Abstract:
BACKGROUND:Xenotransplantation of porcine islets can reverse diabetes in non-human primates. The remaining hurdles for clinical application include safe and effective T-cell-directed immunosuppression, but protection against the innate immune system and coagulation dysfunction may be more difficult to achieve. Islet-targeted genetic manipulation of islet-source pigs represents a powerful tool to protect against graft loss. However, whether these genetic alterations would impair islet function is unknown. METHODS:On a background of α1,3-galactosyltransferase gene-knockout (GTKO)/human (h)CD46, additional genes (hCD39, human tissue factor pathway inhibitor, porcine CTLA4-Ig) were inserted in different combinations under an insulin promoter to promote expression in islets (confirmed by immunofluorescence). Seven pigs were tested for baseline and glucose/arginine-challenged levels of glucose, insulin, C-peptide, and glucagon. RESULTS:This preliminary study did not show definite evidence of β-cell deficiencies, even when three transgenes were expressed under the insulin promoter. Of seven animals, all were normoglycemic at fasting, and five of seven had normal glucose disposal rates after challenge. All animals exhibited insulin, C-peptide, and glucagon responses to both glucose and arginine challenge; however, significant interindividual variation was observed. CONCLUSIONS:Multiple islet-targeted transgenic expression was not associated with an overtly detrimental effect on islet function, suggesting that complex genetic constructs designed for islet protection warrants further testing in islet xenotransplantation models.
journal_name
Xenotransplantationjournal_title
Xenotransplantationauthors
Wijkstrom M,Bottino R,Iwase H,Hara H,Ekser B,van der Windt D,Long C,Toledo FG,Phelps CJ,Trucco M,Cooper DK,Ayares Ddoi
10.1111/xen.12145subject
Has Abstractpub_date
2015-01-01 00:00:00pages
70-9issue
1eissn
0908-665Xissn
1399-3089journal_volume
22pub_type
杂志文章abstract:BACKGROUND:The aim of the present study was to further investigate the characteristics of both graft-infiltrating cells and splenocytes during acute vascular rejection (AVR), cell-mediated rejection and non-rejection of vascularized concordant xenografts, by analysing both proinflammatory [interleukin-1beta (IL-1beta) ...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1034/j.1399-3089.2003.02032.x
更新日期:2003-07-01 00:00:00
abstract:BACKGROUND:In pig-to-human xenotransplantation, interactions between human natural killer (NK) cells and porcine endothelial cells (pEC) are characterized by recruitment and cytotoxicity. Protection from xenogeneic NK cytotoxicity can be achieved in vitro by the expression of the non-classical human leukocyte antigen-E...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12357
更新日期:2018-01-01 00:00:00
abstract:BACKGROUND:The long-term viability and function of transplanted encapsulated neonatal porcine islets was examined in a diabetic patient. METHODS AND RESULTS:A 41-yr-old Caucasian male with type 1 diabetes for 18 yr was given an intraperitoneal transplant of alginate-encapsulated porcine islets at the dose of 15,000 is...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2007.00384.x
更新日期:2007-03-01 00:00:00
abstract:BACKGROUND:In vivo xenotransplantation modeling in large animal species is often performed in nonhuman primates, including baboons. For proper data interpretation, reference values for clinical chemistry and hematology are required. METHODS:These values are available from baseline levels in animals subjected to tolera...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2004.00171.x
更新日期:2004-11-01 00:00:00
abstract::Previous data suggest that natural anti-Galalpha1,3Gal (Gal) antibody (Ab) is produced by mature plasma cells. As thalidomide is effectively used in the treatment of patients with multiple myeloma, its effect on natural anti-Gal Ab production has been assessed in two baboons. During a 10-week course of thalidomide adm...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1034/j.1399-3089.2003.00064.x
更新日期:2003-09-01 00:00:00
abstract:BACKGROUND:Autograft (AG) is the gold standard bone graft due to biocompatibility, osteoconductivity, osteogenicity, and osteoinductivity. Alternatives include allografts and xenografts (XG). METHODS:We investigated the osseointegration and biocompatibility of a decellularized porcine XG within a critical defect anima...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12662
更新日期:2020-11-26 00:00:00
abstract::Islet transplantation is a potential treatment for diabetes mellitus and porcine pancreata may provide a readily available source of islets. The size, number and distribution of islets within the pancreas may influence the choice of age of donor for xenotransplantation. Samples (n = 3 per age group) from the dorsal an...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1034/j.1399-3089.1999.00009.x
更新日期:1999-05-01 00:00:00
