Xenotransplantation (Xenotransplantation )

Publisher: International Xenotransplantation Association, Blackwell Publishing

Description

Xenotransplantation which is published quarterly will provide its readership with rapid communication of new findings in the field of organ and tissue transplantation across species barriers. Unsolicited contributions of full length and brief communications dealing with both basic and applied studies in this field will be considered for publication pending scientific review to assure high quality. In addition review articles of timely subjects will be solicited by the editors.

  • Impact factor
    2.57
  • 5-year impact
    2.18
  • Cited half-life
    5.20
  • Immediacy index
    1.07
  • Eigenfactor
    0.00
  • Article influence
    0.69
  • Website
    Xenotransplantation website
  • Other titles
    Xenotransplantation (Online)
  • ISSN
    1399-3089
  • OCLC
    44974358
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Blackwell Publishing

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
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    • Some journals impose embargoes typically of 6 or 12 months, occasionally of 24 months
    • no listing of affected journals available as yet
  • Conditions
    • See Wiley-Blackwell entry for articles after February 2007
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    • On author or institutional or subject-based server
    • Server must be non-commercial
    • Publisher copyright and source must be acknowledged with set statement ("The definitive version is available at www.blackwell-synergy.com ")
    • Articles in some journals can be made Open Access on payment of additional charge
    • 'Blackwell Publishing' is an imprint of 'Wiley-Blackwell'
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Pig to baboon liver xenotransplantation typically results in severe thrombocytopenia and coagulation disturbances, culminating in death from hemorrhage within 9 days, in spite of continuous transfusions. We studied the contribution of anticoagulant production and clotting pathway deficiencies to fatal bleeding in baboon recipients of porcine livers.Methods By transplanting liver xenografts from α1,3-galactosyltransferase gene-knockout (GalT-KO) miniature swine donors into baboons as auxiliary organs, leaving the native liver in place, we provided the full spectrum of primate clotting factors and allowed in vivo mixing of porcine and primate coagulation systems.ResultsRecipients of auxiliary liver xenografts develop severe thrombocytopenia, comparable to recipients of conventional orthotopic liver xenografts and consistent with hepatic xenograft sequestration. However, baboons with both pig and native livers do not exhibit clinical signs of bleeding and maintain stable blood counts without transfusion for up to 8 consecutive days post-transplantation. Instead, recipients of auxiliary liver xenografts undergo graft failure or die of sepsis, associated with thrombotic microangiopathy in the xenograft, but not the native liver.Conclusion Our data indicate that massive hemorrhage in the setting of liver xenotransplantation might be avoided by supplementation with primate clotting components. However, coagulation competent hepatic xenograft recipients may be predisposed to graft loss related to small vessel thrombosis and ischemic necrosis.
    Xenotransplantation 08/2014;
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    ABSTRACT: Background The need for pig islet xenotransplantation in patients with type 1 diabetes is compelling; however, the ideal age at which islets should be isolated from the donor pig remains uncertain. Pig islet transplantation in primates, as a valuable pre-clinical model, has been explored using adult, neonatal, fetal pig islets, and also pancreatic primordia from pig embryos as beta cell donors. Neonatal pig islets have some advantages over adult and fetal islets, but the optimal age within the first month of life at which neonatal islets should be isolated and transplanted is as yet unclear.Methods In an attempt to answer this question, we carried out a literature search, but limited the search primarily to evidence in the clinically-relevant pig-to-non-human primate model.ResultsWe identified surprisingly few studies in this model directed to this topic. Even in pig-to-rodent models, there were few definitive data.Conclusion From the few data available to us, we conclude that pancreatectomy and islet isolation from neonatal pigs may have advantages over adult pigs and that isolation during the first week of life may have minor advantages over later weeks.
    Xenotransplantation 08/2014;
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    ABSTRACT: Little information is available regarding the precise swine leukocyte antigen (SLA)-derived immunogenic peptides that are presented in the context of human HLA molecules. Here, we identified SLA-derived immunogenic peptides that are presented in association with human HLA-A2 molecule.
