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103. Enhanced protection of the renal vascular endothelium improves early outcome in kidney transplantation : Preclinical investigations in pig and mouse

Author

Nordling, Sofia, Brännström, Johan, Carlsson, Fredrik, Lu, Bo, Salvaris, Evelyn, Wanders, Alkwin, Buijs, Jos, Estrada, Sergio, Tolmachev, Vladimir, Cowan, Peter J., Lorant, Tomas, Magnusson, Peetra U., Nordling, Sofia, Brännström, Johan, Carlsson, Fredrik, Lu, Bo, Salvaris, Evelyn, Wanders, Alkwin, Buijs, Jos, Estrada, Sergio, Tolmachev, Vladimir, Cowan, Peter J., Lorant, Tomas, and Magnusson, Peetra U.

Abstract

Ischemia reperfusion injury is one of the major complications responsible for delayed graft function in kidney transplantation. Applications to reduce reperfusion injury are essential due to the widespread use of kidneys from deceased organ donors where the risk for delayed graft function is especially prominent. We have recently shown that coating of inflamed or damaged endothelial cells with a unique heparin conjugate reduces thrombosis and leukocyte recruitment. In this study we evaluated the binding capacity of the heparin conjugate to cultured human endothelial cells, to kidneys from brain-dead porcine donors, and to murine kidneys during static cold storage. The heparin conjugate was able to stably bind cultured endothelial cells with high avidity, and to the renal vasculature of explanted kidneys from pigs and mice. Treatment of murine kidneys prior to transplantation reduced platelet deposition and leukocyte infiltration 24 hours post-transplantation, and significantly improved graft function. The present study thus shows the benefits of enhanced protection of the renal vasculature during cold storage, whereby increasing the antithrombotic and anti-adhesive properties of the vascular endothelium yields improved renal function early after transplantation.

Published
2018
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104. Modulation of CD39 and Exogenous APT102 Correct Immune Dysfunction in Experimental Colitis and Crohn's Disease.

Author

Robles, René J, Mukherjee, Samiran, Vuerich, Marta, Xie, Anyan, Harshe, Rasika, Cowan, Peter J, Csizmadia, Eva, Wu, Yan, Moss, Alan C, Chen, Ridong, Robson, Simon C, and Longhi, Maria Serena

Abstract

Background and Aims CD39/ENTPD1 scavenges pro-inflammatory nucleotides, to ultimately generate immunosuppressive adenosine, which has a central role in immune homeostasis. Global deletion of Cd39 increases susceptibility to experimental colitis while single nucleotide polymorphisms within the human CD39 promoter, and aberrant patterns of expression during experimental hypoxia, predispose to Crohn's disease. We aimed to define the impact of transgenic human CD39 [hTG] overexpression in experimental colitis and to model therapeutic effects using the recombinant apyrase APT102 in vivo. We also determined the in vitro effects of APT102 on phenotypic and functional properties of regulatory T-lymphocytes derived from patients with Crohn's disease. Methods Colitis was induced by administration of dextran sulfate sodium in wild-type [WT] or hTG mice, and, in another model, by adoptive transfer of CD45RBhigh cells with or without WT or hTG regulatory T cells [Treg]. In additional experiments, mice were treated with APT102. The effects of APT102 on phenotype and function of Treg and type-1 regulatory T [Tr1] cells were also evaluated, after purification from peripheral blood and lamina propria of Crohn's disease patients [ n = 38]. Results Overexpression of human CD39 attenuated experimental colitis and protected from the deleterious effects of systemic hypoxia, pharmacologically induced by deferoxamine. Administration of APT102 in vivo enhanced the beneficial effects of endogenous Cd39 boosted by the administration of the aryl hydrocarbon receptor [AhR] ligand unconjugated bilirubin [UCB]. Importantly, supplemental APT102 restored responsiveness to AhR stimulation by UCB in Treg and Tr1 cells, obtained from Crohn's disease patients. Conclusions hCD39 overexpression ameliorated experimental colitis and prevented hypoxia-related damage in vivo. Exogenous administration of APT102 boosted AhR-mediated regulatory effects in vivo while enhancing Treg functions in Crohn's disease in vitro. [ABSTRACT FROM AUTHOR]

Published
2020
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106. Pig endothelial protein C receptor is functionally compatible with the human protein C pathway.

