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Hayato Iwase, Hong Liu, Tao Li, Zhongquiang Zhang, Bingsi Gao, Hidetaka Hara, Martin Wijkstrom, Cassandra Long, Ryan Saari, David Ayares, David K C Cooper, Mohamed B Ezzelarab
Inflammation is known to preclude tolerance after transplantation. We have previously shown that systemic inflammation in xenograft recipients (SIXR) precedes activation of coagulation in the absence of T cell responses. Accordingly, SIXR may amplify innate and adaptive immune responses against xenografts after pig-to-primate xenotransplantation, even with efficient immunosuppressive therapy. We evaluated the impact of anti-inflammatory agents on pro-inflammatory cytokines and chemokines in pig artery patch and heart xenograft recipients...
March 2017: Xenotransplantation
Norihide Fukushima
Prior to starting clinical cardiac allotransplantation, cardiac xenotransplantation was performed in human in 1960s. In 1964, Hardy performed cardiac transplantation using a chimpanzee heart and Bailey performed cardiac transplantation using a baboon heart to an infant with hypoplastic left heart. The use of cyclosporine has greatly improved the outcome of clinical cardiac transplantation and cardiac allotransplantation became an established treatment strategy for the patients with end-stage heart failure. Although concordant cardiac xenotransplantation from a primate to a human may be successfully performed using current immunosuppressive regimen, a primate heart is not a good candidate for cardiac xenograft due to animal light issues and its size...
January 2017: Kyobu Geka. the Japanese Journal of Thoracic Surgery
Zhengzhao Liu, Wenbao Hu, Tian He, Yifan Dai, Hidetaka Hara, Rita Bottino, David K C Cooper, Zhiming Cai, Lisha Mou
Islet allotransplantation results in increasing success in treating type 1 diabetes, but the shortage of deceased humandonor pancreata limits progress. Islet xenotransplantation, using pigs as sources of islet is a promising approach to overcome this limitation. The greatest obstacle is the primate immune/ inflammatory response to the pig islets, which may take the form of rapid early graft destruction (the instant blood-mediated inflammatory reaction) or T cell-mediated rejection. These problems are being resolved by the genetic engineering of the source pigs combined with improved immunosuppressive therapy...
February 3, 2017: Cell Transplantation
Lu Liu, Hanchao Gao, Chungu Hong, Chen He, Dengke Pan, Yifan Dai, Hidetaka Hara, David K C Cooper, Zesong Li, Zhiming Cai, Lisha Mou
Long-term success in pig-to-primate xenotransplantation is currently hampered by acute vascular rejection (AVR), characterized by endothelial cell (EC) activation and injury. Klotho has anti-apoptotic, anti-inflammatory effects on EC and protects EC against reactive oxygen species, rendering klotho a promising molecule to control AVR. In this study, porcine ECs were pre-incubated with klotho and then exposed to xenoreactive antibodies and complement. Real-time PCR revealed that klotho suppressed antibody-induced pro-inflammatory gene expression of VCAM-1 and IL-1α...
January 28, 2017: Xenotransplantation
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...
February 2017: 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...
April 5, 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
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