by F(ab')(2) DSA. We conclude that antibody mediates CAV through NK cells, by an Fc dependent manner. This new pathway adds to the possible mechanisms of chronic rejection and may relate to the recently described C4d-negative chronic antibody-mediated rejection in humans.
Hirohashi et al. (Wed,) conducted a other in Chronic allograft vasculopathy. Donor specific antibody (DSA) and NK cell depletion vs. Intact DSA vs F(ab')2 fragments / NK cell depletion vs no depletion was evaluated on Severity of DSA-induced CAV. Donor specific antibody mediates chronic allograft vasculopathy through NK cells in an Fc-dependent manner, independent of complement.