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swine models of kidney transplant

Prashanth Vallabhajosyula, Atsushi Hirakata, Matthew Weiss, Adam Griesemer, Akira Shimizu, Hanzhou Hong, Andreas Habertheuer, Vaja Tchipashvili, Kazuhiko Yamada, David H Sachs
In islet transplantation, in addition to immunologic and ischemic factors, the diabetic/hyperglycemic state of the recipient has been proposed, although not yet validated, as a possible cause of islet toxicity, contributing to islet loss during the engraftment period. Using a miniature swine model of islet transplantation, we have now assessed the effect of a persistent state of hyperglycemia on islet engraftment and subsequent function. An islet-kidney (IK) model previously described by our laboratory was utilized...
November 2017: Cell Transplantation
Anita Y Chhabra, Joseph Leventhal, Andrea R Merchak, Suzanne Ildstad
Renal transplantation has become the preferred treatment for end stage kidney failure. Although short-term graft survival has significantly improved as advances in immunosuppression have occurred, long-term patient and graft survival have not. Approximately only 50% of renal transplant recipients are alive at 10 years due to the toxicities of immunosuppression and alloimmunity. Emerging research on cell-based therapies is opening a new door for patients to receive the organs they need without sacrificing quality of life and longevity because of drug-based immunosuppression...
November 2017: Transplantation
Randi Lassiter, Youli Wang, Xuexiu Fang, Matt Winn, Arina Ghaffari, Chak-Sum Ho, Sandra Helman, Ryan Jajosky, Daniel Kleven, N Stanley Nahman, Todd D Merchen
Pigs represent a desirable animal model for the study of rejection in kidney transplantation with inbred Yucatan miniature swine (YMS) the most commonly studied strain due to well defined swine leukocyte antigen (SLA) genotypes. However, limitations to YMS may include cost and availability. Outbred Yorkshire pigs are widely available and significantly cheaper than YMS. Recent advances in SLA genotyping have allowed its application to outbred strains. On this basis, we theorized that Yorkshire pigs would be a viable alternative to YMS for the study of rejection in kidney transplantation...
June 2017: Transplant Immunology
M Avsar, K Jansson, W Sommer, B Kruse, S Thissen, K Dreckmann, A-K Knoefel, J Salman, C Hafer, J Hecker, G Buechler, J H Karstens, D Jonigk, F Länger, V Kaever, C S Falk, M Hewicker-Trautwein, H Ungefroren, A Haverich, M Strüber, G Warnecke
Donor alloantigen infusion induces T cell regulation and transplant tolerance in small animals. Here, we study donor splenocyte infusion in a large animal model of pulmonary transplantation. Major histocompatibility complex-mismatched single lung transplantation was performed in 28 minipigs followed by a 28-day course of methylprednisolone and tacrolimus. Some animals received a perioperative donor or third party splenocyte infusion, with or without low-dose irradiation (IRR) before surgery. Graft survival was significantly prolonged in animals receiving both donor splenocytes and IRR compared with controls with either donor splenocytes or IRR only...
May 2016: American Journal of Transplantation
G Castellano, A Intini, A Stasi, C Divella, M Gigante, P Pontrelli, R Franzin, M Accetturo, A Zito, M Fiorentino, V Montinaro, G Lucarelli, P Ditonno, M Battaglia, A Crovace, F Staffieri, B Oortwijn, E van Amersfoort, G Pertosa, G Grandaliano, L Gesualdo
Klotho is an anti-aging factor mainly produced by renal tubular epithelial cells (TEC) with pleiotropic functions. Klotho is down-regulated in acute kidney injury in native kidney; however, the modulation of Klotho in kidney transplantation has not been investigated. In a swine model of ischemia/reperfusion injury (IRI), we observed a remarkable reduction of renal Klotho by 24 h from IRI. Complement inhibition by C1-inhibitor preserved Klotho expression in vivo by abrogating nuclear factor kappa B (NF-kB) signaling...
January 2016: American Journal of Transplantation
V Villani, K Yamada, J R Scalea, B C Gillon, J S Arn, M Sekijima, M Tasaki, T A Cormack, S G Moran, R Torabi, A Shimizu, D H Sachs
Our recent studies in an inbred swine model demonstrated that both peripheral and intra-graft regulatory cells were required for the adoptive transfer of tolerance to a second, naïve donor-matched kidney. Here, we have asked whether both peripheral and intra-graft regulatory elements are required for adoptive transfer of tolerance when only a long-term tolerant (LTT) kidney is transplanted. Nine highly-inbred swine underwent a tolerance-inducing regimen to prepare LTT kidney grafts which were then transplanted to histocompatible recipients, with or without the peripheral cell populations required for adoptive transfer of tolerance to a naïve kidney...
