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      Control of IBMIR in Neonatal Porcine Islet Xenotransplantation in Baboons

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          Abstract

          The instant blood-mediated inflammatory reaction (IBMIR) is a major obstacle to the engraftment of intraportal pig islet xenografts in primates. Higher expression of the galactose-α1,3-galactose (αGal) xenoantigen on neonatal islet cell clusters (NICC) than on adult pig islets may provoke a stronger reaction, but this has not been tested in the baboon model. Here, we report that WT pig NICC xenografts triggered profound IBMIR in baboons, with intravascular clotting and graft destruction occurring within hours, which was not prevented by anti-thrombin treatment. In contrast, IBMIR was minimal when recipients were immunosuppressed with a clinically relevant protocol and transplanted with NICC from αGal-deficient pigs transgenic for the human complement regulators CD55 and CD59. These genetically modified (GM) NICC were less susceptible to humoral injury in vitro than WT NICC, inducing significantly less complement activation and thrombin generation when incubated with baboon platelet-poor plasma. Recipients of GM NICC developed a variable anti-pig antibody response, and examination of the grafts 1 month after transplant revealed significant cell-mediated rejection, although scattered insulin-positive cells were still present. Our results indicate that IBMIR can be attenuated in this model, but long-term graft survival may require more effective immunosuppression or further donor genetic modification.

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          Most cited references31

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          Thrombin signalling and protease-activated receptors.

          S Coughlin (2000)
          How does the coagulation protease thrombin regulate cellular behaviour? The protease-activated receptors (PARs) provide one answer. In concert with the coagulation cascade, these receptors provide an elegant mechanism linking mechanical information in the form of tissue injury or vascular leakage to cellular responses. Roles for PARs are beginning to emerge in haemostasis and thrombosis, inflammation, and perhaps even blood vessel development.
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            Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways.

            We evaluated the ability of neonatal porcine islets to engraft and restore glucose control in pancreatectomized rhesus macaques. Although porcine islets transplanted into nonimmunosuppressed macaques were rapidly rejected by a process consistent with cellular rejection, recipients treated with a CD28-CD154 costimulation blockade regimen achieved sustained insulin independence (median survival, >140 days) without evidence of porcine endogenous retrovirus dissemination. Thus, neonatal porcine islets represent a promising solution to the crucial supply problem in clinical islet transplantation.
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              Large scale isolation, growth, and function of porcine neonatal islet cells.

              Based upon existing methods of isolating fetal porcine islet tissue, a simple, reliable procedure was developed for the preparation of porcine neonatal islet cell aggregates with a reproducible and defined cellular composition. After 9 d of in vitro culture, tissue from one neonatal pig pancreas yielded approximately 50,000 islet cell aggregates, consisting of primarily epithelial cells (57%) and pancreatic endocrine cells (35%). During the culture period, the total beta cell mass decreased initially, but subsequently increased 1.5-fold between days 3 and 9. Transplantation of grafts consisting of 3 x 10(5) beta cells (1,000 aggregated) under the kidney capsule of alloxan-diabetic nude mice corrected hyperglycemia in 75% (10/13) of the animals, whereas, 100% (20/20) of recipients implanted with 6 x 10(5) beta cells (2,000 aggregates) achieved euglycemia within 8 wk posttransplantation. Nephrectomy of the graft bearing kidney at 14 wk posttransplantation resulted in hyperglycemia in all recipients, and examination of the grafts revealed the presence of numerous well-granulated insulin- and glucagon-containing cells. The cellular insulin content of these grafts was 20 to 30-fold higher than at the time of transplantation. These results indicate that the neonatal porcine pancrease can be used as a source of large numbers of viable islet cells, which have the potential for growth both in vitro and in vivo, and exhibit the metabolic capacity to correct diabetes in nude mice.
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                Author and article information

                Journal
                Am J Transplant
                Am. J. Transplant
                ajt
                American Journal of Transplantation
                Blackwell Publishing Ltd (Oxford, UK )
                1600-6135
                1600-6143
                June 2014
                23 January 2014
                : 14
                : 6
                : 1300-1309
                Affiliations
                [1 ]The Centre for Transplant and Renal Research, Westmead Millennium Institute Westmead, NSW, Australia
                [2 ]University of Sydney at Westmead Hospital Westmead, NSW, Australia
                [3 ]Immunology Research Centre, St. Vincent's Hospital Melbourne, VIC, Australia
                [4 ]Department of Anaesthesia, St. Vincent's Hospital Melbourne, VIC, Australia
                [5 ]Experimental Medical Surgical Unit, St. Vincent's Hospital Melbourne, VIC, Australia
                [6 ]Walter and Eliza Hall Institute Melbourne, VIC, Australia
                [7 ]Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA
                [8 ]Department of Obstetrics and Gynaecology, University of Adelaide Adelaide, SA, Australia
                [9 ]Department of Medicine, University of Melbourne Melbourne, VIC, Australia
                Author notes
                *Corresponding author: Wayne J. Hawthorne, wayneh@ 123456med.usyd.edu.au
                [†]

                Both authors are equal second authors.

                [‡]

                Both authors are equal senior authors.

                Article
                10.1111/ajt.12722
                4204157
                24842781
                119cc067-a36e-401a-8e5a-2c909f4a03e9
                © 2014 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                Categories
                Original Articles

                Transplantation
                hyperacute rejection,instant blood-mediated inflammatory reaction,neonatal islet cell clusters,thrombosis,type 1 diabetes,xenotransplantation

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