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Xenotransplantation
Selected AbstractsThe Ethics of XenotransplantationJOURNAL OF APPLIED PHILOSOPHY, Issue 3 2000Michael J. Reiss First page of article [source] Cardiac Xenotransplantation: Ethics and Potential ApplicationJOURNAL OF CARDIAC SURGERY, Issue 6 2001Robert E. Michler M.D. First page of article [source] Attempts to Prepare Suitable Complement Regulatory Molecules for Clinical XenotransplantationJOURNAL OF CARDIAC SURGERY, Issue 6 2001Shuji Miyagawa M.D. First page of article [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] Failure of xenoimplantation using porcine synovium-derived stem cell-based cartilage tissue constructs for the repair of rabbit osteochondral defectsJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 8 2010Ming Pei Abstract The use of xenogeneic tissues offers many advantages with respect to availability, quality control, and timing of tissue harvest. Our previous study indicated that implantation of premature tissue constructs from allogeneic synovium-derived stem cells (SDSCs) facilitated cartilage tissue regeneration. The present study investigated the feasibility of xenoimplantation of SDSC-based premature tissue constructs for the repair of osteochondral defects. Porcine SDSCs were mixed with fibrin gel, seeded in polyglycolic acid (PGA) scaffolds, and cultured in a rotating bioreactor system supplemented for 1 month with growth factor cocktails. The engineered porcine premature tissues were implanted to repair surgically induced osteochondral defects in the medial femoral condyles of 12 rabbits. Three weeks after surgery, the xenoimplantation group exhibited a smooth, whitish surface while the untreated control remained empty. Surprisingly, 6 months after surgery, the xenoimplantation group displayed some tissue loss while the untreated control group was overgrown with fibrocartilage tissue. In the xenoimplantation group, chronic inflammation was observed in synovial tissue where porcine major histocompatibility complex (MHC) class II antigen positively stained in the engulfed foreign bodies. In addition, porcine source cells also migrated from the implantation site and may have been responsible for the observed loss of glycosaminoglycans (GAGs) underneath surrounding articular cartilage. The histological score was much worse in the xenoimplanted group than in the untreated control. Our study suggested that SDSC-based xenogeneic tissue constructs might cause delayed immune rejection. Xenotransplantation may not be an appropriate approach to repair osteochondral defects. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1064,1070, 2010 [source] Consenting to bio-risk: xenotransplantation and the lawLEGAL STUDIES, Issue 3 2005Barrister, Sara Fovargue LLB Research into alternative sources of organs for transplantation, including the use of organs from non-human genetically engineered animals, has occurred since the introduction of allotransplantation in the 1960s. Xenotransplantation is different from other developing genetic technologies because whilst the potential benefit is to the individual, the possible risks are to society as a whole. The risks include the transmission of unknown and currently indeterminable infectious diseases. This article explores whether the current regulator framework is able to address this issue and, in particular, whether,first-party'consent to involvement in a clinical trial is a sufficient to protect third parties from harm. The competence of a xeno-recipient to consent is also considered, and it is suggested that, at the very least, public debate and participation in deciding whether clinical trials should be permitted must occur, because by allowing xenotransplant trials to help an individual, the risks will be borne by all. [source] Xenotransplantation, Xenogeneic Infections, Biotechnology, and Public HealthMOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 5 2009Louisa E. Chapman MD Abstract Xenotransplantation is the attempt to use living biological material from nonhuman animal species in humans for therapeutic purposes. Clinical trials and preclinical studies have suggested that living cells and tissue from other species have the potential to be used in humans to ameliorate disease. However, the potential for successful xenotransplantation to cure human disease is coupled with the risk that therapeutic use of living nonhuman cells in humans may also serve to introduce xenogeneic infections of unpredictable significance. Animal husbandry practices and xenotransplantation product preparation may eliminate most exogenous infectious agents prior to transplantation. However, endogenous retroviruses are present in the genomes of all mammalian cells, have an inadequately defined ability to infect human cells, and have generated public health concern. The history of xenotransplantation, the implications for public health, the global consensus on public safeguards necessary to accompany clinical trials, and the future direction of xenotransplantation