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Jan-Michael Abicht, Riccardo Sfriso, Bruno Reichart, Matthias Längin, Katja Gahle, Gisella L Puga Yung, Jörg D Seebach, Robert Rieben, David Ayares, Eckhard Wolf, Nikolai Klymiuk, Andrea Baehr, Alexander Kind, Tanja Mayr, Andreas Bauer
BACKGROUND: In pig-to-human xenotransplantation, early cellular rejection reactions are mediated by natural killer cells (NK cells). Human NK cells are inhibited by HLA-E via CD94/NKG2A receptors. To protect porcine grafts against human NK cell responses, transgenic GTKO pigs expressing hCD46 and HLA-E have been generated. The aim of this study was to test the effect of this genetic modification on xenogeneic, and in particular human NK cell response, using an ex vivo perfusion model of pig hearts with human blood...
March 14, 2018: Xenotransplantation
Hironosuke Watanabe, Hisashi Sahara, Shunichiro Nomura, Tatsu Tanabe, Dilrukshi K Ekanayake-Alper, Lennan K Boyd, Nathan J Louras, Arsenoi Asfour, Makenzie A Danton, Siu-Hong Ho, Scott J Arn, Robert J Hawley, Akira Shimizu, Takeshi Nagayasu, David Ayares, Marc I Lorber, Megan Sykes, David H Sachs, Kazuhiko Yamada
BACKGROUND: Despite recent progress in survival times of xenografts in non-human primates, there are no reports of survival beyond 5 days of histologically well-aerated porcine lung grafts in baboons. Here, we report our initial results of pig-to-baboon xeno-lung transplantation (XLTx). METHODS: Eleven baboons received genetically modified porcine left lungs from either GalT-KO alone (n = 3), GalT-KO/humanCD47(hCD47)/hCD55 (n = 3), GalT-KO/hD47/hCD46 (n = 4), or GalT-KO/hCD39/hCD46/hCD55/TBM/EPCR (n = 1) swine...
March 12, 2018: Xenotransplantation
Xiaohong Liu, Ning Li, Dejun Gong, Cuiping Xia, Zhiyun Xu
BACKGROUND: Various detergent-based protocols are used to remove cells and cellular debris in porcine aortic valve (PAV). However, the removal of antigenic cellular components has not been thoroughly elucidated to date. In this study, we used 4 detergent-based protocols to decellularize PAVs and aimed to evaluate their effects on removing antigenic cellular components. METHODS: Porcine aortic valves were decellularized using sodium dodecyl sulfate (SDS), SDS in combination with sodium deoxycholate (SDS/SD), Triton X-100, and Triton X-100 in combination with SD (Triton X-100/SD), respectively...
February 15, 2018: Xenotransplantation
Anna Buermann, Stoyan Petkov, Björn Petersen, Rabea Hein, Andrea Lucas-Hahn, Wiebke Baars, Antje Brinkmann, Heiner Niemann, Reinhard Schwinzer
BACKGROUND: The programmed cell death-1 (PD-1, CD279)/PD-Ligand1 (PD-L1, CD274) receptor system is crucial for controlling the balance between immune activation and induction of tolerance via generation of inhibitory signals. Expression of PD-L1 is associated with reduced immunogenicity and renders cells and tissues to an immune-privileged/tolerogenic state. METHODS: To apply this concept for clinical xenotransplantation, we generated human (h)PD-L1 transgenic pigs and characterized expression and biological function of the transgene at the cellular level...
February 15, 2018: Xenotransplantation
Chengjiang Zhao, David K C Cooper, Yifan Dai, Hidetaka Hara, Zhiming Cai, Lisha Mou
Antibody-mediated rejection is a barrier to the clinical application of xenotransplantation, and xenoantigens play an important role in this process. Early research suggested that N-acetyl-D-galactosamine (GalNAc) could serve as a potential xenoantigen. GalNAc is the immunodominant glycan of the Sda antigen. Recently, knockout of β1,4-N-acetylgalactosaminyltransferase 2 (β1,4GalNAcT-II) from the pig results in a decrease in binding of human serum antibodies to pig cells. It is believed that this is the result of the elimination of the GalNAc on the Sda antigen, which is catalyzed by the enzyme, β1,4GalNAcT-II...
February 11, 2018: Xenotransplantation
Beth M French, Selin Sendil, Krishna Mohan Sepuru, Jolene Ranek, Lars Burdorf, Donald Harris, Emily Redding, Xiangfei Cheng, Christopher T Laird, Yuming Zhao, Benjamin Cerel, Krishna Rajarathnam, Richard N Pierson, Agnes M Azimzadeh
BACKGROUND: Human neutrophils are sequestered by pig lung xenografts within minutes during ex vivo perfusion. This phenomenon is not prevented by pig genetic modifications that remove xeno-antigens or added human regulatory molecules intended to down-regulate activation of complement and coagulation pathways. This study investigated whether recipient and donor interleukin-8 (IL-8), a chemokine known to attract and activate neutrophils during inflammation, is elaborated in the context of xenogeneic injury, and whether human or pig IL-8 promote the adhesion of human neutrophils in in vitro xenograft models...