abstract:BACKGROUND:Our previous study has shown that porcine antigen-primed and CD4+ T cell-activated macrophages are capable of recognition and rejection of porcine xenografts after adoptive transfer. However, whether this is an absolute xenograft specific rejection remains to be confirmed. METHODS:Mouse islet allografts and...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2008.00486.x
更新日期:2008-09-01 00:00:00
abstract::The infusion of large numbers of porcine cells into primates in order to induce specific immunologic tolerance by mixed hematopoietic chimerism, results in thrombotic microangiopathy that can be fatal. For this reason, it is important to study in vitro the interaction of primate endothelial cells with pig cells. We sh...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1034/j.1399-3089.2002.01066.x
更新日期:2002-05-01 00:00:00
abstract:BACKGROUND:ABI793 (ABI) is a human monoclonal antibody (mAb) specific for human CD154. To assess the suitability of ABI for baboon transplantation studies, we carried out in vitro studies to determine ABI's reactivity with baboon cells expressing CD154, performed in vivo pharmacokinetic studies in two baboons, and test...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2004.00148.x
更新日期:2004-07-01 00:00:00
abstract::Acute humoral rejection remains the major barrier to long-term pig-to-primate xenograft survival, and microvascular thrombosis is a critical element of the rejection process. It appears that persistent endothelial cell activation and injury, by even low levels of anti-graft antibodies, eventually overwhelm the cellula...
journal_title:Xenotransplantation
pub_type: 杂志文章,评审
doi:10.1111/j.1399-3089.2006.00368.x
更新日期:2007-01-01 00:00:00
abstract::The activation of the endothelial surface in xenografts is still a poorly understood process and the consequences are unpredictable. The role of Ca2+ -messaging during the activation of endothelial cells is well recognized and routinely measured by synthetic Ca2+ -sensitive fluorophors. However, these compounds requir...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12585
更新日期:2020-09-01 00:00:00
abstract:BACKGROUND:The continued presence of a primate antibody-mediated response to cells and organs from alpha1,3-galactosyltransferase gene-knockout (GTKO) pigs indicates that there may be antigens other than Gal alpha 1,3Gal (alpha Gal) against which primates have xenoreactive antibodies. Human and baboon sera were tested ...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2010.00579.x
更新日期:2010-05-01 00:00:00
abstract::Cultures of hDAF transgenic porcine aortic endothelial cells (TPAEs) with levels of cell surface hDAF expression between 2000 and 300 000 molecules per cell have been used to determine the relationship between expression of hDAF and protection from human complement deposition in an in vitro model. At concentrations be...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1034/j.1399-3089.2001.00086.x
更新日期:2001-05-01 00:00:00
abstract::The aim of the present study was to evaluate the immunosuppressive effect of tacrolimus (TAC) in discordant islet xenotransplantation. Fetal porcine islet-like cell clusters (ICCs) were transplanted under the kidney capsule in normoglycemic rats treated with TAC monotherapy, TAC plus other immunosuppressive drugs or c...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1034/j.1399-3089.2003.00068.x
更新日期:2003-11-01 00:00:00
abstract:BACKGROUND:Type 1 diabetes mellitus is a devastating disease for which there is currently no cure, but only lifetime management. Islet xenotransplantation is a promising technique for the restoration of blood glucose control in patients with diabetes mellitus. The purpose of this study was to explore the potential use ...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12087
更新日期:2014-03-01 00:00:00
abstract:BACKGROUND:Human cytomegalovirus (HCMV) infection or reactivation has been linked to allograft rejection resulting from endothelial injury and immune activation. In pig-to-human xenotransplantation, currently investigated to circumvent the shortage of human organs in transplantation medicine, the porcine endothelium wi...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2010.00594.x
更新日期:2010-07-01 00:00:00
abstract:BACKGROUND:Extensive studies in rodents have identified olfactory ensheathing cells (OECs) as promising candidates for cell-based therapies of spinal cord and peripheral nerve injury. Previously, we demonstrated that short-term cultured adult porcine OECs can remyelinate the rodent and non-human primate spinal cord. He...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2009.00562.x
更新日期:2010-01-01 00:00:00
abstract::Xenotransplantation of porcine organs might provide an unlimited source of donor organs to treat endstage organ failure diseases in humans. However, pigs harbour retroviruses with unknown pathogenic potential as an integral part of their genome. While until recently the risk of interspecies transmission of these porci...
