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BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP‐12
BK polyomavirus (BKPyV) replication causes nephropathy and premature kidney transplant failure. Insufficient BKPyV‐specific T cell control is regarded as a key mechanism, but direct effects of immunosuppressive drugs on BKPyV replication might play an additional role. We compared the effects of mammalian target of rapamycin (mTOR)‐ and calcineurin‐inhibitors on BKPyV replication in primary human renal tubular epithelial cells. Sirolimus impaired BKPyV replication with a 90% inhibitory concentration of 4 ng/mL by interfering with mTOR–SP6‐kinase activation. Sirolimus inhibition was rapid and effective up to 24�...
Source: American Journal of Transplantation - December 7, 2015 Category: Transplant Surgery Authors: H. H. Hirsch, K. Yakhontova, M. Lu, J. Manzetti Tags: Original Article Source Type: research

δV1‐1 Reduces Pulmonary Ischemia Reperfusion‐Induced Lung Injury by Inhibiting Necrosis and Mitochondrial Localization of PKCδ and p53
Ischemia–reperfusion (IR)‐induced lung injury is one of the major contributing factors of morbidity and mortality after lung transplantation. To determine the IR‐induced molecular changes in lung epithelial cells, we developed a cell‐culture model that simulates lung preservation and transplantation. Six hours of cold ischemic time (CIT) and reperfusion elicited production of multiple inflammatory cytokines and chemokines and increased expression of endoplasmic reticulum (ER) proteins. Prolonged hypothermic condition (18 h CIT) reduced ER stress protein levels, and induced apoptosis and necrosis (via mechanisms rel...
Source: American Journal of Transplantation - September 14, 2015 Category: Transplant Surgery Authors: H. Kim, J. Zhao, Q. Zhang, Y. Wang, D. Lee, X. Bai, L. Turrell, M. Chen, W. Gao, S. Keshavjee, M. Liu Tags: Original Article Source Type: research

Role of Sphingosine‐1‐Phosphate in Transplant Vasculopathy Evoked by Anti‐HLA Antibody
Transplant vasculopathy (TV) represents the main cause of late graft failure and limits the long‐term success of organ transplantation. Cellular and humoral immune responses contribute to the pathogenesis of the concentric and diffuse intimal hyperplasia of arteries of the grafted organ. We recently reported that the mitogenic signaling, evoked in human vascular smooth muscle cells (hmSMC) by the anti‐HLA class I monoclonal antibody W6/32, implicates neutral sphingomyelinase‐2, suggesting a role for sphingolipids in intimal hyperplasia of TV. Here, we investigated whether the mitogenic sphingolipid, sphingosine‐1�...
Source: American Journal of Transplantation - May 1, 2015 Category: Transplant Surgery Authors: M. Trayssac, S. Galvani, N. Augé, R. Sabbadini, D. Calise, E. Mucher, F. Sallusto, M. Thomsen, R. Salvayre, A. Nègre‐Salvayre Tags: Original Article Source Type: research

siRNA Mediated Knockdown of Tissue Factor Expression in Pigs for Xenotransplantation
Abstract Acute vascular rejection (AVR), in particular microvascular thrombosis, is an important barrier to successful pig‐to‐primate xenotransplantation. Here, we report the generation of pigs with decreased tissue factor (TF) levels induced by small interfering (si)RNA‐mediated gene silencing. Porcine fibroblasts were transfected with TF‐targeting small hairpin (sh)RNA and used for somatic cell nuclear transfer. Offspring were analyzed for siRNA, TF mRNA and TF protein level. Functionality of TF downregulation was investigated by a whole blood clotting test and a flow chamber assay. TF siRNA was expressed in all ...
Source: American Journal of Transplantation - March 23, 2015 Category: Transplant Surgery Authors: H. E. Ahrens, B. Petersen, D. Herrmann, A. Lucas‐Hahn, P. Hassel, M. Ziegler, W. A. Kues, U. Baulain, W. Baars, R. Schwinzer, J. Denner, D. Rataj, S. Werwitzke, A. Tiede, A. K. Bongoni, P. S. Garimella, A. Despont, R. Rieben, H. Niemann Tags: Brief Communication Source Type: research