Author

Salvaris, Evelyn J., Moran, Christopher J., Roussel, Jean Christian, Fisicaro, Nella, Robson, Simon C., and Cowan, Peter J.

Subjects
PROTEIN C, PROTEIN receptors, AMINO acid sequence, SWINE, THROMBIN, CARRIER proteins, THROMBIN receptors
Abstract

Background: Endothelial protein C receptor (EPCR) plays an anticoagulant and anti‐inflammatory role by promoting the activation of protein C by thrombin bound to thrombomodulin (TBM). Incompatibility between pig TBM and human/primate thrombin is thought to contribute to dysregulated coagulation in pig‐to‐primate organ xenografts, and expression of human TBM (hTBM) in pigs has shown benefit in preclinical models. However, it is not known whether there are incompatibilities—or molecular barriers—between endogenous pig EPCR (pEPCR) and transgenically expressed human TBM. Aim: To clone and express pEPCR, and determine its function in the human protein C pathway in vitro. Methods: Pig endothelial protein C receptor cDNA was generated from pig lung RNA by RT‐PCR. Primate COS‐7 transfectants expressing various combinations of human and pig TBM and EPCR were incubated with human thrombin and human protein C, and tested for TBM cofactor activity. Results: The predicted protein sequence of pEPCR shared 72.3% amino acid sequence identity with hEPCR, and residues critical for protein C binding were conserved. COS‐7 cells transfected with hEPCR, pEPCR or vector showed minimal TBM cofactor activity (0.13 ± 0.04, 0.13 ± 0.02 and 0.14 ± 0.06 U, respectively). The cofactor activity of hTBM‐transfected cells (1.18 ± 0.29 U) was 8‐fold higher than vector‐transfected cells (P =.004) and further increased 4‐fold and 3‐fold by co‐transfection with hEPCR (5.01 ± 1.12 U, P =.004) or pEPCR (3.73 ± 0.65 U, P =.003), respectively. Conclusions: Our data show that pEPCR is largely compatible with the human TBM/thrombin complex, when expressed on COS‐7 cells in vitro, promoting the activation of human protein C. These findings suggest that endogenous pEPCR will enhance the activity of transgenic hTBM in the xenograft setting. [ABSTRACT FROM AUTHOR]

Published
2020
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108. Enhanced protection of the renal vascular endothelium improves early outcome in kidney transplantation: Preclinical investigations in pig and mouse

Author

Nordling, Sofia, primary, Brännström, Johan, additional, Carlsson, Fredrik, additional, Lu, Bo, additional, Salvaris, Evelyn, additional, Wanders, Alkwin, additional, Buijs, Jos, additional, Estrada, Sergio, additional, Tolmachev, Vladimir, additional, Cowan, Peter J., additional, Lorant, Tomas, additional, and Magnusson, Peetra U., additional

Published
2018
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109. CD39 and CD73 activity are protective in a mouse model of antiphospholipid antibody-induced miscarriages

Author

Samudra, Anushka N., primary, Dwyer, Karen M., additional, Selan, Carly, additional, Freddi, Susanna, additional, Murray-Segal, Lisa, additional, Nikpour, Mandana, additional, Hickey, Michael J., additional, Peter, Karlheinz, additional, Robson, Simon C., additional, Sashindranath, Maithili, additional, Cowan, Peter J., additional, and Nandurkar, Harshal H., additional

Published
2018
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110. The CD39-adenosinergic axis in the pathogenesis of immune and nonimmune diabetes

Author

Chia, Joanne S.J., McRae, Jennifer L., Cowan, Peter J., and Dwyer, Karen M.