journal_title:Xenotransplantation
pub_type: 杂志文章,评审
doi:10.1034/j.1399-3089.2002.01110.x
更新日期:2002-07-01 00:00:00
abstract:BACKGROUND:The induced antibodies against Galalpha1,3Gal (Gal) and non-Gal epitopes may contribute to delayed xenograft rejection (DXR). We asked whether blockade of the CD40/CD154 and CD28/B7 co-stimulatory pathways modulates the baboon elicited antibody response to pig Gal and non-Gal antigens. METHODS:Eighteen babo...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2005.00221.x
更新日期:2005-05-01 00:00:00
abstract::Post-transplantation infections are common in allograft recipients and should be expected in all immunocompromised hosts. Based on the need for immunosuppression in xenotransplantation, procedures developed to enhance safety in allotransplantation can be applied in future xenotransplantation clinical trials. Standardi...
journal_title:Xenotransplantation
pub_type: 杂志文章,评审
doi:10.1111/xen.12423
更新日期:2018-07-01 00:00:00
abstract::My purpose in these remarks is to stimulate us to consider the vast array that nature has provided us in the differentiation of species, and to examine the possibility that some of these differences might prove useful in other species, including man. ...
journal_title:Xenotransplantation
pub_type:
doi:10.1034/j.1399-3089.2000.00045.x
更新日期:2000-05-01 00:00:00
abstract:BACKGROUND:Liver fibrosis results from accumulation of extracellular matrix components and is associated with many chronic hepatic diseases. There is to date no specific therapy for this disease, and patients receive treatment for its associated complications. Specific progenitor cells, known as oval cells, are present...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2006.00344.x
更新日期:2006-11-01 00:00:00
abstract::Development of coagulation disorders remains a major challenge in pig-to-primate organ xenotransplantation. Our previous studies demonstrated that porcine aortic endothelial cells (pAEC) activate human platelets to express tissue factor (TF). In this study, we investigated the molecular interaction between human plate...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12068
更新日期:2014-01-01 00:00:00
abstract::We designed this study to define reference values of the cynomolgus monkey coagulation system, as the normal range of values has not been established. Measurement of coagulation function was determined by testing plasma samples from 30 healthy male cynomolgus monkeys. Prothrombin time (PT), PT activity, PT internation...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12457
更新日期:2019-01-01 00:00:00
abstract:BACKGROUND:Islet transplantation is potentially a promising therapy for the restoration of carbohydrate control to diabetic patients. However, the global application of islet transplantation requires a ubiquitous source of beta cells. The xenotransplantation of porcine islets would provide such a source. Success in por...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2009.00548.x
更新日期:2009-11-01 00:00:00
abstract:BACKGROUND:The Westran pig has been purposely inbred for use in xenotransplantation. The herd originated in the wild from a limited gene pool and has been inbred by repeated full-sib matings for nine generations. METHODS:The aim of this study was to evaluate the level of inbreeding by functional assays, such as bi-dir...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2005.00230.x
更新日期:2005-07-01 00:00:00
abstract:BACKGROUND:Porcine islet transplantation is emerging as an attractive option for the treatment of patients with type 1 diabetes, with the possibility of providing islets of higher and more consistent quality and in larger volumes than available from human pancreata. The use of encapsulated neonatal porcine islets (ENPI...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12005
更新日期:2012-11-01 00:00:00
abstract::Xenotransplantation has the potential to alleviate the organ shortage that prevents many patients with end-stage renal disease from enjoying the benefits of kidney transplantation. Despite significant advances in other models, pig-to-primate kidney xenotransplantation has met limited success. Preformed anti-pig antibo...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12166
更新日期:2015-05-01 00:00:00
abstract:BACKGROUND:Dysregulation of coagulation is considered a major barrier against successful pig organ xenotransplantation in non-human primates. Inflammation is known to promote activation of coagulation. The role of pro-inflammatory factors as well as the relationship between inflammation and activation of coagulation in...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12133
更新日期:2015-01-01 00:00:00