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Aseda A Tena, David H Sachs, Christopher Mallard, Yong-Guang Yang, Masayuki Tasaki, Evan Farkash, Ivy A Rosales, Robert B Colvin, David A Leonard, Robert J Hawley
BACKGROUND: Successful xenotransplantation will likely depend, in part, on the induction of immunological tolerance, because the high levels of immunosuppression otherwise required would likely have unacceptable side effects. Rapid clearance of administered porcine hematopoietic stem cells by primate macrophages has hampered previous attempts to induce tolerance through mixed hematopoietic chimerism across a pig-to-primate barrier. Phagocytosis is normally inhibited by binding of cell surface protein CD47 to macrophage signal regulatory protein α receptors...
May 26, 2016: Transplantation
James R Butler, Nicholas J Skill, David L Priestman, Frances M Platt, Ping Li, Jose L Estrada, Gregory R Martens, Joseph M Ladowski, Matthew Tector, A Joseph Tector
BACKGROUND: The Galα(1,3)Gal epitope (α-GAL), created by α-1,3-glycosyltransferase-1 (GGTA1), is a major xenoantigen causing hyperacute rejection in pig-to-primate and pig-to-human xenotransplantation. In response, GGTA1 gene-deleted pigs have been generated. However, it is unclear whether there is a residual small amount of α-Gal epitope expressed in GGTA1(-/-) pigs. Isoglobotrihexosylceramide synthase (iGb3s), another member of the glycosyltransferase family, catalyzes the synthesis of isoglobo-series glycosphingolipids with an α-GAL-terminal disaccharide (iGb3), creating the possibility that iGb3s may be a source of α-GAL epitopes in GGTA1(-/-) animals...
March 2016: Xenotransplantation
Anjan K Bongoni, Nikolai Klymiuk, Eckhard Wolf, David Ayares, Robert Rieben, Peter J Cowan
BACKGROUND: Transgenic expression of human thrombomodulin (hTBM), which has the potential to solve the problem of coagulation dysregulation in pig-to-primate xenotransplantation, may have additional benefits by neutralizing the proinflammatory cytokine high-mobility group box 1 (HMGB1). The aim of this study was to investigate HMGB1-mediated effects on porcine aortic endothelial cells (PAEC) from wild-type (WT) and hTBM transgenic pigs. METHODS: Porcine aortic endothelial cells were treated with HMGB1, human (h)TNFα or lipopolysaccharide (LPS)...
September 2016: Transplantation
Muhammad M Mohiuddin, Avneesh K Singh, Philip C Corcoran, Marvin L Thomas, Tannia Clark, Billeta G Lewis, Robert F Hoyt, Michael Eckhaus, Richard N Pierson, Aaron J Belli, Eckhard Wolf, Nikolai Klymiuk, Carol Phelps, Keith A Reimann, David Ayares, Keith A Horvath
Preventing xenograft rejection is one of the greatest challenges of transplantation medicine. Here, we describe a reproducible, long-term survival of cardiac xenografts from alpha 1-3 galactosyltransferase gene knockout pigs, which express human complement regulatory protein CD46 and human thrombomodulin (GTKO.hCD46.hTBM), that were transplanted into baboons. Our immunomodulatory drug regimen includes induction with anti-thymocyte globulin and αCD20 antibody, followed by maintenance with mycophenolate mofetil and an intensively dosed αCD40 (2C10R4) antibody...
2016: Nature Communications
James Russell Butler, Leela L Paris, Ross L Blankenship, Richard A Sidner, Gregory R Martens, Joseph M Ladowski, Ping Li, Jose L Estrada, Matthew Tector, A Joseph Tector
BACKGROUND: A profound thrombocytopenia limits hepatic xenotransplantation in the pig-to-primate model. Porcine livers also have shown the ability to phagocytose human platelets in the absence of immune-mediated injury. Recently, inactivation of the porcine ASGR1 gene has been shown to decrease this phenomenon. Inactivating GGTA1 and CMAH genes has reduced the antibody-mediated barrier to xenotransplantation; herein, we describe the effect that these modifications have on xenogeneic consumption of human platelets in the absence of immune-mediated graft injury...
March 2016: Transplantation
David K C Cooper, Mohamed B Ezzelarab, Hidetaka Hara, Hayato Iwase, Whayoung Lee, Martin Wijkstrom, Rita Bottino
The immunologic barriers to successful xenotransplantation are related to the presence of natural anti-pig antibodies in humans and non-human primates that bind to antigens expressed on the transplanted pig organ (the most important of which is galactose-α1,3-galactose [Gal]), and activate the complement cascade, which results in rapid destruction of the graft, a process known as hyperacute rejection. High levels of elicited anti-pig IgG may develop if the adaptive immune response is not prevented by adequate immunosuppressive therapy, resulting in activation and injury of the vascular endothelium...
