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 porcine islet xenografting has been achieved in diabetic primates. However, there are few reports of reversal of diabetes with porcine islet xenografts in rodent models of diabetes, relative to the number of successful rodent experiments performed as allografts. Here we report for the first time the inability of porcine (and human) insulin to control blood glucose levels in diabetic rodents determined by a series of dose escalating studies. METHODS:Insulin was administered intravenously to streptozotocin induced diabetic Lewis rats, Balb/c and athymic Balb/c mice (n = 5 per group) at the following doses: Group I "physiological dose" (pd) of 0.16 U/kg for a total dose of 40 mU to a 250 g rat. Group II received 0.64 U/kg (4xpd), group III 1.6 U/kg (10xpd) and group IV 6.4 U/kg (40xpd). Blood glucose levels were monitored in each animal at seven time points: 0 (pre-injection), 10 min, 20 min, 30 min, 45 min, 1 h, 1.5 h, 2 h and 3 h post-injection. Serum insulin levels were also determined. RESULTS:Diabetic Lewis rats achieved a maximum reduction in blood glucose from 22.1 +/- 1.8mmol/l to 8.0 +/- 3.1 mmol/l (a 63.7% reduction), 90 minutes post-injection of 6.4 U/kg dose of porcine insulin (40xpd). Human insulin was less effective at reducing blood glucose levels in rats than porcine insulin (P < 0.001). Porcine insulin reduced blood glucose levels in Balb/c mice from a mean of 18.2 +/- 2.1 mmol/l to a hypoglycemic minimum of 1.26 +/- 0.18 mmol/l a reduction of 93.0%, 60 min post-injection of the maximum dose of 6.4 U/kg. Balb/c mice were significantly more responsive to porcine insulin than Lewis rats at doses of 0.64 U/kg (P < 0.001), 1.6 U/kg (P < 0.05) and 6.4 U/kg (P < 0.001). Athymic Balb/c nude mice reached a maximum reduction in blood glucose from 21.6 +/- 1.8 mmol/l to 3.6 +/- 0.9 mmol/l (a 83.4% reduction) 120 min post-injection at a dose of 6.4 U/kg. Overall, athymic Balb/c nude mice were more resistant to porcine insulin than immunocompetent Balb/c mice at doses of 0.64 U/kg (P < 0.001), 1.6 U/kg (P < 0.001) and 6.4 U/kg (P < 0.05). Insulin diluent alone marginally increased blood glucose levels in all animals tested. CONCLUSIONS:Our results suggest that restoration of normoglycemia in diabetic rodents is not ideal for testing porcine islets xenografts since the reversals of diabetes in these species requires 20 to 40 times the dose of porcine insulin used in humans.
journal_name
Xenotransplantationjournal_title
Xenotransplantationauthors
Pepper AR,Gall C,Mazzuca DM,Melling CW,White DJdoi
10.1111/j.1399-3089.2009.00548.xsubject
Has Abstractpub_date
2009-11-01 00:00:00pages
502-10issue
6eissn
0908-665Xissn
1399-3089pii
XEN548journal_volume
16pub_type
杂志文章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::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: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::The last 15 years or so have seen exciting progress in xenotransplantation, with porcine organ grafts surviving months or even years in non-human primates. These advances reflect the application of new scientific knowledge, improved immunosuppressive agents, and genetic engineering. The field has recently enjoyed a re...
journal_title:Xenotransplantation
pub_type: 杂志文章,评审
doi:10.1111/xen.12419
更新日期:2018-05-01 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:BACKGROUND:Endothelial damage is a critical step in the development of (xeno) transplantation-related and cardiovascular pathology. In humans, the amount of circulating endothelial cells (CEC) correlates to disease intensity and functions as a valuable damage marker. While (xeno) transplantation and cardiovascular rese...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12018
更新日期:2013-01-01 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: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::Highly sensitized patients awaiting kidney transplantation may be potential candidates for future clinical trials using pig organ donors. Because of crossreactivity between human leucocyte antigens (HLA) and swine leucocyte antigens (SLA), such patients might have heightened T-cell responses to porcine xenoantigens. W...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1034/j.1399-3089.2003.00089.x
更新日期:2003-11-01 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: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 process of islet xenograft rejection is still poorly understood. To elucidate further possible mechanism(s) involved in xenograft rejection, the effect of different immunization protocols was investigated. Fetal porcine islet-like cell clusters (ICCs) were transplanted under the kidney capsule in otherwise untreat...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1034/j.1399-3089.1999.00032.x
更新日期:1999-11-01 00:00:00
abstract:BACKGROUND:Innovations in transgenic technology have facilitated improved xenograft survival. Additional gene expression appears to be necessary to overcome the remaining immune and biologic incompatibilities. We report for the first time the novel use of six-gene modifications within a pig-to-baboon cardiac xenotransp...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12330
更新日期:2017-11-01 00:00:00
abstract:BACKGROUND:In pig-to-nonhuman primate solid organ xenotransplantation using organs from donors transgenic for human decay-accelerating factor (hDAF), the main type of rejection is antibody-mediated (acute humoral xenograft rejection, AHXR). This occurs despite the complement-regulatory function of the transgene, neutra...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2004.00184.x
更新日期:2005-01-01 00:00:00
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: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:Swine infectious pathogens, especially viruses, represent a potential public health risk associated with the use of pig tissues for xenotransplantation in humans. We hypothesized that porcine circovirus type I (PCV-1) may infect human mononuclear cells, resulting in ultrastructural alterations of the target ...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/j.1399-3089.2005.00249.x
更新日期:2005-11-01 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: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::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: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::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:BACKGROUND:The JAK/STAT (Janus Tyrosine Kinase, Signal Transducers and Activators of Transcription) pathway is associated with cytokine or growth factor receptors and it is critical for growth control, developmental regulation and homeostasis. The use of porcine ocular cells as putative xenotransplants appears theoreti...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12070
更新日期:2013-11-01 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: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::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: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. METHODS:The SLA-derive...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12119
更新日期:2014-09-01 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::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::Allogeneic hematopoietic stem cell transplantation (HSCT) and xenotransplantation are accompanied by viral reactivations and virus-associated complications resulting from immune deficiency. Here, in a Mauritian cynomolgus macaque model of fully MHC-matched allogeneic HSCT, we report reactivations of cynomolgus polyoma...
journal_title:Xenotransplantation
pub_type: 杂志文章
doi:10.1111/xen.12578
更新日期:2020-07-01 00:00:00