Human leucocyte antigen-G and its recognition by natural killer cells.
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Animals↗
Biomedical subjects
J D Seebach
Publications and source records attributed to J D Seebach.
[Mechanisms of xenotransplant rejection].
The recent shortage of allogeneic human organs in transplantation medicine has led to a renewed interest in evaluating the feasibility of xenotransplantation, particularly of porcine origin. Discordant xenotransplants between phylogenetically distant species such as pig and primates are challenged by a series of strong rejection reactions. Hyperacute rejection is dominantly mediated by humoral responses of the immune system (natural antibodies, complement cascade) and the activation of coagulation factors, whereas delayed xenograft rejection and T-cell mediated responses are also mediated by elements of the cellular immune system. The mechanisms of chronic xenograft rejection remain to be elucidated. The present review is focused on the mechanisms of rejection and the immunobiology of discordant, vascularized xenotransplants. We attempt to provide a brief description of the dynamics, the humoral and cellular mediators, and the pathogenesis of xenograft rejection. Finally, an overview on potentially therapeutic strategies to overcome xenograft rejection is presented.
Animals↗
Cross-species interaction of porcine and human integrins with their respective ligands: implications for xenogeneic tolerance induction.
BACKGROUND: Organ transplantation is limited by the number of available donors. One possible solution would be the use of pigs as organ donors. However, current immunosuppressive protocols cannot prevent rejection of these organs. If donor-specific tolerance toward porcine antigens could be induced in recipients, subsequent implantation of porcine organs would be possible without further immunosuppression. Induction of tolerance can be achieved with a bone marrow transplant if donor antigen-presenting cells successfully differentiate in the recipient thymus to induce deletion of donor-reactive host cells. Migration of porcine progenitor cells to the host marrow and thymus and differentiation into tolerance-inducing antigen-presenting cells is likely to require successful interaction of porcine adhesion molecules with human ligands. In this study, we investigated whether very late antigen (VLA)4 and VLA-6 integrins, which play important roles in homing and differentiation of hematopoietic progenitor cells, function across the pig-to-human species barrier. METHODS: Static cell-to-cell and cell-to-extracellular matrix protein adhesion assays were used to examine the cross-species interaction of porcine adhesion molecules with human ligands. RESULTS: Our studies show that porcine cells adhere to various human endothelial cell monolayers and extracellular matrix proteins and demonstrate that porcine VLA-4 and VLA-6 appear to be fully cross-reactive to the human ligands vascular cell adhesion molecule-1 and laminin, respectively. CONCLUSIONS: It is likely that porcine hematopoietic progenitor cells will be able to successfully employ pVLA-4- and pVLA-6-human ligand interactions in a pig-to-human bone marrow transplantation model in order to induce donor-specific tolerance.
Animals↗
Species differences in the expression of major histocompatibility complex class II antigens on coronary artery endothelium: implications for cell-mediated xenoreactivity.
BACKGROUND: There is controversy in the literature as to whether swine coronary endothelium expresses major histocompatibility complex (MHC) class II antigens constitutively. METHODS: Because this issue has implications for cell-mediated human anti-swine xenogeneic responses, we stained tissue sections from human, pig, rat, and mouse hearts with the anti-class II monoclonal antibody ISCR3, which has a similar specificity and titer when binding to human, porcine, and rodent class II molecules. RESULTS: Immunoperoxidase staining of human and porcine hearts with ISCR3 resulted in a dense reaction on the coronary endothelium of epicardial arteries, intramuscular arterioles, and capillaries. In contrast, the coronary endothelium of rat and mouse hearts did not stain with ISCR3. When freshly harvested porcine aortic endothelial cells were placed in culture, class II MHC antigen expression was lost within three to four passages. CONCLUSIONS: Thus, using a single antibody with cross-species reactivities, we demonstrate that swine coronary endothelium, unlike rodent coronary arteries, expresses similar basal amounts of class II MHC antigens to human coronary vessels. The constitutive expression of class II MHC antigens on swine coronary artery endothelium may contribute to host T cell-mediated xenogeneic responses in clinical pig-to-human cardiac xenotransplantation and thus become a target for therapeutic intervention.
Aged↗
HLA-Cw3 expression on porcine endothelial cells protects against xenogeneic cytotoxicity mediated by a subset of human NK cells.
There is increasing evidence that NK cells make an important contribution to human anti-porcine xenogeneic cytotoxicity. Most allogeneic as well as autologous normal cells are not susceptible to NK cell-mediated cytotoxicity because they express inhibitory molecules encoded within the MHC class I loci. The protective signal is delivered to NK cells through killer cell-inhibitory receptors expressing different MHC class I specificities. It has been proposed that xenogeneic target cells may be susceptible to NK cell-mediated lysis because their MHC class I molecules fail to be recognized by human killer cell-inhibitory receptors. To explore this hypothesis, we examined the effect of human MHC class I expression on porcine target cell lysis by human NK cells. An immortalized porcine bone marrow-derived endothelial cell line (2A2) was transfected with three different human MHC class I allelic genes (HLA-A2, -B27, or -Cw3). The cytotoxic activity of several GL183+ NK clones, which lysed untransfected porcine cells effectively, was substantially blocked by the presence of HLA-Cw3. In contrast, HLA-Cw3-positive cells were not protected against lysis by GL183- EB6+ NK clones. The expression of HLA-B27 or HLA-A2 molecules on pig target cells did not provide substantial protection from lysis by any of the NK clones tested. In addition to confirming the hypothetical basis of NK cell-mediated killing of xenogeneic targets, these results have practical implications as an approach to overcoming NK cell-mediated cytotoxicity, which may be an obstacle to pig-to-human xenotransplantation.
