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- Griessler, Erich, et al.
(författare)
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Xenotransplantation as policy problem : Comparing public debate and policies in an international perspective
- 2012
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Ingår i: Xenotransplantation. - : John Wiley & Sons. - 0908-665X .- 1399-3089. ; 19:1, s. 15-15
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Tidskriftsartikel (refereegranskat)abstract
- Xenotransplantation research had a hype in the late 1990s and early 2000s and was by then considered a therapeutic option with huge financial potential which was to become clinical standard practice in the near future. Driven by these economic hopes and by the expectation that xenotransplantation might alleviate the so-called organ shortage, governmental actors in different countries but also international organizations (WHO, OECD, Council of Europe) and EU institutions started to think about the implications of xenotransplantation and how to regulate this potential new technology.Xenotransplantation, however, for several reasons was not an uncontroversial technology. In the aftermath of food crises, the GMO conflict and blood scandals connected to HIV and hepatitis, xenotransplantation not only raised serious risk problems – connected to xenozoonosis – there were also basic human rights and animal welfare at stake. These were hotly discussed not only within science but also by different NGOs.In this situation many countries and international organizations carried out Technology Assessment (TA) and participatory Technology Assessment (pTA) procedures which should inform policy-makers about what to do.In my presentation I will compare attempts of TA and pTA on xenotransplantation in different countries and international organization (Austria, Canada, Denmark, Latvia, Netherlands, Sweden, UK, Switzerland OECD, and the European Commission). The paper addresses the following questions: How was xenotransplantation framed as a topic in these countries and institutions? In which settings of TA and pTA was xenotransplantation discussed? Who was included and excluded in policy making? In what way? What was the impact of TA and PTA on policy-making? What can we learn from these examples for negotiating techno-scientific futures in complex societies?The paper draws on an international comparative research project about the impact of citizen participation in knowledge-intensive policy fields (CIT-PART) financed by the European Commission within the 7th Framework Programme (Project Number: SSH-CT-2008-225327). For this research, document analysis of literature and media reports has been carried out. One main source, however, were interviews with people involved in pTA and TA either as participants, researchers, civil servants, politicians, stakeholders and practitioners of TA and pTA. For preliminary results see www.cit-art.at.
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- Biglarnia, Alireza, et al.
(författare)
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The free radical scavenger S-PBN significantly prolongs DSG-mediated graft survival in experimental xenotransplantation
- 2012
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Ingår i: Xenotransplantation. - : Wiley. - 0908-665X .- 1399-3089. ; 19:3, s. 166-176
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Tidskriftsartikel (refereegranskat)abstract
- Background: Nitrones such as 2-sulfo-phenyl-N-tert-butyl nitrone (S-PBN) are known to trap and stabilize free radicals and to reduce inflammation. Recently, S-PBN was shown to reduce infiltration of T lymphocytes and the expression of adhesion molecules on the endothelium in experimental traumatic brain injury. We hypothesized that S-PBN could reduce infiltration of T lymphocytes during cell-mediated xenograft rejection and thereby increase graft survival. The concordant mouse-to-rat heart transplantation model was used to test the hypothesis. In this model, grafts undergo acute humoral xenograft rejection (AHXR) almost invariably on day 3 and succumb to cell-mediated rejection on approximately day 8 if AHXR is inhibited by treatment with 15-deoxyspergualin (DSG). Material and methods: Hearts from Naval Medical Research Institute (NMRI) mice were transplanted to the neck vessels of Lewis rats. Recipients were treated with S-PBN (n = 9), DSG (n = 9), S-PBN and DSG in combination (n = 10) or left untreated (n = 9) for survival studies. S-PBN was given daily intraperitoneally at a dose of 150 mg/kg body weight (BW) on day -1 to 30, and DSG was given daily intraperitoneally at a dose of 10 mg/kg BW on day -1 to 4 and 5 mg/kg BW on day 5 to 21. Nine additional recipients were given S-PBN only on days -1 and 0 in combination with continuous DSG treatment. Grafts were monitored until they stopped beating. Additional recipients were treated with S-PBN (n = 5), DSG (n = 5), S-PBN and DSG in combination (n = 6) or left untreated (n = 5) for morphological, immunohistochemical and flow cytometry analyses on days 2 and 6 after transplantation. Results: S-PBN treatment in combination with DSG resulted in increased median graft survival compared to DSG treatment alone (14 vs. 7 days; P = 0.019). Lower number of T lymphocytes on day 6 (P = 0.019) was observed by ex vivo propagation and flow cytometry when combining S-PBN with DSG, whereas immunohistochemical analyses demonstrated a significant reduction in the number of infiltrated CD4+, but not TCR+, cells. S-PBN treatment alone had no impact on graft survival compared to untreated rats (3 vs. 3 days). No differences were seen in ICAM-1 and VCAM-1 expression or in morphology between the groups. Conclusion: The combination of S-PBN and DSG treatment increases xenograft survival. The main effect of S-PBN appears to be in direct connection with the transplantation. Because of its low toxicity, S-PBN could become useful in combination with other immunosuppressants to reduce cell-mediated xenograft rejection.