February 9, 2018: Xenotransplantation
Christopher T Laird, Wessam Hassanein, Natalie A O'Neill, Beth M French, Xiangfei Cheng, William E Fogler, John L Magnani, Dawn Parsell, Arielle Cimeno, Carol J Phelps, David Ayares, Lars Burdorf, Agnes M Azimzadeh, Richard N Pierson
BACKGROUND: Alongside the need to develop more effective and less toxic immunosuppression, the shortage of human organs available for organ transplantation is one of the major hurdles facing the field. Research into xenotransplantation, as an alternative source of organs, has unveiled formidable challenges. Porcine lungs perfused with human blood rapidly sequester the majority of circulating neutrophils and platelets, which leads to inflammation and organ failure within hours, and is not significantly attenuated by genetic modifications to the pig targeted to diminish antibody binding and complement and coagulation cascade activation...
January 23, 2018: Xenotransplantation
Beate Rieblinger, Konrad Fischer, Alexander Kind, Benedikt S Saller, Wiebke Baars, Marion Schuster, Lelia Wolf-van Buerck, Andrea Schäffler, Tatiana Flisikowska, Mayuko Kurome, Valeri Zakhartchenko, Barbara Kessler, Krzysztof Flisikowski, Eckhard Wolf, Jochen Seissler, Reinhard Schwinzer, Angelika Schnieke
BACKGROUND: Multiple xenoprotective transgenes are best grouped at a single locus to avoid segregation during breeding and simplify production of donor animals. METHODS: We used transgene stacking to place a human CD55 transgene adjacent to a human heme oxygenase 1 construct at the porcine ROSA26 locus. A transgenic pig was analyzed by PCR, RT-PCR, droplet digital PCR, immunohistochemistry, immunofluorescence, and flow cytometry. Resistance to complement-mediated cell lysis and caspase 3/7 activation were determined in vitro...
January 23, 2018: Xenotransplantation
Joachim Denner, Bruno Reichart, Matthias Längin
No abstract text is available yet for this article.
January 23, 2018: Xenotransplantation
Hee Jung Kang, Haneulnari Lee, Eun Mi Park, Jong-Min Kim, Jun-Seop Shin, Chung-Gyu Park
BACKGROUND: The development of a precise and easy-to-use tool for monitoring islet graft function is important in clarifying the causes of graft loss, identifying appropriate therapy, and ensuring graft survival in the nonhuman primate (NHP) model of porcine islet transplantation (PITx). Glycated albumin (GA) is an indicator of intermediate-term changes in blood glucose control and is useful in clinical diabetes management. The validity of GA for monitoring graft function in NHP recipients of PITx was evaluated using a retrospective analysis of cohort samples...
January 23, 2018: Xenotransplantation
Eun Mi Lee, Ji-In Jung, Zahid Alam, Hee-Gyeong Yi, Heejin Kim, Jin Woo Choi, Sunghoon Hurh, Young June Kim, Jong Cheol Jeong, Jaeseok Yang, Kook-Hwan Oh, Hee Chan Kim, Byeong Chun Lee, Inho Choi, Dong-Woo Cho, Curie Ahn
BACKGROUND: Islet encapsulation techniques have shown limited success in maintaining islet survival and function because encapsulation decreases oxygen supply. In this study, an oxygen-generating scaffold was fabricated to prevent hypoxic cell damage and improve the viability and insulin secretion of islets. METHODS: We fabricated an oxygen-generating scaffold by mixing calcium peroxide (CaO2 ) with polydimethylsiloxane (PDMS). We evaluated the effects of the oxygen-generating PDMS + CaO2 scaffold on viability, caspase-3 and caspase-7 activity, oxygen consumption rate (OCR), glucose-stimulated insulin secretion (GSIS), hypoxic cell marker expression, and reactive oxygen species (ROS) levels in porcine neonatal pancreatic cell clusters (NPCCs)...
January 10, 2018: Xenotransplantation
Travis R Taylor, Christopher Burlak
No abstract text is available yet for this article.
January 2018: Xenotransplantation
Byoung-Hoon Min, Jun-Seop Shin, Jong-Min Kim, Seong-Jun Kang, Hyun-Je Kim, Il-Hee Yoon, Su-Kyoung Park, Ji-Won Choi, Min-Suk Lee, Chung-Gyu Park
BACKGROUND: Pancreatic islet transplantation is currently proven as a promising treatment for type 1 diabetes patients with labile glycemic control and severe hypoglycemia unawareness. Upon islet transplantation, revascularization is essential for proper functioning of the transplanted islets. As IL-6 is important for endothelial cell survival and systemic inflammation related to xenograft, the effect of IL-6 receptor antagonist, tocilizumab, on revascularization of the transplanted islets was examined in pig to non-human primate islet xenotransplantation model...