January 2016: American Journal of Transplantation
Rahul Krishnan, Brian Buder, Michael Alexander, Clarence E Foster, Jonathan Rt Lakey
BACKGROUND: Porcine islet xenotransplantation has been demonstrated in many animal studies to cure experimentally induced diabetes. However, several issues currently impede the translation of porcine islet xenotransplantation to sustained insulin independence clinically. Although adult pigs have mature islets that secrete insulin in response to a glucose challenge, and are physiologically similar to humans, there are logistical considerations with adult porcine tissue that are not present with juvenile porcine tissue...
April 2015: Transplantation
S Tillet, S Giraud, P O Delpech, R Thuillier, V Ameteau, J M Goujon, B Renelier, L Macchi, T Hauet, G Mauco
BACKGROUND: Deceased after cardiac death donors represent an important source of organs to reduce organ shortage in transplantation. However, these organs are subjected to more ischaemia-reperfusion injury (IRI). Reducing IRI by targeting coagulation is studied here in an experimental model. METHODS: The effect of an anti-Xa compound (fondaparinux) was evaluated using an autotransplanted kidney model in pigs. Kidneys were clamped for 60 min (warm ischaemia) and then preserved for 24 h at 4 °C in University of Wisconsin solution (UW)...
January 2015: British Journal of Surgery
Dieter P Hoyer, Anja Gallinat, Sandra Swoboda, Jeremias Wohlschlaeger, Ursula Rauen, Andreas Paul, Thomas Minor
BACKGROUND: Hypothermic machine perfusion (HMP) for preservation led to compelling success for outcomes of renal transplantation. Application of different concentrations of oxygen during renal HMP has not been systematically analyzed. This study investigates the aspects of renal function and morphology in dependence of oxygen concentrations during HMP in a porcine donation after circulatory death model. METHODS: After 30 min of warm ischemia, porcine kidneys were randomly assigned to preservation for 21 hr by HMP without oxygenation (HMPnoox), oxygenated HMP with air (HMPair), or 100% oxygen (HMPox100%)...
November 15, 2014: Transplantation
P O Delpech, R Thuillier, S Le Pape, L Rossard, C Jayle, C Billault, J M Goujon, T Hauet
BACKGROUND: The increased use of marginal donors highlights the importance of organ quality in transplantation and the identification of prognostic biomarkers. This experimental study investigated modulation of the hypoxia-inducible factor (HIF) 1α pathway in kidney grafts in relation to different degrees of ischaemia. METHODS: In a porcine autotransplantation model, two different kidney graft protocols were compared: standard 24-h cold storage (CS) and 24-h CS preceded by 1 h warm ischaemia (WI + CS)...
December 2014: British Journal of Surgery
Kazuhiko Yamada, Masayuki Tasaki, Mitsuhiro Sekijima, Robert A Wilkinson, Vincenzo Villani, Shannon G Moran, Taylor A Cormack, Isabel M Hanekamp, Robert J Hawley, J Scott Arn, Jay A Fishman, Akira Shimizu, David H Sachs
BACKGROUND: Recent survivals of our pig-to-baboon kidney xenotransplants have been markedly shorter than the graft survivals we previously reported. The discovery of high levels of porcine cytomegalovirus (pCMV) in one of the rejected xenografts led us to evaluate whether this reduction in graft survival might be because of the inadvertent introduction of pCMV into our α1,3-galactosyltransferase gene knockout swine herd. METHODS: Archived frozen sections of xeno-kidney grafts over the past 10 years were analyzed for the presence of pCMV, using real-time polymerase chain reaction...
August 27, 2014: Transplantation
Kohei Miura, Hisashi Sahara, Mitsuhiro Sekijima, Akihiro Kawai, Shiori Waki, Hiroaki Nishimura, Kentaro Setoyama, Eric S Clayman, Akira Shimizu, Kazuhiko Yamada
BACKGROUND: Strategies that reduce ischemia-reperfusion injury (IRI) have the potential to expand the numbers of available organs for transplantation. Recent reports in rodent models have demonstrated that high-mobility group box 1 (HMGB1) acts as an alarm in initiating the inflammatory response resulting from ischemic injury. The aim of this study was to evaluate the cytoprotective effects of anti-HMGB1 antibodies on renal IRI in preclinical large animals. METHODS: One hundred twenty minutes of warm and 60 min of cold renal ischemia were induced in 8 CLAWN miniature swine...
November 15, 2014: Transplantation
J R Scalea, M Okumi, V Villani, A Shimizu, H Nishimura, B C Gillon, R Torabi, T Cormack, S Moran, C LeGuern, D H Sachs, K Yamada
We have previously demonstrated that long-term tolerance (LTT) of an MHC class-I mismatched renal allograft can be achieved with a short course of cyclosporine. In order to examine regulatory mechanisms underlying tolerance in this model, we assessed the contributions of factors within the graft and in the peripheral blood for their relative roles in the maintenance of stable tolerance. Twelve LTT recipients of MHC class-I mismatched primary kidneys were subjected to a treatment consisting of donor-specific transfusion followed by leukapheresis, in order to remove peripheral leukocytes, including putative regulatory T cells (Tregs)...