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- Brandhorst, Daniel, 1961-, et al.
(författare)
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Pancreas storage in oxygenated perfluorodecalin does not restore post-transplant function of isolated pig islets pre-damaged by warm ischemia
- 2006
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Ingår i: Xenotransplantation. - : Wiley. - 0908-665X .- 1399-3089. ; 13:5, s. 465-470
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cold storage in oxygenated perfluorodecalin (PFD) restores transplant function of ischemically damaged dog pancreata and reduces the impact of cold ischemia on recovery of isolated human islets. Whether PFD storage can improve islet isolation from pancreata exposed to significant warm ischemia (WI) is unclear yet. The present study aimed to clarify this question in adult pigs. Methods: After exsanguination, the intestine was removed immediately or left in the cavity for 30 min of WI. Resected pancreata were intraductally flushed with cold University of Wisconsin solution. Subsequently, pancreata were processed immediately by digestion-filtration (group I: 0 min WI, n = 6; II: 30 min WI, n = 6) or first stored for 3 h in oxygenated PFD (III: 0 min WI + PFD, n = 5; IV: 30 min WI + PFD, n = 6). Results: Pancreata subjected to 30 min of WI yielded significantly less islets compared with the corresponding non-ischemic organs (I vs. II, P < 0.01; III vs. IV, P < 0.05). Oxygenation did not ameliorate the loss in islet yield (II vs. IV, NS). Ischemic islets were characterized by depleted ATP stores (388 +/- 73 (I) vs. 133 +/- 22 ng/1000 IEQ (II), P < 0.01) and diminished insulin response to glucose calculated as stimulation index (SI; 2.47 +/- 0.36 (I) vs. 0.25 +/- 0.17 (II), P < 0.05). PFD storage of ischemic organs partially restored ATP content (217 +/- 23 ng/1000 IEQ, II vs. IV, P < 0.05) and glucose SI (1.60 +/- 0.09, II vs. IV, P < 0.05) to a significant extent that reached the level of corresponding PFD-stored, non-ischemic pancreata (III vs. IV, NS). Sustained normoglycemia was exclusively observed in diabetic nude mice transplanted with islets isolated from non-ischemic organs. The significantly reduced graft function of ischemic islets (I vs. II, III vs. IV, P < 0.001) was not increased by pancreatic oxygenation (II vs. IV, NS). Conclusions: The present study suggests that pancreas short-term storage in oxygenated PFD improves in vitro but not the in vivo function of ischemically damaged pig islets.
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- Breimer, Michael, 1951, et al.
(författare)
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Extracorporeal ("ex vivo") connection of pig kidneys to humans. I. Clinical data and studies of platelet destruction.