    Xenotransplantation 07/2014;
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    ABSTRACT: Porcine islet xenotransplantation is emerging as a potential alternative for allogeneic clinical islet transplantation. Optimization of porcine islet isolation in terms of yield and quality is critical for the success and cost-effectiveness of this approach. Incomplete pancreas distention and inhomogeneous enzyme distribution have been identified as key factors for limiting viable islet yield per porcine pancreas. The aim of this study was to explore the utility of magnetic resonance imaging (MRI) as a tool to investigate the homogeneity of enzyme delivery in porcine pancreata. Traditional and novel methods for enzyme delivery aimed at optimizing enzyme distribution were examined. Pancreata were procured from Landrace pigs via en bloc viscerectomy. The main pancreatic duct was then cannulated with an 18-g winged catheter and MRI performed at 1.5-T. Images were collected before and after ductal infusion of chilled MRI contrast agent (gadolinium) in physiological saline. Regions of the distal aspect of the splenic lobe and portions of the connecting lobe and bridge exhibited reduced delivery of solution when traditional methods of distention were utilized. Use of alternative methods of delivery (such as selective re-cannulation and distention of identified problem regions) resolved these issues, and MRI was successfully utilized as a guide and assessment tool for improved delivery. Current methods of porcine pancreas distention do not consistently deliver enzyme uniformly or adequately to all regions of the pancreas. Novel methods of enzyme delivery should be investigated and implemented for improved enzyme distribution. MRI serves as a valuable tool to visualize and evaluate the efficacy of current and prospective methods of pancreas distention and enzyme delivery.
    Xenotransplantation 07/2014;
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    ABSTRACT: Pig erythrocytes are potentially useful to solve the worldwide shortage of human blood for transfusion. Domestic pig erythrocytes, however, express antigens that are bound by human preformed antibodies. Advances in genetic engineering have made it possible to rapidly knock out the genes of multiple xenoantigens, namely galactose α1,3 galactose (aGal) and N-glycolylneuraminic acid (Neu5Gc). We have recently targeted the GGTA1 and CMAH genes with zinc finger endonucleases resulting in double knockout pigs that no longer express aGal or Neu5Gc and attract significantly fewer human antibodies. In this study, we characterized erythrocytes from domestic and genetically modified pigs, baboons, chimpanzees, and humans for binding of human and baboon natural antibody, and complement-mediated lysis.
    Xenotransplantation 07/2014;
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    ABSTRACT: Background Although xenotransplantation of vascularized organs/cells has not yet reached the clinic, glutaraldehyde-treated bioprosthetic heart valves (BHV), derived from porcine or bovine tissues, are today used for clinical replacement of diseased heart valves. However, the durability of these valve cusps is limited partly due to the onset of immune responses to the grafts. The xenoantigen-determinant Galα3Gal- and corresponding anti-Gal antibodies have been postulated to in part contribute to BHV damage. However, the presence of other non-Gal carbohydrate antigen determinants as well as the immune response to these non-Gal antigens and the inflammatory response generated by their interaction with the immune system has not been studied. In this study, we have isolated and structurally characterized both non-acid and acid glycosphingolipids from naïve porcine aortic and pulmonary valve cusps.Methods Total non-acid and acid glycosphingolipids were isolated from porcine aortic and pulmonalis valve cusps of 20 animals. Glycosphingolipid components were structurally characterized by thin-layer chromatography, liquid chromatography–mass spectrometry and binding of monoclonal antibodies and lectins.ResultsThe non-acid glycosphingolipids were characterized as globotetraosylceramide, H-type 2 pentaosylceramide, fucosyl-gangliotetraosylceramide, and Galα3neolactotetraosylceramide. The acid glycosphingolipid fractions had both sulfatide and gangliosides (GM3, GM2, GM1, fucosyl-GM1, GD3 and GD1a), and all gangliosides contained N-acetyl-neuraminic acid. Significantly, the N-glycolyl-neuraminic acid (NeuGc) variant, a major component in many pig organs and to which humans can develop antibodies, was not detected among the gangliosides.Conclusions Pig valve cusps contain several complex lipid-bound carbohydrate structures that may be targets for the human immune system. Notable, the NeuGc determinant was absent in the cusp gangliosides. This work forms a platform for further characterizing the antibody reactivity of patients with porcine-derived BHV.