are discussed in the context of public health. Mt Sinai J Med 76:435,441, 2009. © 2009 Mount Sinai School of Medicine [source] Retroviral Restriction Factors and Infectious Risk in XenotransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2010Y. Meije The clinical application of xenotransplantation poses immunologic, ethical, and microbiologic challenges. Significant progress has been made in the investigation of each of these areas. Among concerns regarding infectious risks for human xenograft recipients is the identification in swine of infectious agents including porcine endogenous retroviruses (PERV) that are capable of replication in some human cell lines. PERV replication has, however, been difficult to demonstrate in primate-derived cell lines and in preclinical studies of non-human primates receiving porcine xenografts. Endogenous ,retroviral restriction factors' are intracellular proteins and components of the innate immune system that act at various steps in retroviral replication. Recent studies suggest that some of these factors may have applications in the management of endogenous retroviruses in xenotransplantation. The risks of PERV infection and the potential role of retroviral restriction factors in xenotransplantation are reviewed in detail. [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] Long-Term Controlled Normoglycemia in Diabetic Non-Human Primates After Transplantation with hCD46 Transgenic Porcine IsletsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2009D. J. Van Der Windt Xenotransplantation of porcine islets into diabetic non-human primates is characterized by (i) an initial massive graft loss possibly due to the instant blood-mediated inflammatory reaction and (ii) the requirement of intensive, clinically unfriendly immunosuppressive therapy. We investigated whether the transgenic expression of a human complement-regulatory protein (hCD46) on porcine islets would improve the outcome of islet xenotransplantation in streptozotocin-induced diabetic Cynomolgus monkeys. Immunosuppression consisted of thymoglobulin, anti-CD154 mAb for costimulation blockade, and mycophenolate mofetil. Following the transplantation of islets from wild-type pigs (n = 2) or from 1,3-galactosyltransferase gene-knockout pigs (n = 2), islets survived for a maximum of only 46 days, as evidenced by return to hyperglycemia and the need for exogenous insulin therapy. The transplantation of islets from hCD46 pigs resulted in graft survival and insulin-independent normoglycemia in four of five monkeys for the 3 months follow-up of the experiment. One normalized recipient, selected at random, was followed for >12 months. Inhibition of complement activation by the expression of hCD46 on the pig islets did not substantially reduce the initial loss of islet mass, rather was effective in limiting antibody-mediated rejection. This resulted in a reduced need for immunosuppression to preserve a sufficient islet mass to maintain normoglycemia long-term. [source] Renal and Cardiac Endothelial Heterogeneity Impact Acute Vascular Rejection in Pig-to-Baboon XenotransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2009C. Knosalla Xenograft outcomes are dictated by xenoantigen expression, for example, Gal ,1, 3Gal (Gal), but might also depend on differing vascular responses. We investigated whether differential vascular gene expression in kidney and cardiac xenografts correlate with development of thrombotic microangiopathy (TM) and consumptive coagulation (CC). Immunosuppressed baboons underwent miniswine or hDAF pig kidney (n = 6) or heart (n = 7), or Gal-transferase gene-knockout (GalT-KO) (thymo)kidney transplantation (n = 14). Porcine cDNA miniarrays determined donor proinflammatory, apoptosis-related and vascular coagulant/fibrinolytic gene expression at defined time points; validated by mRNA, protein levels and immunopathology. hDAF-transgenic and GalT-KO xenografts, (particularly thymokidneys) exhibited prolonged survival. CC was seen with Gal-expressing porcine kidneys (3 of 6), only 1 of 7 baboons postcardiac xenotransplantation and was infrequent following GalT-KO grafts (1 of 14). Protective-type genes (heme oxygenase-I, superoxide dismutases and CD39) together with von Willebrand factor and P-selectin were upregulated in all renal grafts. Transcriptional responses in Gal-expressing xenografts were comparable to those seen in the infrequent GalT-KO rejection. In cardiac xenografts, fibrin deposition was associated with increased plasminogen activator inhibitor-1 expression establishing that gene expression profiles in renal and cardiac xenografts differ in a quantitative manner. These findings suggest that therapeutic targets may differ for renal and cardiac xenotransplants. [source] SARS, Xenotransplantation and Bioterrorism: Preventing the Next EpidemicAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2003Jay A. Fishman First page of article [source] Comparison of PERV genomic locations between Asian and European pigsANIMAL GENETICS, Issue 1 2010W. Y. Jung