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      Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injury

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          Abstract

          The susceptibility of xenografts to hyperacute rejection is postulated to reflect in part failure of complement regulatory proteins (CRPs) to control activation of heterologous complement on graft endothelium. To test this concept, transgenic swine expressing the human CRP decay accelerating factor and CD59 were developed using a novel expression system involving transfer of the proteins from erythrocytes to endothelial cells. Hearts from transgenic swine transplanted into baboons had markedly less vascular injury and functioned for prolonged periods compared to hearts from nontransgenic swine. These results indicate that expression of human CRPs in xenogeneic organs may contribute to successful xenografting and suggest that intercellular protein transfer might be a useful approach for expression of heterologous proteins in endothelial cells.

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          Most cited references 17

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          CD59, an LY-6-like protein expressed in human lymphoid cells, regulates the action of the complement membrane attack complex on homologous cells

          A novel cell surface antigen has been identified on a wide range of lymphoid cells and erythrocytes. A mAb YTH 53.1 (CD59) against this antigen enhanced the lysis of human red cells and lymphocytes by homologous complement. Studies of reactive lysis using different species of C56, and of whole serum used as a source of C7-9, indicated that the inhibitory activity of the CD59 antigen is directed towards the homologous membrane attack complex. CD59 antigen was purified from human urine and erythrocyte stroma by affinity chromatography using the mAb YTH 53.1 immobilized on Sepharose, and, following transient expression of a human T cell cDNA library in COS cells, the corresponding cDNA also identified using the antibody. It was found that the CD59 antigen is a small protein (approximately 20 kD as judged by SDS-PAGE, 11.5 kD predicted from the isolated cDNA) sometimes associated with larger components (45 and 80 kD) in urine. The sequence of CD59 antigen is unlike that of other complement components or regulatory proteins, but shows 26% identity with that of the murine LY- 6 antigen. CD59 antigen was released from the surface of transfected COS cells by phosphatidylinositol-specific phospholipase C, demonstrating that it is attached to the cell membrane by means of a glycolipid anchor; it is therefore likely to be absent from the surface of affected erythrocytes in the disease paroxysmal nocturnal hemoglobinuria.
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            Transplantation of discordant xenografts: a review of progress.

            Hyperacute rejection, apparently initiated by natural antibodies and complement, has been viewed as an absolute barrier to the xenotransplantation of vascularized grafts between different species. Until recently, little was known about the molecular and physiological basis for this barrier nor was there evidence that the barrier might be more than transiently breached. In this paper Jeffrey Platt, Fritz Bach and colleagues describe a model of hyperacute rejection and propose that, if hyperacute rejection can be averted for a period after transplantation, prolonged xenograft survival will be possible.
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              Immunopathology of hyperacute xenograft rejection in a swine-to-primate model.

              Hyperacute rejection is the inevitable consequence of the transplantation of vascularized organs between phylogenetically distant species. The nature of the incompatibility and the pathogenetic mechanisms that lead to hyperacute xenograft rejection are incompletely understood. We investigated these issues by the immunopathological analysis of tissues from swine renal and cardiac xenografts placed in rhesus monkeys. Hyperacute rejection was associated with deposition of recipient IgM and classic but not alternative complement pathway components along endothelial surfaces, the formation of platelet and fibrin thrombi, and the infiltration of neutrophils. In animals from which natural antibody was temporarily depleted by organ perfusion, rejection was observed at 3 days to 5 days posttransplant. The immunopathology of rejection in these tissues revealed focal vascular changes similar to those observed in hyperacute rejection. A xenograft functioning for a prolonged period in a recipient temporarily depleted of circulating natural antibody contained recipient IgM along endothelial surfaces but no evidence for significant deposition of complement, formation of platelet and fibrin thrombi, or infiltration of neutrophils. These results suggest that rhesus IgM contributes significantly to the development of hyperacute rejection in the swine to Rhesus model and that the fixation of complement is a critical factor in the recruitment of the coagulation cascade and platelet aggregation--and possibly in the adherence and infiltration of PMN.
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                Author and article information

                Journal
                Nature Medicine
                Nat Med
                Springer Science and Business Media LLC
                1078-8956
                1546-170X
                May 1995
                May 1 1995
                May 1995
                : 1
                : 5
                : 423-427
                Article
                10.1038/nm0595-423
                7585088
                © 1995

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