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Hyperacute Rejection (hyperacute + rejection)
Selected AbstractsDONOR ORGANS TRANSGENIC FOR HUMAN COMPLEMENT REGULATORY FACTORS TO OVERCOME XENOGRAFT HYPERACUTE REJECTION: SMALL ANIMAL VX PIG-TO-PRIMATE IN VIVO MODELSNEPHROLOGY, Issue 3 2000Gock H [source] Immunoaffinity removal of xenoreactive antibodies using modified dialysis or microfiltration membranesBIOTECHNOLOGY & BIOENGINEERING, Issue 2 2003Sujatha Karoor Abstract Hyperacute rejection following xenogeneic transplantation in primates is mediated by naturally occurring IgM antibodies, which are specifically directed to ,-Galactosyl residues on many nonprimate mammalian cells. Current approaches to remove these anti-,Gal IgM include plasmapheresis followed by immunoaffinity adsorption on bead columns using synthetic Gal epitopes, which requires two pieces of complex equipment. In this study, we explored the use of immunoaffinity adsorption with hollow fiber microporous or dialysis membranes to which a synthetic ,Gal trisaccharide ligand is bound. Covalent attachment of ligand directly to the surface produced negligible binding, but use of long-chain polyamines as reactive spacers yielded binding densities for anti-,Gal IgM as high as 89 mg/mL membrane volume in breakthrough curve experiments with microporous nylon membranes having an internal surface area of 4.2 m2/mL membrane volume. A crossflow microfilter fabricated from the membranes described in this study and having about 0.4 m2 luminal surface area would be able to carry out plasma separation and immunoadsorption in a single device with a large excess of binding capacity to ensure that all plasma that filters across the device and is returned to a human patient is essentially free of anti-,Gal IgM. We conclude that immunoaffinity removal of xenoreactive antibodies using microfiltration hollow fiber membranes is feasible and has potential advantages of efficiency and simplicity for clinical application. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 134,148, 2003. [source] The Immunological Hurdles to Cardiac XenotransplantationJOURNAL OF CARDIAC SURGERY, Issue 6 2001Jeffrey L. Platt M.D. ABSTRACT The main hurdle to clinical application of cardiac xenotransplantation is the immune response of the recipient against the graft. Although all xenografts arouse an intense immune response, the effect of that response depends very much on whether the graft consists of isolated cells or an intact organ, such as the heart. Intact organs, which are transplanted by primary vascular anastomosis, are subject to severe vascular injury owing to the reaction of immune elements with the endothelial lining of donor blood vessels. Vascular injury leads to hyperacute rejection, acute vascular rejection, and chronic rejection. The immunological basis for these types of rejection and potential therapies, which might be used to avert them, are discussed. [source] The Pathology of Cardiac XenograftsJOURNAL OF CARDIAC SURGERY, Issue 5 2001Matilde Bustos M.D. ABSTRACT The pathology of cardiac xenografts has yielded critical insights into the mechanisms of xenograft rejection and the therapeutic procedures that might be applied to preventing or treating it. The conditions seen in rejecting cardiac xenografts include hyperacute rejection, acute vascular rejection, and cellular rejection. Hyperacute and acute vascular rejection of cardiac xenografts have features typical of humoral injury. Less is known about cellular rejection and only speculation can be offered about chronic rejection. Still, these features allow critical testing of pathogenetic mechanisms and therapies. [source] Biostability and pharmacokinetics of LJP 920, an octameric Gal (,1,3) Gal conjugate for the inhibition of xenotransplantation rejectionJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2001Lee Jia Antibodies to an ,-galactosyl saccharide structure present in human serum are associated with hyperacute rejection and delayed xenograft rejection after pig-to-primate xenotransplantation. To overcome this major barrier to the xenotransplantation, LJP 920, a galactosyl ,1,3 galactose (Gal (,1,3) Gal) coupled to a non-immunogenic platform at a valency of eight Gal (,1,3) Gal molecules/platform, was synthesized to clear circulating antibodies and to inhibit their production by B cells that produce these antibodies. Herein we report on the stability of LJP 920 in biological media and its pharmacokinetic profile. Incubation of LJP 920 with mouse serum or liver microsomes at 37°C for 2 days showed no indication of degradation of the conjugate as detected by a reversed-phase HPLC method, indicating that the conjugate is not subject to enzymatic metabolism. After intravenous administration of LJP 920 to mice at the doses of 20 and 100 mg kg,1, LJP 920 serum concentration decreased rapidly, showing a biphasic pattern, with a distribution half-life of 3 min and an