Summary Xenotransplantation from pigs provides a possible solution to the shortage of human organs for allotransplantation. Porcine endogenous retroviruses (PERVs) are a possible obstacle to using porcine organs in addition to the immunological barriers. Three main types of PERVs (A, B and C) have been previously investigated in diverse pig breeds. To examine the copy numbers of PERVs and their genomic locations in the Korean native pig genome, we screened a BAC (Bacterial Artificial Chromosome) library with PERV-specific protease primers for initial recognition of PERV-positive clones and three sets of envelope-specific primers for the identification of PERV types. A total of 45 PERV-positive clones, nine PERV-A and 36 PERV-B, have been identified from the library screening and the BAC contigs were constructed using the primers designed from BAC end sequences (BESs). These primers were also used for SCH (Somatic Cell Hybrid) and RH (Radiation Hybrid) mapping of the PERV-positive clones. The results indicate that 45 PERV-positive BAC clones belong to nine contigs and a singleton. SCH and IMpRH (INRA-Minnesota Porcine Radiation Hybrid) mapping results indicated that there are at least eight separate PERV genomic locations, consisting of three PERV-A and five PERV-B. One contig could not be mapped, and two contigs are closely located on SSC7. Southern blotting indicates there may be up to 15 additional sites. Further investigation of these clones will contribute to a general strategy to generate PERV-free lines of pigs suitable for xenotransplantation. [source] The Effect of Lyophilization on Graft Acceptance in Experimental Xenotransplantation Using Porcine CorneaARTIFICIAL ORGANS, Issue 1 2010Jeong-Kyu Lee Abstract The immunogenicity of lyophilized porcine cornea is unknown. The purpose of this study was to examine the possibility of using lyophilized porcine cornea as a substrate for ocular surface reconstruction. A porcine cornea stromal button was freeze-dried and vacuum-packed. Lyophilized and fresh porcine corneas were examined histologically, and then implanted into intrastromal pockets in live rat corneas. Cytokine concentrations in plasma and protein extracts from the corneal buttons of rats were measured using the fluorokine multianalyte profiling assay, and histologic examination was performed. Immunoreactivity to the ,-gal epitope was not found in lyophilized porcine corneas, whereas it was found in several keratocytes in fresh porcine corneas. The median survival time of rat corneas receiving lyophilized porcine transplants was 28.0 days, significantly longer than the 14.0-day survival of rat corneas that received fresh porcine transplants (P < 0.05). CD45RO+ and CD68+ cells were observed in rejected corneas, and interleukin-2 and interferon-, were elevated in rat plasma and corneal tissue. The lyophilized porcine corneal stroma, which is devoid of ,-gal epitope, is less antigenic, and may be a useful biomaterial for ocular surface reconstruction and corneal collagen supplementation. [source] ,v -Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascinINTERNATIONAL JOURNAL OF CANCER, Issue 5 2002Takashi Taga Abstract Orthotopic brain tumor growth is inhibited in athymic mice by the daily systemic administration of the ,v -integrin antagonist EMD 121974. This compound, a cyclic RGD-penta-peptide, is a potent inhibitor of angiogenesis, which induces apoptosis of growing endothelial cells through inhibition of their ,v -integrin interaction with the matrix proteins vitronectin and tenascin. Here we show that EMD 121974 also induces apoptosis in the ,v -integrin-expressing tumor cell lines U87 MG and DAOY by detaching them from vitronectin and tenascin, matrix proteins known to be essential for brain tumor growth and invasion. These matrix proteins are shown to be produced by the brain tumor cells in vitro and in vivo. Furthermore, only tumor cells expressing ,v -integrins responded to the treatment with EMD 121974, after xenotransplantation into the forebrain of nude mice, supporting the importance of tumor cell-matrix interactions in tumor cell survival in the brain. Thus, the ,v -antagonist EMD 121974 suppresses brain tumor growth through induction of apoptosis in both brain capillary and brain tumor cells by preventing their interaction with the matrix proteins vitronectin and tenascin. The dual action of this peptide explains its potent growth suppression of orthotopically transplanted brain tumors. © 2002 Wiley-Liss, Inc. [source] Sequence-based characterization of the eight SLA loci in Korean native pigsINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 4-5 2008Y. J. Lee Summary Eight swine leucocyte antigen (SLA) gene (SLA-1, SLA-2, SLA-3, SLA-6, DRA, DRB1, DQA, DQB1) alleles were identified using sequence-based typing method in three Korean native pigs used for breeding at the National Institute of Animal Science in Korea. Six new alleles in class I genes and three new alleles in class II genes have been identified in this breed and can give