Animals↗
Human cell-mediated rejection of porcine xenografts in an immunodeficient mouse model.
BACKGROUND: In this study, we describe the development of a novel experimental system in which rejection of porcine skin grafts by human peripheral blood cells can be studied directly in vivo in immunodeficient mice. METHODS: To construct a small animal model of discordant xenograft rejection, recombinase-activating gene-deficient mice (R-) lacking both mature B and T cells were grafted with porcine skin grafts and administered, by adoptive cell transfer, human cells stimulated in vitro with irradiated porcine peripheral blood cells to create Hu-R- mice. RESULTS: R- mice accepted porcine skin grafts indefinitely without the need for immunosuppression. In contrast, Hu-R- mice were able to reject porcine skin grafts. Immunohistochemical analysis of rejecting skin grafts revealed the accumulation of human T cells around dermal porcine vessels and focally in the epidermis. Graft rejection was manifested by vascular endothelial cell proliferation, edema at the dermal-epidermal border, and perivascular hemorrhage. The tissue damage observed in the rejecting grafts was similar to that observed in delayed primate anti-porcine cell-mediated rejection of vascularized organ xenografts. CONCLUSIONS: The development and characterization of a small animal model, to study cellular immune responses of human cells to discordant xenografts in vivo, should provide a convenient means for asking mechanistic questions related to discordant xenotransplantation, and may also provide a practical system for testing new approaches designed to prevent xenograft rejection.
Adoptive Transfer↗
The diagnostic value of the neutrophil left shift in predicting inflammatory and infectious disease.
The use of neutrophil left-shift parameters in the diagnosis of inflammatory and infective disease (ID) was evaluated. The level of C-reactive protein (CRP), currently the best quantitative parameter of inflammation, was used as the gold standard. Of 292 patients, 230 (79%) had a level of CRP of 1.0 mg/dL or greater and were classified as having inflammation, whereas 62 (21%) had normal levels. The neutrophil band count in each patient was determined by microscopic examination of 200 WBCs. The diagnostic value of the band count as an indicator for ID was evaluated in comparison to the WBC count, the neutrophil count, and the left-shift indicators of two automated hematologic analyzers, H*1 Technicon (Bayer Technicon Instruments, Tarrytown, NY) and Coulter MAX M (Coulter Electronics, Hialeah, Fla). When receiver operating characteristics were used, the band count was superior to the immature to total neutrophil count (I/T) ratio, the total WBC count, and the neutrophil count. The sensitivity and specificity in identifying ID at designated cutoff points were as follows: band count of 20% or greater of total WBC count (53% and 79%, respectively), I/T ratio of 0.25 or greater (59% and 63%), total WBC count of 9.6 x 10(6)/mL or greater (68% and 56%), and neutrophil count of 8.0 x 10(6)/mL or greater (60% and 58%). The performance of the H*1 Technicon left-shift flag was similar but slightly inferior to the band count (sensitivity, 44%; specificity, 79%), whereas the Coulter MAX M flags had a clearly higher sensitivity (79%) and lower specificity (53%). In addition, microscopic evaluation to determine the presence of reactive morphologic changes in neutrophils, such as toxic granules, Döhle bodies, and cytoplasmic vacuoles, had a high sensitivity (80%) but a low specificity (58%) in predicting ID. The diagnostic value of both microscopic and automated neutrophil left-shift parameters as indicators for ID is limited. Morphologic changes in neutrophils, however, either have a high specificity (band count) or a high sensitivity (toxic signs) in predicting ID and therefore may be a clinically useful tool.
Adolescent↗
Human NK cells lyse porcine endothelial cells via the perforin/granzyme B pathway.
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Animals↗
Adhesive interactions between human NK cells and porcine endothelial cells.
Human natural killer (NK) cells are able to adhere to xenogeneic porcine endothelial cells (EC) and evidence from in vitro studies as well as animal models suggests a potential role for NK cells in the cellular recognition and damage of porcine xenogeneic tissues. One possible explanation for the observed NK cell-mediated xenogeneic cytotoxicity against porcine EC is the molecular incompatibility between porcine major histocompatibility complex (MHC) class I molecules and MHC-specific inhibitory receptors on human NK cells. In this review we attempt to summarize the current knowledge concerning adhesive interactions between human NK cells and porcine EC under special considerations of the cross-species receptor-ligand interactions. Methodological differences in assessing adhesion between various studies are reviewed and comparisons to the syngeneic/allogeneic adhesion mechanisms are made. Finally, the therapeutic potential of blocking antibodies and transgenic HLA expression in preventing NK-cell adhesion and xenogeneic cytotoxicity is discussed.
Animals↗