These investigators then went on to document distinct patterns of transcript manifestation in biopsies from grafts with early/cell-mediated rejection versus late/AMR.3 Early cell-mediated rejection was associated with transcripts indicative of T cell activation within the allograft (eg, CD3D, TcR chain, and CXCR6) whereas the late AMR episode transcript profiles were indicative of NK cell activation (eg, CX3CR1, KLRF1, MybL1, and Sh2D1B). and NK cell-associated transcripts and the presence of CD16+, but not CD3+, cells in biopsies from individuals with high DSA. These investigators then went on to document unique patterns of transcript manifestation in biopsies from grafts with early/cell-mediated rejection versus late/AMR.3 Early cell-mediated rejection was associated with transcripts indicative of T cell activation within the allograft (eg, CD3D, TcR chain, and CXCR6) whereas the late AMR episode transcript profiles were indicative of NK cell activation (eg, CX3CR1, KLRF1, MybL1, and Sh2D1B). These initial studies indicated the presence of NK cells in the microcirculation of kidney grafts during AMR. However, it has been more difficult to provide insights into mechanisms of NK cell function that might mediate kidney graft injury during AMR. In vitro studies have shown the role of the NK cellCexpressed Fc receptor, CD16a/FcRIIIa, Citiolone in antibody-mediated activation of NK cells to produce cytokines and mediate antibody-dependent cell-mediated cytotoxicity, resulting IL12RB2 in lysis of tumors and allogeneic bone marrow cells.4 In the current issue of em Transplantation /em , Citiolone Parkes5 have used a clever strategy to link CD16a signaling during NK cell activation within kidney grafts during AMR. First, activation of peripheral blood NK cells in vitro by crosslinking CD16a resulted in the upregulated manifestation of more than 270 transcripts when compared with transcript profiles from control, nonactivated NK cells. Then, the CD16a-triggered NK cell transcript profile was compared with the profile acquired in kidney graft biopsies during AMR to identify 8 shared transcripts. Two of these shared transcripts are unique to NK cells, the chemokine XCL1 and CD160, a glycoprotein indicated on NK cells and T cells. One interesting facet of these studies is that the upregulation of the previous NK cell transcript profile they had reported during AMR was not observed during crosslinking of Citiolone CD16a within the NK cells, suggesting that expression of these genes is more likely constitutively indicated by NK cells. The key observation of these studies is the recognition of 2 genes indicated during CD16a-mediated activation of NK cells that appear in biopsies during ongoing AMR. An obvious caveat is definitely that such CD16a-mediated NK cell activation is certain to occur in an inflammatory environment within the graft that is not present in the in vitro study design. DSA binding to the graft microvasculature may induce the manifestation of endothelial adhesion molecules, chemokines, or additional proinflammatory cytokines that could synergize with signals transduced by CD16a crosslinking to provoke additional functions of the NK cells during AMR. With this in mind, it might be useful extending the current in vitro studies by screening the effect of integrin, chemokine receptor, and/or cytokine activation within the transcription profile following CD16a crosslinking on NK cells. Although these studies provide strong evidence linking NK cell activation through CD16a crosslinking with AMR, Citiolone the CD16a induced functions that mediate graft injury remain unclear. In mouse models, cotransfer of allograft-reactive monoclonal antibody and NK cells to immunodeficient recipients of heterotopically transplanted heart allografts has advertised the development of graft aortic vasculopathy.6,7 These studies possess recognized NK cellCderived IFN- as an important mediator of this vasculopathy, and studies from your Gill laboratory have indicated that both NK cell IFN- and cytolytic function mediated through either FasL or perforin/granzyme B are required for the cardiac allograft vasculopathy. NK cells have also been implicated in antibody-independent kidney allograft injury in crazy type and Rag1?/? mice as allograft injury was reduced in recipients treated with NK cellCdepleting antibodies.8 In support of the clinical studies,.