January 2018: Xenotransplantation
Avneesh K Singh, Joshua L Chan, Caleb N Seavey, Philip C Corcoran, Robert F Hoyt, Billeta G T Lewis, Marvin L Thomas, David L Ayares, Keith A Horvath, Muhammad M Mohiuddin
BACKGROUND: CD4+CD25Hi FoxP3+ T (Treg) cells are a small subset of CD4+ T cells that have been shown to exhibit immunoregulatory function. Although the absolute number of Treg cells in peripheral blood lymphocytes (PBL) is very small, they play an important role in suppressing immune reactivity. Several studies have demonstrated that the number of Treg cells, rather than their intrinsic suppressive capacity, may contribute to determining the long-term fate of transplanted grafts. In this study, we analyzed Treg cells in PBL of long-term baboon recipients who have received genetically modified cardiac xenografts from pig donors...
December 17, 2017: Xenotransplantation
Claire Crossan, Zoe O'Hara, Nizar Mourad, Pierre Gianello, Linda Scobie
With an onus on safety in the potential use of porcine islet cells as a treatment for diabetes, the use of animals lacking exogenous pathogens is clearly important and multilevel screening strategies have been presented on testing animals and the product. In this study, we wished to investigate whether islet cells indeed harboured the same viral pathogens of concern in the source animal. PMBC and islet cells from both adult and neonatal source animals were directly compared and tested for PCMV, PLHV, PCV2, PPV and HEV using both molecular and serological assays...
December 7, 2017: Xenotransplantation
Han-Sin Lee, Sanghyun Song, Du Yeon Shin, Geun-Soo Kim, Jong-Hyun Lee, Chan Woo Cho, Kyo Won Lee, Hyojun Park, Curie Ahn, Jaeseok Yang, Heung-Mo Yang, Jae Berm Park, Sung-Joo Kim
BACKGROUND: Porcine islet xenotransplantation is considered an attractive alternative treatment for type 1 diabetes mellitus. However, it is largely limited because of initial rejection due to Instant Blood-Mediated Inflammatory Reaction (IBMIR), oxidative stress, and inflammatory responses. Recently, soluble tumor necrosis factor-ɑ receptor type I (sTNF-αR) and heme oxygenase (HO)-1 genes (HO-1/sTNF-αR) have been shown to improve the viability and functionality of porcine islets after transplantation...
November 14, 2017: Xenotransplantation
Xiaoqian Ma, Cejun Yang, Juan Zhang, Jia Wang, Wei Li, Chang Xu, Pengfei Rong, Bin Ye, Minghua Wu, Jianhui Jiang, Shounan Yi, Wei Wang
BACKGROUND: Neonatal pig islet-like cell clusters (NICC) are an attractive source of insulin-producing tissue for potential transplantation treatment of type 1 diabetic patients. However, a considerable loss of NICC after their transplantation due to apoptosis resulted from islet isolation and instant blood-mediated inflammatory reaction remains to be overcome. METHODS: EGM2 medium depleted with hydrocortisone and supplemented with 50 mmol/L isobutylmethylxanthine, 10 mmol/L nicotinamide, and 10 mmol/L glucose was used to culture NICC at day 1, the day after isolation and changed every other day...
November 12, 2017: Xenotransplantation
Jae-Il Lee, Jiyeon Kim, Yun-Jung Choi, Hi-Jung Park, Hye-Jin Park, Hae Joo Wi, Sunok Yoon, Jun-Seop Shin, Jin Kyun Park, Kyeong Cheon Jung, Eun Bong Lee, Hee Jung Kang, Eung Soo Hwang, Sang-Joon Kim, Chung-Gyu Park, Seong Hoe Park
BACKGROUND: Pig islet xenotransplantation is a promising alternative to allogeneic transplantation. However, the wide immunologic barrier between pigs and primates limits the long-term survival of the graft. MD-3, a novel monoclonal antibody (mAb) that recognizes a particular epitope of human ICAM-1, can render T cells tolerant to a xenograft by arresting dendritic cell maturation. We report the long-term survival of adult wild-type pig islets and successful retransplantation in nonhuman primates using a protocol comprising induction with MD-3 mAb and maintenance with anti-CD154 mAb and sirolimus...
November 12, 2017: Xenotransplantation
David K C Cooper, Peter Cowan, Jay A Fishman, Bernhard J Hering, Muhammad M Mohiuddin, Richard N Pierson, David H Sachs, Henk-Jan Schuurman, John U Dennis, Ralf R Tönjes
No abstract text is available yet for this article.
November 2017: Xenotransplantation
Xiang Li, Yi Wang, Shaoping Deng
No abstract text is available yet for this article.
November 2017: Xenotransplantation
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