March 2016: Xenotransplantation
Shabir Hassan, Anha Bhat, Ramesh R Bhonde, Museer A Lone
Increasing incidence of diabetes and shortage of specific beta cells, hormonal switches like that of delta and PP cells of the islets for transplantation, have forced the scientific community to look for alternative sources through xenotransplantation and nanomedicine. The Edmonton protocol of islet transplantation has shown proof of principle of long term survival of islets in type I diabetic patients, leading to insulin prick free life. Copious volume of literature exists on the use of mammalian islets, especially of porcine origin for diabetes reversal in humans with follow-up studies upto 10 yrs...
2016: Current Pharmaceutical Design
John M Stewart, Alice F Tarantal, Wayne J Hawthorne, Evelyn J Salvaris, Philip J O'Connell, Mark B Nottle, Anthony J F d'Apice, Peter J Cowan, Mary Kearns-Jonker
BACKGROUND: Survival of vascularized xenografts is dependent on pre-emptive inhibition of the xenoantibody response against galactosyltransferase knockout (GTKO) porcine organs. Our analysis in multiple GTKO pig-to-primate models of xenotransplantation has demonstrated that the anti-non-gal-α-1,3-gal (anti-non-Gal) xenoantibody response displays limited structural diversity. This allowed our group to identify an experimental compound which selectively inhibited induced anti-non-Gal IgM xenoantibodies...
November 2015: Xenotransplantation
Marta Vadori, Romina Aron Badin, Philippe Hantraye, Emanuele Cozzi
Neural cell transplantation has long been considered as an option for the treatment of neurodegenerative disorders. To date, several patients with Parkinson's and Huntington's diseases have been treated with human fetal-derived neurons with disparate results. However, the limited efficacy to date combined with the scarce availability of human fetal tissues and ethical concerns render this procedure inapplicable to a wide population scale. With a view to overcoming these shortcomings, transplantation of pig-derived cell precursors has been proposed and applied in preclinical and clinical trials...
November 2015: International Journal of Surgery
Corinne Kostic, Yvan Arsenijevic
Disease-causing variants of a large number of genes trigger inherited retinal degeneration leading to photoreceptor loss. Because cones are essential for daylight and central vision such as reading, mobility, and face recognition, this review focuses on a variety of animal models for cone diseases. The pertinence of using these models to reveal genotype/phenotype correlations and to evaluate new therapeutic strategies is discussed. Interestingly, several large animal models recapitulate human diseases and can serve as a strong base from which to study the biology of disease and to assess the scale-up of new therapies...
January 2016: Journal of Pathology
S Kölle
The integrity of transport, distribution and elimination of sperm in the female genital tract plays a pivotal role for successful reproduction in mammals. At coitus, millions or billions of sperm are deposited either into the anterior vagina (human, primates), the cervix (most mammalian species) or the uterus (pig). In most species, the first anatomical barrier is the cervix, where spermatozoa with poor morphology and motility are filtered out by sticking to the cervical mucus. The second anatomical barrier is the uterotubal junction (UTJ) with its tortuous and narrow lumen...
September 2015: Reproduction in Domestic Animals, Zuchthygiene
Joachim Denner
Porcine microorganisms may be transmitted to the human recipient when xenotransplantation with pig cells, tissues, and organs will be performed. Most of such microorganisms can be eliminated from the donor pig by specified or designated pathogen-free production of the animals. As human cytomegalovirus causes severe transplant rejection in allotransplantation, considerable concern is warranted on the potential pathogenicity of porcine cytomegalovirus (PCMV) in the setting of xenotransplantation. On the other hand, despite having a similar name, PCMV is different from HCMV...
September 2015: Xenotransplantation
Young-Jo Song, Woo-Jung Park, Byung-Joo Park, Sang-Woo Kwak, Yong-Hyeon Kim, Joong-Bok Lee, Seung-Yong Park, Chang-Seon Song, Sang-Won Lee, Kun-Ho Seo, Young-Sun Kang, Choi-Kyu Park, Jae-Young Song, In-Soo Choi
Hepatitis A virus (HAV) is the leading cause of acute viral hepatitis worldwide, with HAV infection being restricted to humans and nonhuman primates. In this study, HAV infection status was serologically determined in domestic pigs and experimental infections of HAV were attempted to verify HAV infectivity in pigs. Antibodies specific to HAV or HAV-like agents were detected in 3.5% of serum samples collected from pigs in swine farms. When the pigs were infected intravenously with 2 × 10(5) 50% tissue culture infectious dose (TCID50 ) of HAV, shedding of the virus in feces, viremia, and seroconversion were detected...