elimination half-life of more than 30 min, respectively. The serum-to-erythrocyte concentration ratio of LJP 920 was 33- and 36-fold excess at 0.5 and 5 min, respectively, after intravenous administration (100 mg kg,1). Both Cmax and AUC values increased in a dose-proportional manner. LJP 920 displayed a great distribution to well-perfused tissues. It was eliminated mainly through renal excretion in the unchanged form, which accounted for 23% of the total amount within 8 h of dosing. [source] Recipient Tissue Factor Expression Is Associated With Consumptive Coagulopathy in Pig-to-Primate Kidney XenotransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2010C. C. Lin Consumptive coagulopathy (CC) remains a challenge in pig-to-primate organ xenotransplantation (Tx). This study investigated the role of tissue factor (TF) expression on circulating platelets and peripheral blood mononuclear cells (PBMCs). Baboons (n = 9) received a kidney graft from pigs that were either wild-type (n = 2), ,1,3-galactosyltransferase gene-knockout (GT-KO; n = 1) or GT-KO and transgenic for the complement-regulatory protein, CD46 (GT-KO/CD46, n = 6). In the baboon where the graft developed hyperacute rejection (n = 1), the platelets and PBMCs expressed TF within 4 h of Tx. In the remaining baboons, TF was detected on platelets on post-Tx day 1. Subsequently, platelet-leukocyte aggregation developed with formation of thrombin. In the six baboons with CC, TF was not detected on baboon PBMCs until CC was beginning to develop. Graft histopathology showed fibrin deposition and platelet aggregation (n = 6), but with only minor or no features indicating a humoral immune response (n = 3), and no macrophage, B or T cell infiltration (n = 6). Activation of platelets to express TF was associated with the initiation of CC, whereas TF expression on PBMCs was concomitant with the onset of CC, often in the relative absence of features of acute humoral xenograft rejection. Prevention of recipient platelet activation may be crucial for successful pig-to-primate kidney Tx. [source] Results of Gal-Knockout Porcine Thymokidney XenograftsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2009A. D. Griesemer Clinical transplantation for the treatment of end-stage organ disease is limited by a shortage of donor organs. Successful xenotransplantation could immediately overcome this limitation. The development of homozygous ,1,3-galactosyltransferase knockout (GalT-KO) pigs removed hyperacute rejection as the major immunologic hurdle to xenotransplantation. Nevertheless, GalT-KO organs stimulate robust immunologic responses that are not prevented by immunosuppressive drugs. Murine studies show that recipient thymopoiesis in thymic xenografts induces xenotolerance. We transplanted life-supporting composite thymokidneys (composite thymus and kidneys) prepared in GalT-KO miniature swine to baboons in an attempt to induce tolerance in a preclinical xenotransplant model. Here, we report the results of seven xenogenic thymokidney transplants using a steroid-free immunosuppressive regimen that eliminated whole-body irradiation in all but one recipient. The regimen resulted in average recipient survival of over 50 days. This was associated with donor-specific unresponsiveness in vitro and early baboon thymopoiesis in the porcine thymus tissue of these grafts, suggesting the development of T-cell tolerance. The kidney grafts had no signs of cellular infiltration or deposition of IgG, and no grafts were lost due to rejection. These results show that xenogeneic thymus transplantation can support early primate thymopoiesis, which in turn may induce T-cell tolerance to solid organ xenografts. [source] Platelets Influence Vascularized Organ Transplants from Start to FinishAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2009A. D. Kirk This review relates the basic functions of platelets to specific aspects of organ allograft rejection. Platelet activation can occur in the donor or recipient before transplantation as well as during antibody- and cell-mediated rejection. Biopsies taken during organ procurement from cadaver donors have documented that activated platelets are attached to vascular endothelial cells or leukocytes. In addition, many patients waiting for transplants have activated platelets due to the diseases that lead to organ failure or as a result of interventions used to support patients before and during transplantation. The contribution of platelets to hyperacute rejection of both allografts and xenografts is well recognized. Intravascular aggregates of platelets can also be prominent in experimental and clinical transplants that undergo acute antibody or cell-mediated rejection. In acute rejection, platelets can recruit mononuclear cells by secretion of chemokines. After contact, monocytes, macrophages and T cells interact with platelets through receptor/ligand pairs, including P-selectin/PSGL-1 and CD40/CD154. There