ATF6 Mediates a Pro‐Inflammatory Synergy Between ER Stress and TLR Activation in the Pathogenesis of Liver Ischemia‐Reperfusion Injury
Although the roles of the metabolic stress in organ ischemia‐reperfusion injury (IRI) have been well recognized, the question of whether and how these stress responses regulate innate immune activation against IR remains unclear. In a murine liver partial warm ischemia mode, we showed that prolonged ischemia triggered endoplasmic reticulum (ER) stress response, particularly, the activating transcription factor 6 (ATF6) branch, in liver Kupffer cells (KCs) and altered their responsiveness against Toll‐like receptor (TLR) stimulation. Ischemia‐primed cells increased pro‐, but decreased anti‐, inflammatory cytokine ...
Source: American Journal of Transplantation - June 1, 2014 Category: Transplant Surgery Authors: J. Rao, S. Yue, Y. Fu, J. Zhu, X. Wang, R. W. Busuttil, J. W. Kupiec‐Weglinski, L. Lu, Y. Zhai Tags: Original Article Source Type: research

Immune Cell‐Derived C3a and C5a Costimulate Human T Cell Alloimmunity
Abstract Emerging evidence indicates that complement provides costimulatory signals for murine T cells but whether complement impacts human T cells remains unclear. We observed production of complement activation products C3a and C5a during in vitro cultures of human T cells responding to allogeneic dendritic cells (DC). Both partners expressed the receptors for C3a (C3aR) and C5a (C5aR) and C3aR‐ and C5aR‐antagonists inhibited T cell proliferation. Recombinant C3a/C5a promoted CD4+ T cell expansion, bypassed the inhibitory effects of CTLA4‐Ig, and induced AKT phosphorylation, the latter biochemically linking C3aR/C5...
Source: American Journal of Transplantation - September 6, 2013 Category: Transplant Surgery Authors: P. Cravedi, J. Leventhal, P. Lakhani, S. C. Ward, M. J. Donovan, P. S. Heeger Tags: Original Article Source Type: research

PI3Kδ Inhibition Augments the Efficacy of Rapamycin in Suppressing Proliferation of Epstein−Barr Virus (EBV)+ B Cell Lymphomas
Abstract Posttransplant lymphoproliferative disorder (PTLD) continues to be a devastating and potentially life‐threatening complication in organ transplant recipients. PTLD is associated with EBV infection and can result in malignant B cell lymphomas. Here we demonstrate that the PI3K/Akt/mTOR pathway is highly activated in EBV+ B cell lymphoma lines derived from patients with PTLD. Treatment with the mTORC1 inhibitor Rapamycin (RAPA) partially inhibited the proliferation of EBV+ B cell lines. Resistance to RAPA treatment correlated with high levels of Akt phosphorylation. An mTORC1/2 inhibitor and a PI3K/mTOR dual inhib...
Source: American Journal of Transplantation - July 10, 2013 Category: Transplant Surgery Authors: S. Furukawa, L. Wei, S. M. Krams, C. O. Esquivel, O. M. Martinez Tags: Original Article Source Type: research

Xenon Treatment Protects Against Cold Ischemia Associated Delayed Graft Function and Prolongs Graft Survival in Rats
Abstract Prolonged hypothermic storage causes ischemia‐reperfusion injury (IRI) in the renal graft, which is considered to contribute to the occurrence of the delayed graft function (DGF) and chronic graft failure. Strategies are required to protect the graft and to prolong renal graft survival. We demonstrated that xenon exposure to human proximal tubular cells (HK‐2) led to activation of range of protective proteins. Xenon treatment prior to or after hypothermia–hypoxia challenge stabilized the HK‐2 cellular structure, diminished cytoplasmic translocation of high‐mobility group box (HMGB) 1 and suppressed NF‐...
Source: American Journal of Transplantation - May 24, 2013 Category: Transplant Surgery Authors: H. Zhao, H. R. Watts, M. Chong, H. Huang, C. Tralau‐Stewart, P. H. Maxwell, M. Maze, A. J. T. George, D. Ma Tags: Original Article Source Type: research