April 2016: Journal of Medical Virology
M Vadori, E Cozzi
The availability of cells, tissues and organs from a non-human species such as the pig could, at least in theory, meet the demand of organs necessary for clinical transplantation. At this stage, the important goal of getting over the first year of survival has been reported for both cellular and solid organ xenotransplantation in relevant preclinical primate models. In addition, xenotransplantation is already in the clinic as shown by the broad use of animal-derived medical devices, such as bioprosthetic heart valves and biological materials used for surgical tissue repair...
October 2015: Tissue Antigens
James R Butler, Gregory R Martens, Ping Li, Zheng-Yu Wang, Jose L Estrada, Joseph M Ladowski, Matt Tector, A Joseph Tector
BACKGROUND: Thrombocytopenia may represent a significant challenge to the clinical application of solid-organ xenotransplantation. When studied in a pig-to-primate model, consumptive coagulopathy has challenged renal xenografts. New strategies of genetic manipulation have altered porcine carbohydrate profiles to significantly reduce human antibody binding to pig cells. As this process continues to eliminate immunologic barriers to clinical xenotransplantation, the relationship between human platelets and pig organs must be considered...
February 2016: Journal of Surgical Research
Mohamed B F Hawash, Lee O Andersen, Robin B Gasser, Christen Rune Stensvold, Peter Nejsum
BACKGROUND: The whipworms Trichuris trichiura and Trichuris suis are two parasitic nematodes of humans and pigs, respectively. Although whipworms in human and non-human primates historically have been referred to as T. trichiura, recent reports suggest that several Trichuris spp. are found in primates. METHODS AND FINDINGS: We sequenced and annotated complete mitochondrial genomes of Trichuris recovered from a human in Uganda, an olive baboon in the US, a hamadryas baboon in Denmark, and two pigs from Denmark and Uganda...
2015: PLoS Neglected Tropical Diseases
David K C Cooper, Burcin Ekser, Jagdeece Ramsoondar, Carol Phelps, David Ayares
There is a critical shortage in the number of deceased human organs that become available for the purposes of clinical transplantation. This problem might be resolved by the transplantation of organs from pigs genetically engineered to protect them from the human immune response. The pathobiological barriers to successful pig organ transplantation in primates include activation of the innate and adaptive immune systems, coagulation dysregulation and inflammation. Genetic engineering of the pig as an organ source has increased the survival of the transplanted pig heart, kidney, islet and corneal graft in non-human primates (NHPs) from minutes to months or occasionally years...
January 2016: Journal of Pathology
Sebastian D McBride, Nicholas Perentos, A Jennifer Morton
BACKGROUND: For reasons of cost and ethical concerns, models of neurodegenerative disorders such as Huntington disease (HD) are currently being developed in farm animals, as an alternative to non-human primates. Developing reliable methods of testing cognitive function is essential to determining the usefulness of such models. Nevertheless, cognitive testing of farm animal species presents a unique set of challenges. The primary aims of this study were to develop and validate a mobile operant system suitable for high throughput cognitive testing of sheep...
May 30, 2016: Journal of Neuroscience Methods
Guerard W Byrne, Christopher G A McGregor, Michael E Breimer
Genetic engineering of donor pigs to eliminate expression of the dominant xenogeneic antigen galactose α1,3 galactose (Gal) has created a sea change in the immunobiology of xenograft rejection. Antibody mediated xenograft rejection of GGTA-1 α-galactosyltransferase (GTKO) deficient organs is now directed to a combination of non-Gal pig protein and carbohydrate antigens. Glycan analysis of GTKO tissues identified no new neo-antigens but detected high levels of N-acetylneuraminic acid (Neu5Gc) modified glycoproteins and glycolipids...
November 2015: International Journal of Surgery
Pierre Gianello
A bioartificial pancreas, in which islets of Langerhans are encapsulated within a semipermeable membrane, may be an alternative therapeutic device for diabetic patients. It may constitute another safe and simple method of transplanting islets without the need for immunosuppressive therapy. Since the semipermeable membrane protects the islets from the host immune system, the islets are likely to survive and release insulin for a long period of time, thereby controlling glucose metabolism in the absence of immunosuppressive medication...
2015: Advances in Experimental Medicine and Biology
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