    Xenotransplantation 07/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Human corneal allografting is an established procedure to cure corneal blindness. However, a shortage of human donor corneas as well as compounding economic, cultural, and organizational reasons in many countries limit its widespread use. Artificial corneas as well as porcine corneal xenografts have been considered as possible alternatives. To date, all preclinical studies using de-cellularized pig corneas have shown encouraging graft survival results; however, relatively few studies have been conducted in pig to non-human primate (NHP) models, and particularly using genetically engineered donors.Methods In this study, we assessed the potential benefit of using either hCTLA4-Ig transgenic or α1,3-Galactosyl Transferase (GT) Knock-Out (KO) plus transgenic hCD39/hCD55/hCD59/fucosyl-transferase pig lines in an anterior lamellar keratoplasty pig to NHP model.ResultsCorneas from transgenic animals expressing hCTLA4-Ig under the transcriptional control of a neuron-specific enolase promoter showed transgene expression in corneal keratocytes of the stroma and expression was maintained after transplantation. Although a first acute rejection episode occurred in all animals during the second week post-keratoplasty, the median final rejection time was 70 days in the hCTLA4-Ig group vs. 21 days in the wild-type (WT) control group. In contrast, no benefit for corneal xenograft survival from the GTKO/transgenic pig line was found. At rejection, cell infiltration in hCTLA4Ig transgenic grafts was mainly composed of macrophages with fewer CD3+ CD4+ and CD79+ cells than in other types of grafts. Anti-donor xenoantibodies increased dramatically between days 9 and 14 post-surgery in all animals.Conclusions Local expression of the hCTLA4-Ig transgene dampens rejection of xenogeneic corneal grafts in this pig-to-NHP lamellar keratoplasty model. The hCTLA4-Ig transgene seems to target T-cell responses without impacting humoral responses, the control of which would presumably require additional peripheral immunosuppression.
    Xenotransplantation 07/2014;
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    ABSTRACT: Most islet xenotransplantation laboratories have focused on porcine islets, which are both costly and difficult to isolate. Teleost (bony) fish, such as tilapia, possess macroscopically visible distinct islet organs called Brockmann bodies which can be inexpensively harvested. When transplanted into diabetic nude mice, tilapia islets maintain long-term normoglycemia and provide human-like glucose tolerance profiles. Like porcine islets, when transplanted into euthymic mice, they are rejected in a CD4 T-cell-dependent manner. However, unlike pigs, tilapia are so phylogenetically primitive that their cells do not express α(1,3)Gal and, because tilapia are highly evolved to live in warm stagnant waters nearly devoid of dissolved oxygen, their islet cells are exceedingly resistant to hypoxia, making them ideal for transplantation within encapsulation devices. Encapsulation, especially when combined with co-stimulatory blockade, markedly prolongs tilapia islet xenograft survival in small animal recipients, and a collaborator has shown function in diabetic cynomolgus monkeys. In anticipation of preclinical xenotransplantation studies, we have extensively characterized tilapia islets (morphology, embryologic development, cell biology, peptides, etc.) and their regulation of glucose homeostasis. Because tilapia insulin differs structurally from human insulin by 17 amino acids, we have produced transgenic tilapia whose islets stably express physiological levels of humanized insulin and have now bred these to homozygosity. These transgenic fish can serve as a platform for further development into a cell therapy product for diabetes.
    Xenotransplantation 07/2014;
  • Xenotransplantation 07/2014; 21(4).
