A Novel Pathway of Chronic Allograft Rejection Mediated by NK Cells and Alloantibody

Abstract

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-2b) mice received B10.BR (H-2k) heart allografts and repeated doses of IgG2a, IgG1 or F(ab’)2 fragments of IgG2a DSA (anti-H-2k). 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.

What’s New and What’s Hot? Basic Science at the American Transplant Congress 2012

“…NK cell burden and production of endothelial activation transcripts correlated with chronic ABMR and graft loss. These data are consistent with the growing evidence that NK cells play a previously underestimated role in ABMR (10)(11)(12) New roles for the innate immune system can also be demonstrated in Rag knockout mice deficient for T and B cells. In this model, NK cells are the primary effector cells in rejection of allogeneic cells in naive mice.…”

Non-Complement–Binding De Novo Donor-Specific Anti-HLA Antibodies and Kidney Allograft Survival

“…26 On the one hand, as C1q is the complement classic pathway's first protagonist, the ability of DSA to bind C1q in vitro should determine its ability to activate the complement cascade in vivo, 27 before membrane attack complex formation and subsequent lysis of renal endothelial cells, which lead relatively quickly to graft loss. On the other hand, C1q2 dnDSAs could cause long-term graft loss independently of complement activation by inducing persistent microcirculation inflammation and antibody-dependent cell cytotoxicity, 28,29 or by direct activation of endothelial cell survival and proliferation. 30 The association between complement-binding ability and time to graft loss in patients with DSAcouldalso have a therapeutic effect.…”

The Cell Biology of Cytomegalovirus: Implications for Transplantation

“…In solid organ transplant patients, acute CMV infection increases the CD57+ NKGDC hi (memory phenotype) pool, which appears to be CMV specific (179). The effects of CMV and NK cells in the setting of MHC-mismatched grafts are linked to coronary vasculopathy and renal graft injury (180)(181)(182)(183)(184)(185)(186)(187)(188). In part, this is mediated by cytokine-mediated stimulation of alloreactive T cells and by direct alloimmune injury (156).…”