Subjects
Diabetes -- Physiological aspects, Physiology, Pathological -- Research, Biotechnology industry, High technology industry, Physiological aspects, Research
Abstract

Diabetes mellitus encompasses two distinct disease processes: autoimmune Type 1 (T1D) and nonimmune Type 2 (T2D) diabetes. Despite the disparate aetiologies, the disease phenotype of hyperglycemia and the associated complications are similar. In this paper, we discuss the role of the CD39-adenosinergic axis in the pathogenesis of both T1D and T2D, with particular emphasis on the role of CD39 and CD73., 1. Introduction Extracellular nucleotides, such as adenosine triphosphate (ATP), are important signalling molecules involved in many biological processes. Under basal conditions extracellular concentrations of ATP are maintained at low levels. [...]

Published
2012
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111. Surface modification of pig endothelial cells with a branched heparin conjugate improves their compatibility with human blood

Author

Bongoni, Anjan K., Salvaris, Evelyn, Nordling, Sofia, Klymiuk, Nikolai, Wolf, Eckhard, Ayares, David L., Rieben, Robert, Magnusson, Peetra, Cowan, Peter J., Bongoni, Anjan K., Salvaris, Evelyn, Nordling, Sofia, Klymiuk, Nikolai, Wolf, Eckhard, Ayares, David L., Rieben, Robert, Magnusson, Peetra, and Cowan, Peter J.

Abstract

Corline Heparin Conjugate (CHC), a compound of multiple unfractionated heparin chains, coats cells with a glycocalyx-like layer and may inhibit (xeno) transplant-associated activation of the plasma cascade systems. Here, we investigated the use of CHC to protect WT and genetically modified (GTKO. hCD46. hTBM) pig aortic endothelial cells (PAEC) in two pig-to-human in vitro xenotransplantation settings. Model 1: incubation of untreated or hTNFa-treated PAEC with 10% human plasma induced complement C3b/c and C5b-9 deposition, cellular activation and coagulation activation in WT and GTKO. hCD46. hTBM PAEC. Coating of untreated or hTNFa-treated PAEC with CHC (100 mu g/ml) protected against human plasma-induced endothelial activation and damage. Model 2: PAEC were grown on microcarrier beads, coated with CHC, and incubated with non-anticoagulated whole human blood. Genetically modified PAEC significantly prolonged clotting time of human blood (115.0 +/- 16.1 min, p < 0.001) compared to WT PAEC (34.0 +/- 8.2 min). Surface CHC significantly improved the human blood compatibility of PAEC, as shown by increased clotting time (WT: 84.3 +/- 11.3 min, p < 0.001; GTKO. hCD46. hTBM: 146.2 +/- 20.4 min, p < 0.05) and reduced platelet adhesion, complement activation, coagulation activation and inhibition of fibrinolysis. The combination of CHC coating and genetic modification provided the greatest compatibility with human blood, suggesting that pre-transplant perfusion of genetically modified porcine organs with CHC may benefit post-transplant xenograft function.

Published
2017
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115. Regulation of Clinical Xenotransplantation—Time for a Reappraisal

Author

Cooper, David K.C., primary, Pierson, Richard N., additional, Hering, Bernhard J., additional, Mohiuddin, Muhammad M., additional, Fishman, Jay A., additional, Denner, Joachim, additional, Ahn, Curie, additional, Azimzadeh, Agnes M., additional, Buhler, Leo H., additional, Cowan, Peter J., additional, Hawthorne, Wayne J., additional, Kobayashi, Takaaki, additional, and Sachs, David H., additional

Published
2017
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125. Role of the CD39/CD73 Purinergic Pathway in Modulating Arterial Thrombosis in Mice