September 2014: American Journal of Transplantation
Sarah A Hosgood, Lucy V Randle, Meeta Patel, Christopher J Watson, John A Bradley, Michael L Nicholson
INTRODUCTION: Phosphodiesterase-5 inhibitors prevent the breakdown of cyclic guanosine 3',5'-monophosphate (cGMP) and therefore may be useful in reducing the detrimental effects of ischemia-reperfusion (I/R) injury. The aim of this study was to assess the effects of the phosphodiesterase-5 inhibitor sildenafil, on I/R injury in a porcine model of donation after circulatory death kidney transplantation. METHODS: Kidneys were subjected to 20 min warm ischemia followed by 2 or 18 hr of cold storage (n=6 kidneys per group)...
September 27, 2014: Transplantation
Joseph R Scalea, Vincenzo Villani, Bradford C Gillon, Joshua Weiner, Pierre Gianello, Nicole Turcotte, John Scott Arn, Kazuhiko Yamada, David H Sachs
BACKGROUND: The clinical significance of antibodies directed against antigens other than major histocompatibility complex (MHC) antigens is poorly understood, and there are few large animal models in which such antibodies can be examined. We studied, both retrospectively and prospectively, the development of antibodies to non-MHC antigens in tolerant miniature swine. METHODS: Our database was assessed for cases of antidonor antibody formation in tolerant animals over the last 20 years...
September 15, 2014: Transplantation
Niels Secher, Peter Soendergaard, Kristian Ravlo, Christoffer Soelling, Asger Granfeldt, Lise Wogensen, Anna K Keller, Ulla Moeldrup, Ernst O Ostraat, Troels M Joergensen, Bente Jespersen, Else Toennesen
MAIN PROBLEM: Delayed graft function after kidney transplantation is associated with decreased graft survival and increased patient mortality but the pathogenesis is poorly understood. Remote ischaemic conditioning (rIC) may prevent delayed graft function by an anti-inflammatory effect. In a porcine model of transplantation from adults to children, we investigated the inflammatory response in the transplanted kidney and the effect of rIC. METHODS: Kidneys were recovered from brain dead donor pigs(63kg) and transplanted into two groups of recipient pigs(15kg) after 22h of cold ischaemia...
August 2014: Transplant Immunology
Mohammad A Hossain, Ayesha I De Souza, Atul Bagul, Iain A M MacPhee, Nicos Kessaris, Mohamed A Morsy
BACKGROUND: The use of donation after circulatory death (DCD) kidneys for transplantation is increasing. Subsequent delayed graft function is related to ischaemia/reperfusion injury (I/R), warm ischaemia (WI) being one of the main contributing factors. This proteomics study aimed to identify candidate biomarkers of WI. METHODS: Termination biopsies were obtained over 180min in 6 pigs. Proteins were subjected to differential in-gel electrophoresis (DIGE) and identified using LC MS/MS...
August 28, 2014: Journal of Proteomics
Marina Figliuzzi, Giuseppe Remuzzi, Andrea Remuzzi
BACKGROUND: Chronic kidney disease (CKD) is a global public health issue with an estimated prevalence of 8-16% worldwide. End-stage renal disease eventually develops every year in 0.15-0.2% of patients with overt CKD, and renal replacement therapy (RRT) with dialysis or transplantation is required. Although approximately 2 million people worldwide are currently on RRT to sustain life, this likely represents less than 10% of those who need it. The kidney transplant approach is also seriously impaired by limited graft survival and by the scarce availability of donors...
2014: Nephron. Experimental Nephrology
Edouard Baulier, Frederic Favreau, Amélie Le Corf, Christophe Jayle, Fabrice Schneider, Jean-Michel Goujon, Olivier Feraud, Annelise Bennaceur-Griscelli, Thierry Hauet, Ali G Turhan
It is well known that ischemia/reperfusion injuries strongly affect the success of human organ transplantation. Development of interstitial fibrosis and tubular atrophy is the main deleterious phenomenon involved. Stem cells are a promising therapeutic tool already validated in various ischemic diseases. Amniotic fluid-derived mesenchymal stem cells (af-MSCs), a subpopulation of multipotent cells identified in amniotic fluid, are known to secrete growth factors and anti-inflammatory cytokines. In addition, these cells are easy to collect, present higher proliferation and self-renewal rates compared with other adult stem cells (ASCs), and are suitable for banking...
July 2014: Stem Cells Translational Medicine
Makoto Tonsho, Sebastian Michel, Zain Ahmed, Alessandro Alessandrini, Joren C Madsen
There has been significant progress in the field of heart transplantation over the last 45 years. The 1-yr survival rates following heart transplantation have improved from 30% in the 1970s to almost 90% in the 2000s. However, there has been little change in long-term outcomes. This is mainly due to chronic rejection, malignancy, and the detrimental side effects of chronic immunosuppression. In addition, over the last decade, new challenges have arisen such as increasingly complicated recipients and antibody-mediated rejection...
May 2014: Cold Spring Harbor Perspectives in Medicine
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