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 xenograft recipients is poorly understood. METHODS:Baboons received kidney (n=3), heart (n=4), or artery patch (n=8) xenografts from α1,3-galactosyltransferase gene-knockout (GTKO) pigs or GTKO pigs additionally transgenic for human complement-regulatory protein CD46 (GTKO/CD46). Immunosuppression (IS) was based on either CTLA4Ig or anti-CD154 costimulation blockade. Three artery patch recipients did not receive IS. Pro-inflammatory cytokines, chemokines, and coagulation parameters were evaluated in the circulation after transplantation. In artery patch recipients, monocytes and dendritic cells (DC) were monitored in peripheral blood. Expression of tissue factor (TF) and CD40 on monocytes and DC were assessed by flow cytometry. C-reactive protein (C-RP) levels in the blood and C-RP deposition in xenografts as well as native organs were evaluated. Baboon and pig C-RP mRNA in heart and kidney xenografts were evaluated. RESULTS:In heart and kidney xenograft recipients, the levels of INFγ, TNF-α, IL-12, and IL-8 were not significantly higher after transplantation. However, MCP-1 and IL-6 levels were significantly higher after transplantation, particularly in kidney recipients. Elevated C-RP levels preceded activation of coagulation in heart and kidney recipients, where high levels of C-RP were maintained until the time of euthanasia in both heart and kidney recipients. In artery patch recipients, INFγ, TNF-α, IL-12, IL-8, and MCP-1 were elevated with no IS, while IL-6 was not. With IS, INFγ, TNF-α, IL-12, IL-8, and MCP-1 were reduced, but IL-6 was elevated. Elevated IL-6 levels were observed as early as 2 weeks in artery patch recipients. While IS was associated with reduced thrombin activation, fibrinogen and C-RP levels were increased when IS was given. There was a significant positive correlation between C-RP, IL-6, and fibrinogen levels. Additionally, absolute numbers of monocytes were significantly increased when IS was given, but not without IS. This was associated with increased CD40 and TF expression on CD14+ monocytes and lineage(neg) CD11c+ DC, with increased differentiation of the pro-inflammatory CD14+ CD11c+ monocyte population. At the time of euthanasia, C-RP deposition in kidney and heart xenografts, C-RP positive cells in artery patch xenograft and native lungs were detected. Finally, high levels of both pig and baboon C-RP mRNA were detected in heart and kidney xenografts. CONCLUSIONS:Inflammatory responses precede activation of coagulation after organ xenotransplantation. Early upregulation of C-RP and IL-6 levels may amplify activation of coagulation through upregulation of TF on innate immune cells. Prevention of systemic inflammation in xenograft recipients (SIXR) may be required to prevent dysregulation of coagulation and avoid excessive IS after xenotransplantation.
journal_name
Xenotransplantationjournal_title
Xenotransplantationauthors
Ezzelarab MB,Ekser B,Azimzadeh A,Lin CC,Zhao Y,Rodriguez R,Echeverri GJ,Iwase H,Long C,Hara H,Ayares D,Pierson RN,Thomson AW,Cooper DKdoi
10.1111/xen.12133subject
Has Abstractpub_date
2015-01-01 00:00:00pages
32-47issue
1eissn
0908-665Xissn
1399-3089journal_volume
22pub_type
杂志文章abstract:AIM:To provide information on the specificity of induced anti-pig antibodies (Abs) in baboons after exposure and sensitization to pig antigens. MATERIALS AND METHODS:Baboons (n=7) received either porcine mobilized peripheral blood progenitor cells (n=3), kidney (n=3) or heart (n=1) transplants. After rejection of thes...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1034/j.1399-3089.2003.01122.x
更新日期:2003-01-01 00:00:00
abstract:BACKGROUND:Manipulating the pig genome to increase compatibility with human biology may facilitate the clinical application of xenotransplantation. Genetic modifications to pig cells have been made by sequential recombination in fetal fibroblasts and liver-derived cells followed by cross-breeding or somatic cell nuclea...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12131
更新日期:2015-01-01 00:00:00
abstract::The outstanding results recently obtained in islet xenotransplantation suggest that porcine islet clinical trials may soon be scientifically appropriate. Before the initiation of such clinical studies, however, it is essential that a series of key ethical and regulatory conditions are satisfied. As far as ethics is co...
journal_title:Xenotransplantation
pub_type: 共识发展会议,杂志文章
doi:10.1111/j.1399-3089.2009.00540.x
更新日期:2009-07-01 00:00:00
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: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: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 xen...
journal_title:Xenotransplantation
pub_type: 杂志文章,评审
doi:10.1111/xen.12120
更新日期:2014-11-01 00:00:00
abstract::We describe in this report the production and characterization of monoclonal antibodies (mAb) to the swine homologues of CD11a and CD18 antigens, and their use for phenotypic and functional analysis of porcine leukocytes. Monoclonal antibodies BL1H8 and BL2F1 precipitated two bands of approximately 170 and 95 kDa, whe...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1034/j.1399-3089.2000.00574.x
更新日期:2000-11-01 00:00:00
abstract:BACKGROUND:TNF and its receptors TNF-Receptor 1 (TNFR1, CD120a) and TNF-Receptor 2 (TNFR2, CD120b) have been implicated in the rejection of transplanted cells and organs. Although pig TNFR1 (pTNFR1) is known to mediate the effects of human TNF in a xenogeneic setting, it is unclear whether pig TNFR2 (pTNFR2) could cont...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2011.00634.x
更新日期:2011-03-01 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:BACKGROUND:Young people, and students in particular, generally have a positive attitude to xenotransplantation. We reported previously that university students attending their first year approved of the idea of transplanting animal organs into humans. The aim of this study was to evaluate the impact of a 3-yr course at...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2006.00307.x
更新日期:2006-05-01 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::Orthotopic liver transplantation (OLT) is the only definitive treatment option for many patients with end-stage liver disease. Current supply of donor livers for OLT is not keeping up with the growing demand. To overcome this problem, a number of experimental strategies have been developed either to provide a bridge t...