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    ABSTRACT: Porcine islet xenotransplantation is a promising alternative to human islet allotransplantation. Porcine pancreas cooling needs to be optimized to reduce the warm ischemia time (WIT) following donation after cardiac death, which is associated with poorer islet isolation outcomes. This study examines the effect of four different cooling Methods on core porcine pancreas temperature (n = 24) and histopathology (n = 16). All Methods involved surface cooling with crushed ice and chilled irrigation. Method A, which is the standard for porcine pancreas procurement, used only surface cooling. Method B involved an intravascular flush with cold solution through the pancreas arterial system. Method C involved an intraductal infusion with cold solution through the major pancreatic duct, and Method D combined all three cooling Methods. Surface cooling alone (Method A) gradually decreased core pancreas temperature to <10 °C after 30 min. Using an intravascular flush (Method B) improved cooling during the entire duration of procurement, but incorporating an intraductal infusion (Method C) rapidly reduced core temperature 15–20 °C within the first 2 min of cooling. Combining all methods (Method D) was the most effective at rapidly reducing temperature and providing sustained cooling throughout the duration of procurement, although the recorded WIT was not different between Methods (P = 0.36). Histological scores were different between the cooling Methods (P = 0.02) and the worst with Method A. There were differences in histological scores between Methods A and C (P = 0.02) and Methods A and D (P = 0.02), but not between Methods C and D (P = 0.95), which may highlight the importance of early cooling using an intraductal infusion. In conclusion, surface cooling alone cannot rapidly cool large (porcine or human) pancreata. Additional cooling with an intravascular flush and intraductal infusion results in improved core porcine pancreas temperature profiles during procurement and histopathology scores. These data may also have implications on human pancreas procurement as use of an intraductal infusion is not common practice.
    Xenotransplantation 07/2014;
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    ABSTRACT: Although xenografts have always held immeasurable potential as an inexhaustible source of donor organs, immunological barriers and physiological incompatibility have proved to be formidable obstacles to clinical utility. An exciting, new regenerative medicine-based approach termed “semi-xenotransplantation” (SX) seeks to overcome these obstacles by combining the availability and reproducibility of animal organs with the biocompatibility and functionality of human allografts. Compared to conventional xenotransplantation wherein the whole organ is animal-derived, SX grafts are cleansed of their antigenic cellular compartment to produce whole-organ extracellular matrix scaffolds that retain their innate structure and vascular channels. These scaffolds are then repopulated with recipient or donor human stem cells to generate biocompatible semi-xenografts with the structure and function of native human organs. While numerous hurdles must be still overcome in order for SX to become a viable treatment option for end-stage organ failure, the immense potential of SX for meeting the urgent needs for a new source of organs and immunosuppression-free transplantation justifies the interest that the transplant community is committing to the field.
    Xenotransplantation 07/2014;
  • Xenotransplantation 07/2014;
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    ABSTRACT: Xenotransplantation has undergone important progress in controlling initial hyperacute rejection in many preclinical models, with some cell, tissue, and organ xenografts advancing toward clinical trials. However, acute injury, driven primarily by innate immune and inflammatory responses, continues to limit results in lung xenograft models. The purpose of this article is to review the current status of lung xenotransplantation—including the seemingly unique challenges posed by this organ—and summarize proven and emerging means of overcoming acute lung xenograft injury.
    Xenotransplantation 07/2014;
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    ABSTRACT: Background Over time, the notion of public has evolved. While the concept of public was initially conceived of as a single undifferentiated entity, the common understanding is now that a variety of differentiated, multifaceted and multiple public(s) can be constructed for different purposes. This is equally true in xenotransplantation; the literature shows how different kind of publics can be introduced as relevant. The paper explores the notion of public and the contemporary participatory procedures as participatory rights for citizens in decisions concerning technoscience and society. Its perspective, thus, is normative; namely, it aims at understanding how the political role of citizens is changing in democratic societies where matters of innovation are concerned. It is focused on xenotransplantation whose connections with public discourse and practices are quite paradigmatic among new emerging biomedical technologies, due to its peculiar risks.Methods and resultsThe paper reviews the historical background of risk communication and public involvement in science-based decision-making and provides an overview of the current roles and meanings of deliberative procedures in xenotransplantation. After a short discussion of the history of the social implementation of xenotransplantation, the construction of the different publics dealing with this biomedical technology is briefly analysed. Publics have been firstly conceived of as objects of research, which has looked at them to quantify people's positive and negative attitudes towards xenotransplantation. Further developments have led to the notion of the public as composed of citizens, empowered as subjects of decisions. In both Canadian and Australian consultations, citizens were engaged in a complex learning process aimed at committing them to a decision. Despite the fact both public consultations represented important forms of experimental democracy, they were still focused on seeking consensus and assessing compliance from citizens. New Zealand is the most recent example of public consultation in xenotransplantation. Likewise, several public consultations have recently been launched by the European Commission on Advanced Therapies. Unlike in the Canadian and Australian cases, the latter initiatives aimed to reach only certain parts of the population, and the overall consultations were prepared to seek approval.Conclusions Several categories of individuals may be interesting and interested publics in xenotransplantation. This is a field in which the importance of the potential risks that xenotransplants pose to society has been widely discussed. The point is that publics should not only be educated about the risk but should be given an opportunity to participate actively in the decision about whether and under what conditions they are exposed to the risk. Likewise, the boundaries between surveys, consultations and collection of advice may be blurred in actual practices. The hope remains that all different instruments either to collect or disseminate knowledge, and to explore new tools of governance may help connect science and policy to society in deeper and more complex ways. The next step points to a different meaning of public participation. It is shifting from participation as mere consensus and risk acceptance, to public engagement as a form of shared responsibility for risk control and regulatory decision-making.