valuable information for xenotransplantation and disease resistance. [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] Therapeutic Strategies for Xenograft RejectionJOURNAL OF CARDIAC SURGERY, Issue 5 2001Ph.D., Shu S. Lin M.D. ABSTRACT The increasing demand for transplantable organs over the past several decades has stimulated the idea of using animal organs in lieu of cadaveric organs in clinical transplantation. Pigs are now considered to be the most suitable source of organs for transplantation because of their abundant availability, their appropriate size, their relatively short gestation period, and the recent development in the technology to genetically manipulate them. In the past few years, some of the seemingly complex immunologic responses in pig-to-primate transplantation have been elucidated. This progress has allowed us to focus our efforts on devising specific therapeutic strategies to overcome or prevent some of the responses that contribute to rejection of the xenograft. In this article, we review the various approaches that might allow clinical xenotransplantation to come to fruition. [source] Functional hepatic recovery after xenotransplantation of cryopreserved fetal liver cells or soluble cell-factor administration in a cirrhotic rat model: Are viable cells necessary?JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7pt2 2008Olga V Ochenashko Abstract Background and Aim:, Chronic liver failure results in the decrease of the number of functioning hepatocytes. It dictates the necessity of using exogenous viable cells or/and agents that can stimulate hepatic regenerative processes. Fetal liver contains both hepatic and hematopoietic stem cells with high proliferative potential, which may replace damaged cells. Also, immature cells produce fetal-specific factors which may support the injured liver. Our aim was to test the ability of human fetal liver cells and cell-free fetal-specific factors of non-hepatic origin to stimulate recovery processes in an experimental model of carbon tetrachloride,induced cirrhosis in rats. Methods:, Cirrhotic rats were intrasplenically injected with fetal liver cells (1 × 107 cells/0.3 mL medium) or cell-free fetal-specific factors (0.3 mL/1 mg protein). Control groups received medium alone. Serum indexes, hepatic functions, and morphology were evaluated for 15 days. Result:, Human fetal liver cell transplantation was shown to abrogate the mortality of cirrhotic animals, to improve serum markers, and to restore liver mitochondrial function and detoxification. Morphological patterns of liver recovery were observed by histology. In comparison, an injection of fetal-specific factors produced similar functional recovery, whilst a more limited liver regeneration was observed by histology. Conclusions:, The positive effects of fetal liver cell and cell-free fetal-specific factors in experimental cirrhosis may result from the presence of stage-specific factors activating hepatocellular repair. [source] Absence of transmission of potentially xenotic viruses in a prospective pig to primate islet xenotransplantation study,JOURNAL OF MEDICAL VIROLOGY, Issue 11 2008Olga Garkavenko Abstract Shortage of human donor organs for transplantation has prompted usage of animals as an alternative donor source. Pigs are the most acceptable candidate animals but issues of xenozoonoses remain. Despite careful monitoring of designated pathogen free pigs there is still a risk that their tissues may carry infectious agents. Thus xenotransplantation requires extensive pre-clinical study on safety of the graft especially for those viruses that are either potentially oncogenic and/or immunosuppressive, or can establish persistent infection. A prospective pig-to-primate islet xenotransplantation study was performed which includes monitoring for potentially xenotic viruses namely porcine endogenous retrovirus (PERV), porcine cytomegalovirus (PCMV), porcine lymphotropic herpesvirus (PLHV), and porcine circovirus (PCV) using both molecular diagnostic,PCR and RT-PCR and serology methods. There was no evidence of pig virus transmission into primate recipients. This preclinical study underlines the information concerning viral safety of islet cell xenograft in pig-to-primate xenotransplantation. J. Med. Virol. 80:2046,2052, 2008. © 2008 Wiley-Liss, Inc. [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] Atorvastatin or transgenic expression of TFPI inhibits coagulation initiated by anti-nonGal IgG binding to porcine aortic endothelial cellsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2010C. C. LIN Summary.,Background:,Intravascular thrombosis remains a barrier to successful xenotransplantation. Tissue factor (TF) expression on porcine aortic endothelial cells (PAECs), which results from their activation by xenoreactive antibodies (Abs) to Gal,1,3Gal (Gal) and subsequent complement activation, plays an important role. Objectives:,The present study aimed to clarify the role of Abs directed against nonGal antigens in the activation of PAECs to express