is a potential for therapy to inhibit platelet mediated immune stimulation, but it is counterbalanced by the need to maintain coagulation in the perioperative period. [source] Engraftment of Adult Porcine Islet Xenografts in Diabetic Nonhuman Primates Through Targeting of Costimulation PathwaysAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2007K. Cardona Recent advances in human allogeneic islet transplantation have established ,-cell replacement therapy as a potentially viable treatment option for individuals afflicted with Type 1 diabetes. Two recent successes, one involving neonatal porcine islet xenografts transplanted into diabetic rhesus macaques treated with a costimulation blockade-based regimen and the other involving diabetic cynomolgus monkeys transplanted with adult porcine islet xenografts treated with an alternative multidrug immunosuppressive regimen have demonstrated the feasibility of porcine islet xenotransplantation in nonhuman primate models. In the current study, we assessed whether transplantation of adult porcine islet xenografts into pancreatectomized macaques, under the cover of a costimulation blockade-based immunosuppressive regimen (CD28 and CD154 blockade), could correct hyperglycemia. Our findings suggest that the adult porcine islets transplanted into rhesus macaques receiving a costimulation blockade-based regimen are not uniformly subject to hyperacute rejection, can engraft (2/5 recipients), and have the potential to provide sustained normoglycemia. These results provide further evidence to suggest that porcine islet xenotransplantation may be an attainable strategy to alleviate the islet supply crisis that is one of the principal obstacles to large-scale application of islet replacement therapy in the treatment of Type 1 diabetes. [source] Modulation of the pathology of late xenograft rejection by PAF-antagonist UR-12670 in the hamster-to-rat liver xenotransplant model,APMIS, Issue 3 2003PAF antagonist alleviates xenogeneic rejection PAF antagonists have been used in xenotransplantation to alleviate the pathogenesis of hyperacute rejection. This study evaluated the ability of the PAF antagonist UR-12670 to improve graft function in late xenograft rejection (LXR) in an orthotopic liver xenotransplantation model, and the involvement of PAF (platelet activating factor) in this type of rejection. The recipients of a hamster xenograft received standard immunosuppression (tacrolimus 0.2 mg/kg/30 days, MMF 25 mg/kg/8 days). Study groups: group A, without UR-12670, group B, UR-12670 (20 mg/kg/8 d) and group C, continuous administration of UR-12670 (20 mg/kg/d). Serum levels of xenoantibodies were evaluated by flow cytometry and tissue deposits by immunofluorescence. Immunoblot and indirect immunofluorescence assessed specificity of xenoantibodies. Conventional histology was performed. Continuous administration of UR-12670 improved the histological pattern of liver xenografts, especially necrosis, loss of hepatocytes, hemorrhage, sinusoidal congestion and lymphocyte infiltration. There was not a shift in specificity of xenoantibodies at different times posttransplantation, as demonstrated by immunoblotting and indirect immunofluorescence. UR-12670 administration had a beneficial effect on graft function and considerably improved the histopathological pattern, but it failed to induce tolerance after withdrawal of immunosuppression. UR-12670 had an immunomodulatory effect on cellular response but not on antibody production. There was not a change in the specificity of xenoantibodies produced at LXR compared with pretransplant antibodies. [source] Production of ,-Galactosyl Epitopes via Combined Use of Two Recombinant Whole Cells Harboring UDP-Galactose 4-Epimerase and ,-1,3-GalactosyltransferaseBIOTECHNOLOGY PROGRESS, Issue 4 2000Xi Chen ,-Galactosyl epitopes (or ,-Gal, oligosaccharides with a terminal Gal,1,3Gal sequence) are a class of biologically important oligosaccharides in great demand in bulk quantities for basic and clinical studies on preventing hyperacute rejection in pig-to-primate organ xenotransplantaion. A truncated bovine ,-1,3-galactosyltransferase, the key enzyme responsible for the biosynthesis of the terminal structure of ,-Gal, was cloned and overexpressed previously. The acceptor specificity was further studied in the present paper, and lactose and galactose derivatives were found to be good acceptors. To develop a more proficient reaction process, we report herein an example of an efficient enzymatic synthesis of ,-Gal oligosaccharides catalyzed by the combination of two recombinant Escherichia coli whole cells harboring the genes of a UDP-galactose 4-epimerase and the ,-1,3-galactosyltransferase, respectively. Using lactosyl azide (LacN3) as the acceptor for the glycosyltransferase, the combined use of the two recombinant cells efficiently produced ,-Gal epitope Gal,1,3LacN3 in 60,68% yield. [source] | |||||||||||||