Ischemia/reperfusion injury (IRI) has a major impact on short- and long-term renal allograft survival by increasing graft immunogenicity. Donor preconditioning by inducing heme oxygenase 1 (HO-1) has been proven to exert cytoprotective and antiinflammatory effects on the graft, thus resulting in reduced graft immunogenicity. The study analyzed the effects and mechanisms of HO-1-mediated cytoprotection in rat kidney transplants exposed to cold preservation. We studied the differential gene-expression patterns of allografts after either short or long cold ischemia using a customized cDNA microarray. Prolonged cold ischemia led, 12 h after engraftment, to enhanced levels of adhesion molecules, heat-shock proteins, chemokines (CXCL10), and a remarkable upregulation of immunoproteasomes. Next we addressed the question whether induction of HO-1 or its byproduct carbon monoxide (CO) in organ donors targets these candidate markers related to enhanced immunogenicity. Induction of HO-1 or CO in organ donors 24 h before organ harvesting resulted in reduced mRNA levels of immunoproteasomes, MHC class II expression, and co-stimulatory molecules in the recipient's spleen, suggesting diminished migration and activation of donor dendritic cells. This observation suggests that HO-1/CO induction protects marginal allografts by inhibiting the immunogenicity of donor-derived dendritic cells.
T cell depleting strategies are an integral part of immunosuppressive regimens widely used in the hematological and solid organ transplant setting. Although it is known to induce lymphocytopenia, little is known about the effects of the polyclonal rabbit antithymocyte globulin (rATG) or the monoclonal anti-CD52 antibody alemtuzumab on Natural Killer (NK) cells in detail. Here, we demonstrate that induction therapy with rATG following kidney/pancreas transplantation results in a rapid depletion of NK cells. Treatment of NK cells with rATG and alemtuzumab in vitro leads to impairment of cytotoxicity and induction of apoptosis even at a 10-fold lower concentration (0.1 µg/ml) compared with T and B cells. By generating Fc-parts of rATG and alemtuzumab we illustrate that their ligation to FcγRIII (CD16) is sufficient for the significant induction of degranulation, apoptosis and inflammatory cytokine release (FasL, TNFα and IFNγ) exclusively in CD3−CD56dim NK cells whereas application of rATG and alemtuzumab F(ab) fragments abolishes these effects. These findings are of general importance as our data suggest that NK cells are also mediators of the clinically relevant cytokine release syndrome and that their targeting by therapeutic antibodies should be considered as they are functionally relevant for the effective clearance of opportunistic viral infections and anti-tumor activity posttransplantation.
Aim: In the allogeneic transplant setting, NK cell infiltration of renal and cardiac allografts has been observed shortly after transplantation in both clinical and experimental models. This infiltration often occurs before evidence of T cell infiltration and is consistent with the role of NK cells as early innate effector cells.Recently it has been shown that host NK cells and not NKT cells contribute to heart allograft rejection in CD28 -/-deficient mice and that allograft infiltrating cells express activating receptors for donor MHC and low levels of inhibitory receptors (McNerney et al. 2006).Methods: To further elucidate the mechanisms by which NK cells promote cardiac allograft rejection we investigated gene expression profiles of activating NK cell receptors in grafts and host spleens during acute rejection in a well established murine cardiac transplant model (BALB/c into C57BL/6). Animals (nϭ4) were sacrificed after 7 days post transplantation and grafts were analysed by real-time RT-PCR.Scope: The analysis revealed in allogeneic hearts a significant induction of the activating receptor NKG2D and its associated protein DAP12 compared to syngeneic controls (pϽ0.001) whereas no differences for both markers could be observed in the spleen. A similar gene expression pattern could be detected for the activating receptor Ly49H. Although we expected higher frequencies of graft infiltrating NK cells bearing the activating NK cell receptor NKP46, no significant gene expression could be observed in acute rejecting allografts versus syngeneic controls.Conclusions: Our data confirm previous data from our group of elevated NKG2D mRNA expression in rejecting human kidney allografts but give further insights into the mechanisms mediated by NK cells and their subsets during solid organ transplant rejection.
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