functional TF and to investigate selected methods of inhibiting TF activity. Methods:,PAECs from wild-type (WT), ,1,3-galactosyltransferase gene-knockout (GT-KO) pigs, or pigs transgenic for CD46 or tissue factor pathway inhibitor (TFPI), were incubated with naïve baboon serum (BS) or sensitized BS (with high anti-nonGal Ab levels). TF activity of PAECs was assessed. Results:,Only fresh, but not heat-inactivated (HI), naïve BS activated WT PAECs to express functional TF. Similarly, PAECs from CD46 pigs were resistant to activation by naïve BS, but not to activation by fresh or HI sensitized BS. HI sensitized BS also activated GT-KO PAECs to induce TF activity. TF expression on PAECs induced by anti-nonGal Abs was inhibited if serum was pretreated with (i) an anti-IgG Fab Ab or (ii) atorvastatin, or (iii) when PAECs were transgenic for TFPI. Conclusions:,Anti-nonGal IgG Abs activated PAECs to induce TF activity through a complement-independent pathway. This implies that GT-KO pigs expressing a complement-regulatory protein may be insufficient to prevent the activation of PAECs. Genetic modification with an ,anticoagulant' gene (e.g. TFPI) or a therapeutic approach (e.g. atorvastatin) will be required to prevent coagulation dysregulation after pig-to-primate organ transplantation. [source] Consenting to bio-risk: xenotransplantation and the lawLEGAL STUDIES, Issue 3 2005Barrister, Sara Fovargue LLB Research into alternative sources of organs for transplantation, including the use of organs from non-human genetically engineered animals, has occurred since the introduction of allotransplantation in the 1960s. Xenotransplantation is different from other developing genetic technologies because whilst the potential benefit is to the individual, the possible risks are to society as a whole. The risks include the transmission of unknown and currently indeterminable infectious diseases. This article explores whether the current regulator framework is able to address this issue and, in particular, whether,first-party'consent to involvement in a clinical trial is a sufficient to protect third parties from harm. The competence of a xeno-recipient to consent is also considered, and it is suggested that, at the very least, public debate and participation in deciding whether clinical trials should be permitted must occur, because by allowing xenotransplant trials to help an individual, the risks will be borne by all. [source] Xenotransplantation, Xenogeneic Infections, Biotechnology, and Public HealthMOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 5 2009Louisa E. Chapman MD Abstract Xenotransplantation is the attempt to use living biological material from nonhuman animal species in humans for therapeutic purposes. Clinical trials and preclinical studies have suggested that living cells and tissue from other species have the potential to be used in humans to ameliorate disease. However, the potential for successful xenotransplantation to cure human disease is coupled with the risk that therapeutic use of living nonhuman cells in humans may also serve to introduce xenogeneic infections of unpredictable significance. Animal husbandry practices and xenotransplantation product preparation may eliminate most exogenous infectious agents prior to transplantation. However, endogenous retroviruses are present in the genomes of all mammalian cells, have an inadequately defined ability to infect human cells, and have generated public health concern. The history of xenotransplantation, the implications for public health, the global consensus on public safeguards necessary to accompany clinical trials, and the future direction of xenotransplantation are discussed in the context of public health. Mt Sinai J Med 76:435,441, 2009. © 2009 Mount Sinai School of Medicine [source] Retroviral Restriction Factors and Infectious Risk in XenotransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2010Y. Meije The clinical application of xenotransplantation poses immunologic, ethical, and microbiologic challenges. Significant progress has been made in the investigation of each of these areas. Among concerns regarding infectious risks for human xenograft recipients is the identification in swine of infectious agents including porcine endogenous retroviruses (PERV) that are capable of replication in some human cell lines. PERV replication has, however, been difficult to demonstrate in primate-derived cell lines and in preclinical studies of non-human primates receiving porcine xenografts. Endogenous ,retroviral restriction factors' are intracellular proteins and components of the innate immune system that act at various steps in retroviral replication. Recent studies suggest that some of these factors may have applications in the management of endogenous retroviruses in xenotransplantation. The risks of PERV infection and the potential role of retroviral restriction factors in xenotransplantation are reviewed in detail. [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] Long-Term Controlled Normoglycemia