    Xenotransplantation 07/2014;
  • Xenotransplantation 07/2014;
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    ABSTRACT: Background Programmed death-1 (PD-1) costimulation acts as a negative regulator of T-cell responses to allografts. However, the role of the PD-1 pathway in xenotransplantation is not well defined yet. We have shown previously that human in vitro T-cell responses to porcine transfectants overexpressing PD-Ligand1 (L23-PD-L1 cells) are remarkably weak. In this report, we asked whether the PD-1/PD-L1 pathway has the potential to diminish xenogeneic immune responses also in vivo.MethodsL23-PD-L1 or mock transfected control cells (L23-GFP) were transplanted under the kidney capsule of rats. The occurrence of kidney-infiltrating rat leukocytes and the induction of anti-pig antibodies were monitored in grafted animals.ResultsAssessment of cellular infiltrates revealed similar numbers of macrophages in kidneys grafted with L23-PD-L1 or L23-GFP control cells. However, the level of MHC class-II molecules was reduced on macrophages responding to L23-PD-L1 grafts, suggesting a lower state of activation. Furthermore, less T cells were found in kidneys receiving L23-PD-L1 cells. In addition, the titers of induced anti-pig antibodies were significantly lower in rats grafted with L23-PD-L1 cells.Conclusions These data suggest that signals triggered by PD-1–PD-L1 interaction interfere with activation pathways involved in the induction of cellular and antibody-mediated immune responses to xenografts in vivo. Targeting of PD-1 and/or PD-L1 may be a promising approach for immune modulation after xenotransplantation.
    Xenotransplantation 07/2014;
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    ABSTRACT: For the sake of therapy of diabetes, it is critical to understand human beta cell function in detail in health and disease. Current studies of human beta cell physiology in vivo are mostly limited to immunodeficient mouse models, which possess significant technical limitations. This study aimed to create a new model for the study of human islets through induction of transplant tolerance in immunosufficient mice. B6 diabetic mice were transplanted with human islets and treated with anti-CD45RB. To assess whether anti-CD45RB-induced transplant tolerance requires B cells, B6 recipients received additional anti-CD20 or B6μMT−/− mice were used. For some anti-CD45RB-treated B6μMT−/− mice, additional anti-CD25 mAb was applied at the early or late stage post-transplant. Immunohistology was performed to show the Foxp3 cells in grafted anti-CD45RB/anti-CD20-treated Foxp3-GFP B6 mice. The results showed that anti-CD45RB alone allowed indefinite graft survival in 26.6% of B6 mice, however 100% of xenografts were accepted in mice treated simultaneously with anti-CD20, and 88.9% of xenografts accepted in anti-CD45RB-treated μMT−/− mice. These μMT−/− mice accepted the islets from another human donor but rejected the islets from baboon. Additional administration of anti-CD25 mAb at the time of transplantation resulted in 100% rejection, whereas 40% of grafts were rejected while the antibody was administrated at days 60 post-transplant. Immunohistologic examination showed Foxp3+ cells accumulated around grafts. We conclude that induction of tolerance to human islets in an immunosufficient mouse model could be generated by targeting murine CD45RB and CD20. This new system will facilitate study of human islets and accelerate the dissection of the critical mechanisms underlying islet health in human disease.