journal_title:Xenotransplantation
pub_type: 杂志文章,评审
doi:10.1111/xen.12668
更新日期:2020-12-08 00:00:00
abstract:BACKGROUND:Intravascular thrombosis and systemic coagulation abnormalities are major hurdles to successful xenotransplantation and are signs of acute humoral rejection. Increased expression of tissue factor (TF) is associated with the development of microvascular thrombosis in xenografts. To develop an effective strate...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2012.00704.x
更新日期:2012-05-01 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:UNLABELLED:Xenotransplantation using porcine organs may resolve a chronic shortage of donor organs for clinical transplantation if significant immunological barriers can be overcome. To determine the potential role of T lymphocytes in Xenograft (Xg) rejection, we transplanted transgenic hCD46 porcine hearts heterotopic...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2005.00258.x
更新日期:2006-01-01 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:Whilst macrohemodynamic function of porcine xenografts transplanted into baboons has been assessed perioperatively, the ability of the xenograft to maintain systemic microcirculatory perfusion has not been investigated after pig-to-baboon xenotransplantation so far. METHODS:We investigated the sublingual mi...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2011.00645.x
更新日期:2011-07-01 00:00:00
abstract::In addition to providing a large source of donor tissue, xenogeneic islet transplantation might avoid recurrent autoimmunity in patients with type 1 diabetes. To examine this possibility further, xenogeneic pig islets were transplanted into recipient mice in the presence or absence of autoimmunity. Spontaneously, non-...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1034/j.1399-3089.2003.02040.x
更新日期:2003-03-01 00:00:00
abstract:BACKGROUND:Xenotransplantation of porcine islets has emerged in recent decades as a potential treatment for type 1 diabetes (T1D). Current methods of detection, indicative of successful engraftment, occur downstream of actual islet death. Epigenetic biomarkers can be detected in circulating cell-free DNA (cfDNA) to pro...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12570
更新日期:2020-03-01 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::Mouse CD4+ T cells efficiently develop in fetal pig thymus (FP THY) grafts and repopulate the periphery of T cell and NK cell-depleted, thymectomized (ATX) mice. However, efficient peripheral repopulation of mouse CD8+ T cells does not occur in these mice. We have therefore evaluated the maturation and function of mou...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.1998.tb00015.x
更新日期:1998-02-01 00:00:00
abstract:BACKGROUND:One-half of all orthopedic surgeries require bone grafting for successful outcomes in fusions, reconstructive procedures, and the treatment of osseous defects resulting from trauma, tumor, infection, or congenital deformity. Autologous bone grafts are taken from the patient's own body and remain the "gold st...
journal_title:Xenotransplantation
pub_type: 杂志文章,评审
doi:10.1111/xen.12600
更新日期:2020-09-01 00:00:00
abstract::The effects of pre-transplant blood transfusion vary from induction of antibodies and accelerated graft rejection, to prolonged survival and even tolerance. The beneficial 'transfusion effect' in allotransplantation is believed to be merely T-cell mediated. In xenotransplantation, T-cell independent mechanisms form a ...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1034/j.1399-3089.2001.00102.x
更新日期:2001-11-01 00:00:00
abstract:BACKGROUND:Both the complement and the coagulation systems play important roles in the development of hyperacute or acute antibody-mediated xenograft rejection. Atrase B is a novel metalloproteinase isolated from the venom of Naja atra. In this study, we investigated the inhibitory effects of atrase B on complement act...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12616
更新日期:2020-09-01 00:00:00
abstract::The first blood transfusions in humans were xenotransfusions, carried out by Jean-Baptiste Denis beginning in 1667. Richard Lower, Matthäus Purmann and Georges Mercklin also experimented with the use of animal blood for transfusion until this practice was forbidden in 1670, after the death of one of Denis's patients. ...
journal_title:Xenotransplantation
pub_type: 历史文章,杂志文章
doi:10.1111/j.1399-3089.2007.00404.x
更新日期:2007-05-01 00:00:00
abstract::Xenotransplantion remains the most viable option for significant expansion of the donor organ pool in clinical transplantation. With the advent of nuclear transfer technologies, the production of transgenic swine has become a possibility. These animals have allowed transplant investigators to overcome humoral mechanis...
journal_title:Xenotransplantation
pub_type: 杂志文章,评审
doi:10.1111/j.1399-3089.2011.00687.x
更新日期:2012-01-01 00:00:00
abstract::When clinical xenotransplantation is introduced, the costs associated with acquisition of a genetically engineered pig organ are as yet unknown. How will these costs compare with those currently associated with the acquisition of deceased human organs? An understanding of the financial aspects of deceased organ and ti...
journal_title:Xenotransplantation
pub_type: 杂志文章,评审
doi:10.1111/xen.12322
更新日期:2017-07-01 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::Islets isolated from multiple pancreas donors are often necessary to achieve euglycemia in type 1 diabetic patients treated by islet allotransplantation. This increases the burden on the limited pool of donor organs. After infusion into the portal vein, a substantial percentage of islets are lost in the immediate post...
journal_title:Xenotransplantation
pub_type: 杂志文章,评审
doi:10.1111/j.1399-3089.2007.00419.x
更新日期:2007-07-01 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