in Diabetic Non-Human Primates After Transplantation with hCD46 Transgenic Porcine IsletsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2009D. J. Van Der Windt Xenotransplantation of porcine islets into diabetic non-human primates is characterized by (i) an initial massive graft loss possibly due to the instant blood-mediated inflammatory reaction and (ii) the requirement of intensive, clinically unfriendly immunosuppressive therapy. We investigated whether the transgenic expression of a human complement-regulatory protein (hCD46) on porcine islets would improve the outcome of islet xenotransplantation in streptozotocin-induced diabetic Cynomolgus monkeys. Immunosuppression consisted of thymoglobulin, anti-CD154 mAb for costimulation blockade, and mycophenolate mofetil. Following the transplantation of islets from wild-type pigs (n = 2) or from 1,3-galactosyltransferase gene-knockout pigs (n = 2), islets survived for a maximum of only 46 days, as evidenced by return to hyperglycemia and the need for exogenous insulin therapy. The transplantation of islets from hCD46 pigs resulted in graft survival and insulin-independent normoglycemia in four of five monkeys for the 3 months follow-up of the experiment. One normalized recipient, selected at random, was followed for >12 months. Inhibition of complement activation by the expression of hCD46 on the pig islets did not substantially reduce the initial loss of islet mass, rather was effective in limiting antibody-mediated rejection. This resulted in a reduced need for immunosuppression to preserve a sufficient islet mass to maintain normoglycemia long-term. [source] Induction of Human T-Cell Tolerance to Pig Xenoantigens via Thymus Transplantation in Mice with an Established Human Immune SystemAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2009K. Habiro Thymus xenotransplantation has been shown to induce tolerance to porcine xenografts in mice and to permit survival of ,1,3Gal-transferase knockout porcine kidney xenografts for months in nonhuman primates. We evaluated the ability of porcine thymus xenotransplantation to induce human T-cell tolerance using a humanized mouse (hu-mouse) model, where a human immune system is preestablished by implantation of fetal human thymus tissue under the kidney capsule and intravenous injection of CD34+ hematopoietic stem/progenitor cells. Human T-cell depletion with an anti-CD2 mAb following surgical removal of human thymic grafts prevented the initial rejection of porcine thymic xenografts in hu-mice. In these hu-mice, porcine thymic grafts were capable of supporting human thymopoiesis and T-cell development, and inducing human T-cell tolerance to porcine xenoantigens. Human T cells from these mice responded strongly to third-party pig, but not to the thymic donor swine leukocyte antigen (SLA)-matched pig stimulators in a mixed lymphocyte reaction (MLR) assay. Anti-pig xenoreactive antibodies declined in these hu-mice, whereas antibody levels increased in nontolerant animals that rejected porcine thymus grafts. These data show that porcine thymic xenotransplantation can induce donor-specific tolerance in immunocompetent hu-mice, supporting this approach for tolerance induction in clinical xenotransplantation. [source] Renal and Cardiac Endothelial Heterogeneity Impact Acute Vascular Rejection in Pig-to-Baboon XenotransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2009C. Knosalla Xenograft outcomes are dictated by xenoantigen expression, for example, Gal ,1, 3Gal (Gal), but might also depend on differing vascular responses. We investigated whether differential vascular gene expression in kidney and cardiac xenografts correlate with development of thrombotic microangiopathy (TM) and consumptive coagulation (CC). Immunosuppressed baboons underwent miniswine or hDAF pig kidney (n = 6) or heart (n = 7), or Gal-transferase gene-knockout (GalT-KO) (thymo)kidney transplantation (n = 14). Porcine cDNA miniarrays determined donor proinflammatory, apoptosis-related and vascular coagulant/fibrinolytic gene expression at defined time points; validated by mRNA, protein levels and immunopathology. hDAF-transgenic and GalT-KO xenografts, (particularly thymokidneys) exhibited prolonged survival. CC was seen with Gal-expressing porcine kidneys (3 of 6), only 1 of 7 baboons postcardiac xenotransplantation and was infrequent following GalT-KO grafts (1 of 14). Protective-type genes (heme oxygenase-I, superoxide dismutases and CD39) together with von Willebrand factor and P-selectin were upregulated in all renal grafts. Transcriptional responses in Gal-expressing xenografts were comparable to those seen in the infrequent GalT-KO rejection. In cardiac xenografts, fibrin deposition was associated with increased plasminogen activator inhibitor-1 expression establishing that gene expression profiles in renal and cardiac xenografts differ in a quantitative manner. These findings suggest that therapeutic targets may differ for renal and cardiac xenotransplants. [source] | |||||||||||||||||||||||||||||||