Abstract:
BACKGROUND:Recently, we have shown that an immunosuppression regimen including costimulation blockade via anti-CD154 antibody significantly prolongs the cardiac xenograft survival in a GTKO.hCD46Tg pig-to-baboon heterotopic xenotransplantation model. Unfortunately, many coagulation disorders were observed with the use of anti-CD154 antibody, and recipient survival was markedly reduced by these complications. MATERIAL AND METHODS:In this experiment, we replaced anti-CD154 antibody with a more clinically acceptable anti-CD40 antibody while keeping the rest of the immunosuppressive regimen and the donor pig genetics the same. This was carried out to evaluate the antibody's role in xenograft survival and prevention of coagulopathies. Two available clones of anti-CD40 antibody were tested. One mouse anti-human CD40 antibody, (clone 3A8), activated B lymphocytes in vitro and only modestly suppressed antibody production in vivo. Whereas a recombinant mouse non-human primate chimeric raised against macaque CD40, (clone 2C10R4), blocked B-cell activation in vitro and completely blocked antibody production in vivo. RESULTS:The thrombotic complications seen with anti-CD154 antibody were effectively avoided but the graft survival, although extended, was not as prolonged as observed with anti-CD154 antibody treatment. The longest survival for the 3A8 antibody group was 27 days, and the longest graft survival in the 2C10R4 antibody group was 146 days. All of the grafts except two rejected and were explanted. Only two recipient baboons had to be euthanized due to unrelated complications, and the rest of the baboons remained healthy throughout the graft survival period or after graft explantation. In contrast to our anti-CD 154 antibody-treated baboons, the non-Gal antibody levels started to rise after B cells made their appearance around 8 weeks post-transplantation. CONCLUSIONS:Anti-CD40 antibody at the current dose does not induce any coagulopathies but while effective, had reduced efficacy to induce similar long-term graft survival as with anti-CD154 antibody perhaps due to ineffective control of B-cell function and antibody production at the present dose. More experiments are required to determine antibody affinity and effective dose for inducing long-term cardiac xenograft survival.
journal_name
Xenotransplantationjournal_title
Xenotransplantationauthors
Mohiuddin MM,Singh AK,Corcoran PC,Hoyt RF,Thomas ML 3rd,Lewis BG,Eckhaus M,Dabkowski NL,Belli AJ,Reimann KA,Ayares D,Horvath KAdoi
10.1111/xen.12066subject
Has Abstractpub_date
2014-01-01 00:00:00pages
35-45issue
1eissn
0908-665Xissn
1399-3089journal_volume
21pub_type
杂志文章abstract:BACKGROUND:We have successfully performed heart transplantation despite the most unfavourable risk factors for graft and patient survival: the presence of a high level of antibodies (Abs) against the donor's human leukocyte antigens (HLA) class I/II and blood group A1 antigens. The present study concerns post-transplan...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2006.00276.x
更新日期:2006-03-01 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: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:Microvascular thrombosis is a prominent characteristic of delayed xenograft rejection, therefore the effects of antiplatelet therapy with aspirin and clopidogrel on long-term cardiac xenograft function was investigated in a heterotopic pig-to-baboon cardiac transplant model. METHODS:Donor hearts from human ...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2004.00159.x
更新日期:2004-09-01 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:BACKGROUND:Blood group ABO-incompatible live donor (LD) renal transplantation may provide a significant source of organs. We report the results of our first 14 cases of ABO-incompatible LD renal transplantation using specific anti-A/B antibody (Ab) immunoadsorption (IA) and anti-CD20 monoclonal Ab (mAb) treatment. PATI...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2006.00280.x
更新日期:2006-03-01 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::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: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::The newborn infant with severe cardiac failure owed to congenital structural heart disease or cardiomyopathy poses a daunting therapeutic challenge. The ideal solution for both might be cardiac transplantation if availability of hearts was not limiting and if tolerance could be induced, obviating toxicity of immunosup...