Author

Covarrubias, Roman, primary, Chepurko, Elena, additional, Reynolds, Adam, additional, Huttinger, Zachary M., additional, Huttinger, Ryan, additional, Stanfill, Katherine, additional, Wheeler, Debra G., additional, Novitskaya, Tatiana, additional, Robson, Simon C., additional, Dwyer, Karen M., additional, Cowan, Peter J., additional, and Gumina, Richard J., additional

Published
2016
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127. Antibody-Mediated Rejection in a Blood Group A-Transgenic Mouse Model of ABO-Incompatible Heart Transplantation

Author

Motyka, Bruce, primary, Fisicaro, Nella, additional, Wang, Szu-I, additional, Kratochvil, Annetta, additional, Labonte, Katrina, additional, Tao, Kesheng, additional, Pearcey, Jean, additional, Marshall, Thuraya, additional, Mengel, Michael, additional, Sis, Banu, additional, Fan, Xiaohu, additional, d'Apice, Anthony J. F., additional, Cowan, Peter J., additional, and West, Lori J., additional

Published
2016
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131. Abstract 75: Ischemic Heart Failure is Exacerbated in CD39-null Mice

Author

Novitskaya, Tatiana, primary, Wheeler, Debra G, additional, Xu, Zhaobin, additional, Chepurko, Elena, additional, Zhang, Bo, additional, Koch, Walter, additional, Dwyer, Karen M, additional, Cowan, Peter J, additional, Robson, Simon C, additional, Gao, Erhe, additional, and Gumina, Richard J, additional

Published
2015
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132. Ambient Fine Particulate Matter Suppresses In Vivo Proliferation of Bone Marrow Stem Cells through Reactive Oxygen Species Formation

Author

Cui, Yuqi, primary, Jia, Fengpeng, additional, He, Jianfeng, additional, Xie, Xiaoyun, additional, Li, Zhihong, additional, Fu, Minghuan, additional, Hao, Hong, additional, Liu, Ying, additional, Liu, Dylan Z., additional, Cowan, Peter J., additional, Zhu, Hua, additional, Sun, Qinghua, additional, and Liu, Zhenguo, additional

Published
2015
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135. Ambient Fine Particulate Matter Induces Apoptosis of Endothelial Progenitor Cells Through Reactive Oxygen Species Formation

Author

Cui, Yuqi, primary, Xie, Xiaoyun, additional, Jia, Fengpeng, additional, He, Jianfeng, additional, Li, Zhihong, additional, Fu, Minghuan, additional, Hao, Hong, additional, Liu, Ying, additional, Liu, Jason Z., additional, Cowan, Peter J., additional, Zhu, Hua, additional, Sun, Qinghua, additional, and Liu, Zhenguo, additional

Published
2015
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137. Gut Microbiota Elicits a Protective Immune Response against Malaria Transmission

Author

Yilmaz, Bahtiyar, primary, Portugal, Silvia, additional, Tran, Tuan M., additional, Gozzelino, Raffaella, additional, Ramos, Susana, additional, Gomes, Joana, additional, Regalado, Ana, additional, Cowan, Peter J., additional, d’Apice, Anthony J.F., additional, Chong, Anita S., additional, Doumbo, Ogobara K., additional, Traore, Boubacar, additional, Crompton, Peter D., additional, Silveira, Henrique, additional, and Soares, Miguel P., additional

Published
2014
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144. Regulatory T cells participate in CD39-mediated protection from renal injury

Author

Wang, Yuan Min, McRae, Jennifer L., Robson, Simon C., Cowan, Peter J., Zhang, Geoff Y., Hu, Min, Polhill, Tania, Wang, Yiping, Zheng, Guoping, Wang, Ya, Lee, Vincent W.S., Unwin, Robert J., Harris, David C.H., Dwyer, Karen M., Alexander, Stephen I., Wang, Yuan Min, McRae, Jennifer L., Robson, Simon C., Cowan, Peter J., Zhang, Geoff Y., Hu, Min, Polhill, Tania, Wang, Yiping, Zheng, Guoping, Wang, Ya, Lee, Vincent W.S., Unwin, Robert J., Harris, David C.H., Dwyer, Karen M., and Alexander, Stephen I.