    Xenotransplantation 07/2014;
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    ABSTRACT: Background Costimulation blockade can prevent rejection of islet xenografts in naïve but not sensitized recipients. Donor-specific antibodies (DSA) may partly explain this observation. The effect of DSA on rat islet xenograft survival in mice receiving costimulation blockade was investigated.Methods Naïve C57BL/6 mice with alloxan-induced diabetes were transplanted under the left kidney capsule with 100 Lewis rat islets. Recipients were divided into three groups receiving: (i) isotype control antibodies (Abs); (ii) anti-CD154 and CTLA4Ig; or (iii) anti-CD154, CTLA4Ig, and anti-LFA-1 every second day, day 0–8. At the time of transplantation (Tx), half of the animals in each group received naïve mouse serum and half xenoimmune serum derived from mice previously transplanted with rat islets. Non-fasting blood glucose levels and body weight were followed daily. Cured mice were examined by intraperitoneal glucose tolerance (IPGT) tests at 1 and 4 months after transplantation.ResultsDonor-specific antibodies were detected in immune serum-injected recipients up to at least 96 h post-Tx. Short term (≤96 h), there was no significant difference with regard to graft mass, infiltrating and apoptotic cells between groups of mice receiving naïve and immune sera. A moderate infiltration of polymorphonuclear and mononuclear cells was seen 96 h post-Tx in mice given control Abs, whether or not they received immune or naïve mouse serum. Mice given costimulation blockade had well-maintained endocrine tissue and very little cell infiltration. There was no significant difference in islet xenograft function and survival long term between groups receiving naïve and immune sera in combination with costimulation blockade. About half of the mice receiving costimulation blockade lost graft function within 110 days.Conclusion The presence at Tx of DSA does not appear to negatively influence early and late islet xenograft survival in mice receiving costimulation blockade.
    Xenotransplantation 05/2014;
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    ABSTRACT: Background Xenotransplantation of porcine organs holds promise of solving the human organ donor shortage. The use of α-1,3-galactosyltransferase knockout (GTKO) pig donors mitigates hyperacute rejection, while delayed rejection is currently precipitated by potent immune and hemostatic complications. Previous analysis by our laboratory suggests that clotting factor VIII (FVIII) inhibitors might be elicited by the structurally restricted xenoantibody response which occurs after transplantation of either pig GTKO/hCD55/hCD59/hHT transgenic neonatal islet cell clusters or GTKO endothelial cells.MethodsA recombinant xenoantibody was generated using sequences from baboons demonstrating an active xenoantibody response at day 28 after GTKO/hCD55/hCD59/hHT transgenic pig neonatal islet cell cluster transplantation. Rhesus monkeys were immunized with GTKO pig endothelial cells to stimulate an anti-non-Gal xenoantibody response. Serum was collected at days 0 and 7 after immunization. A two-stage chromogenic assay was used to measure FVIII cofactor activity and identify antibodies which inhibit FVIII function. Molecular modeling and molecular dynamics simulations were used to predict antibody structure and the residues which contribute to antibody-FVIII interactions. Competition ELISA was used to verify predictions at the domain structural level.ResultsAntibodies that inhibit recombinant human FVIII function are elicited after non-human primates are transplanted with either GTKO pig neonatal islet cell clusters or endothelial cells. There is an apparent increase in inhibitor titer by 15 Bethesda units (Bu) after transplant, where an increase greater than 5 Bu can indicate pathology in humans. Furthermore, competition ELISA verifies the computer modeled prediction that the recombinant xenoantibody, H66K12, binds the C1 domain of FVIII.Conclusions The development of FVIII inhibitors is a novel illustration of the potential impact the humoral immune response can have on coagulative dysfunction in xenotransplantation. However, the contribution of these antibodies to rejection pathology requires further evaluation because “normal” coagulation parameters after successful xenotransplantation are not fully understood.
    Xenotransplantation 05/2014;

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