journal_title:Xenotransplantation
pub_type: 杂志文章,评审
doi:10.1111/xen.12479
更新日期:2018-11-01 00:00:00
abstract::Neonatal porcine islets are characterized by reproducible isolation success and high yields, sizable advantages over adult islets. In this work we have analyzed selected phenotypic and functional characteristics of porcine neonatal islets relevant to their possible use for transplant in humans. We show that porcine is...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1034/j.1399-3089.2002.0o128.x
更新日期:2002-01-01 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: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:Activation of the clotting cascade is central in acute xenograft rejection (AHXR) that occurs when pig organs are transplanted into primates. The coagulopathy reported in this model is a very complex process that involves simultaneously coagulation factors, platelets and phospholipid-bearing cells (i.e., leu...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12024
更新日期:2013-03-01 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: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: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-ta...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12145
更新日期:2015-01-01 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:BACKGROUND: Various groups have reported prolonged diabetes reversal and graft function after porcine islet transplantation into diabetic macaques using different experimental designs (macaque source, islet source, type of immunosuppression): subsequently, the International Xenotransplantation Association has publishe...
journal_title:Xenotransplantation
pub_type: 杂志文章,评审
doi:10.1111/xen.12012
更新日期:2013-01-01 00:00:00
abstract:BACKGROUND:Pig islets represent an alternative to the current modes of treatment for patients with diabetes. However, the concerns over pathogen transmission including that of PERV limit their immediate, widespread usage in humans. It has been previously demonstrated that PERV copy number and particularly expression le...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12311
更新日期:2017-07-01 00:00:00
abstract::Fetal pig islets, xenografted after organ culture into non-immunosuppressed prediabetic NOD mice, are rejected within 10 days. Immunosuppression with anti-T cell (anti-CD4 and anti-CD3) monoclonal antibodies alone is highly effective in delaying graft rejection in this discordant model, but rejection eventually occurs...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.1998.tb00030.x
更新日期:1998-08-01 00:00:00
abstract::Exposure to human serum induces the lysis of xenogeneic cells through natural antibodies and complement activation. The carbohydrate Galactose-alpha1,3-Galactose (Gal-alpha1,3-Gal) epitope, has been shown to be the principal antigenic determinant on target cells. This reaction is, therefore, particularly important for...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1034/j.1399-3089.2003.00110.x
更新日期:2003-05-01 00:00:00
abstract::The present study was undertaken to establish a rat-to-mouse vascularized small bowel xenotransplantation model to study acute vascular and hyperacute xenograft rejection, and xenogenic cell migration. Lewis rat small bowel grafts were transplanted heterotopically to group 1, Balb/c mice, and group 2, Balb/c mice pre-...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1034/j.1399-3089.1999.00001.x
更新日期:1999-02-01 00:00:00
abstract:BACKGROUND:Sertoli cells (SC) are known to have active mechanism for evading humoral immune response and are known to have immune modulatory effects in the presence of other antigens. This has led us to hypothesize that systemic immune modulating effect of SC might be optimized by their residence on peripheral lymph no...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2007.00435.x
更新日期:2007-11-01 00:00:00
abstract:AIM:to study whether sensitization to pig antigens results in humoral and/or cellular sensitization to alloantigens in baboons, and thus increases the risks of organ allotransplantation after xenotransplantation. Serum from baboons that were naive (n = 4), sensitized to Gal alpha 1,3Gal (Gal) antigens (n = 2), or sensi...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2004.00075.x
更新日期:2004-01-01 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 use of xenogeneic porcine pancreatic islets has been shown to be a potentially promising alternative to using human allogeneic islets to treat insulin-dependent type 1 diabetes (T1D). This article provides an overview of the existing FDA regulatory framework that would be applied to the regulation of clinical tria...
journal_title:Xenotransplantation
pub_type: 杂志文章,评审
doi:10.1111/j.1399-3089.2010.00592.x
更新日期:2010-09-01 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:BACKGROUND:The pig pancreas is considered to be the most suitable source of islets for xenotransplantation in patients with type I diabetes. The objective of this study was to assess the antigenicity of neonatal porcine islet-like cell clusters (NPCC), including the Galalpha1-3Galbeta1-4GlcNAc-R (alpha-Gal) and Hanganu...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2006.00335.x
更新日期:2006-09-01 00:00:00