Published
2012

145. Ectonucleotide triphosphate diphosphohydrolase-1 (CD39) mediates resistance to occlusive arterial thrombus formation after vascular injury in mice

Author

Huttinger, Zachery M., Milks, Michael W., Nickoli, Michael S., Aurand, William L., Long, Lawrence C., Wheeler, Debra G., Dwyer, Karen M., d'Apice, Anthony J.F., Robson, Simon C., Cowan, Peter J., Gumina, Richard J., Huttinger, Zachery M., Milks, Michael W., Nickoli, Michael S., Aurand, William L., Long, Lawrence C., Wheeler, Debra G., Dwyer, Karen M., d'Apice, Anthony J.F., Robson, Simon C., Cowan, Peter J., and Gumina, Richard J.

Published
2012

146. Modification of kidney barrier function by the urokinase receptor

Author

Wei, Changli, Möller, Clemens C., Altintas, Mehmet M., Li, Jing, Schwarz, Karin, Zacchigna, Serena, Xie, Liang, Henger, Anna, Schmid, Holger, Rastaldi, María P., Cowan, Peter J., Kretzler, Matthias, Parrilla, Roberto L., Bendayan, Möise, Gupta, Vineet, Nikolic, Boris, Kalluri, Raghu, Carmeliet, Peter, Mundel, Peter, Reiser, Jonche, Wei, Changli, Möller, Clemens C., Altintas, Mehmet M., Li, Jing, Schwarz, Karin, Zacchigna, Serena, Xie, Liang, Henger, Anna, Schmid, Holger, Rastaldi, María P., Cowan, Peter J., Kretzler, Matthias, Parrilla, Roberto L., Bendayan, Möise, Gupta, Vineet, Nikolic, Boris, Kalluri, Raghu, Carmeliet, Peter, Mundel, Peter, and Reiser, Jonche

Abstract

Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of v3 integrin. Mice lacking uPAR (Plaur- /- ) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active 3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate v3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of v3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeability

Published
2008

150. First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes-Chapter 2b: genetically modified source pigs.

Author

Cowan, Peter J., Ayares, David, Wolf, Eckhard, and Cooper, David K. C.

Subjects
*XENOGRAFTS, *ANTICOAGULANTS, *TRANSGENES, *GENOME editing, *CLINICAL trials
Abstract

Genetic modification of the source pig offers the opportunity to improve the engraftment and survival of islet xenografts. The type of modification can be tailored to the transplant setting; for example, intraportal islet xenografts have been shown to benefit from the expression of anticoagulant and anti-inflammatory transgenes, whereas cytoprotective transgenes are probably more relevant for encapsulated islets. The rapid development of pig genetic engineering, particularly with the introduction of genome editing techniques such as CRISPR-Cas, has accelerated the generation of new pig lines with multiple modifications. With pre-clinical testing in progress, it is an opportune time to consider any implications of genetic modification for the conditions for undertaking clinical trials. Obviously, the stringent requirements to fulfill designated pathogen-free status that are applied to wild-type pigs will apply equally to genetically modified ( GM) source pigs. In addition, it is important from a safety perspective that the genetic modifications are characterized at the molecular level (e.g., integration site, absence of off-target mutations), the phenotypic level (e.g., durability and stability of transgene expression), and the functional level (e.g., protection of islets in vitro or in vivo, absence of detrimental effects on insulin secretion). The assessment of clinical trial protocols using GM pig islets will need to be performed on a case-by-case basis, taking into account a range of factors including the particular genetic modification(s) and the site and method of delivery. [ABSTRACT FROM AUTHOR]

Published
2016
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