- 1996
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Ingår i: Xenotransplantation. - : Wiley. - 0908-665X .- 1399-3089. ; 3:4, s. 328-39
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Tidskriftsartikel (refereegranskat)abstract
- The pioneering experiment by Welsh et al. (Immunological Lett 1991:29:167-170) connecting a pig kidney to the human circulation has been repeated in a modified manner. Two volunteer dialysis patients were pretreated by daily plasmapheresis on days -2,-1, and 0 to remove the naturally occurring anti-pig xenoantibodies. The anti-pig lymphocytotoxic liters were reduced from 1:8 to 1:2 in patient 1 and from 1:8 to 1:1 in patient 2. No steroids or immunosuppressive drugs were administrated before or during the experiments. A sterile pig kidney was extracorporeally ("ex vivo") connected to the patients a/v fistula using an arterial and a venous pump similar to a dialysis. The two experiments gave different results. In the first experiment the perfusion pressure was kept at 100 mmHg for the initial 25 min by reducing the pump speed until the minimum blood flow of 30 ml/min was reached. Thereafter, the pressure rose continuously and the experiment was terminated at 65 min at a perfusion pressure of 200 mmHg. The patient did not feel any discomfort during the perfusion. In the second experiment, a stable blood flow of 200 ml/min was reached at a pressure of 100 mmHg after a few minutes. The perfusion was terminated at 15 min when the patient developed chest and abdominal pain, hypotension, and electrocardiographic signs of myocardial ischemia. The patient recovered quickly. In the first experiment, small volumes of clear urine was produced until the pressure rose above 100 mmHg, which resulted in hematuria. In the second experiment clear urine (4 ml/min) was produced. (51)Chromium clearance values were after 15 min <1 ml/min for kidney 1 and 12 ml/min (8 ml/min/100 g) for kidney 2. A drastic reduction in platelet count (128 to 48 and 64 to 8 × 10(9)/1, respectively) during the passage through the kidney was found in blood samples collected simultaneously before and after the organ. No change in hemoglobin values and leucocyte counts were found. Light- and electron-microscopical analysis of the kidney tissues revealed for kidney 1 focal areas with obliteration of the glomerular and peritubular capillaries by platelets and PMN cells and severe damage of the endothelial cells comparable to a picture of a hyperacute rejection. In kidney 2, all vessels were patent but in the capillaries large amount of membrane fragments were detected by electron microscopy and a discrete damage of the endothelial cells were seen in some segments. No intact platelets were present in the vascular tree. These human experiments support the hypothesis that hyperacute rejection of pig to human xenografts is delayed in time by removal of the preformed anti-pig xenoantibodies. A new finding was a very rapid destruction of platelets occurring in the kidney of patient 2 who had very low liters of xenoantibodies. The humoral immune response is described in detail in an accompanying paper (Rydberg et al., this issue).
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| 10. |
- Breimer, Michael, 1951
(författare)
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Gal/non-Gal antigens in pig tissues and human non-Gal antibodies in the GalT-KO era.
- 2011
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Ingår i: Xenotransplantation. - : Wiley. - 1399-3089 .- 0908-665X. ; 18:4, s. 215-28
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Tidskriftsartikel (refereegranskat)abstract
- Our knowledge regarding Gal and non-Gal antigens in GalT-KO pig tissues can be summarized as α3Galactosyl-tranferase gene knock out eliminates the Galα3Galβ4GlcNAc-R antigen expression in pig tissues as well as anti-Gal antibody binding. Other Galα-terminating saccharides (e.g. iGb3 glycolipids and Galα2 determinants) may be present but have not been documented. α3Galactosyl-tranferase gene knock out slightly changes the carbohydrate antigen expression but no "new" antigens recognized by the human immune system have been found. Non-Gal antigens are both of protein and carbohydrate nature but their exact chemical structures are poorly defined. Regarding human non-Gal antibodies our knowledge is as Non-Gal antibodies exist naturally and increase in humans/non-human primate (NHP) receiving WT or GalT-KO pig grafts. Non-Gal antibodies with new antigen epitope recognition can be induced in humans/NHP after challenge by WT or GalT-KO pig grafts. Non-Gal antibodies react with both carbohydrates and proteins. Part of the protein reactivity is directed to glycoprotein carbohydrates chains. Non-Gal antibodies reacting with neuraminic acid terminated saccharides (both N-Acetyl and N-Glycoloyl variants) are present in humans/NHP. Anti-neuraminic acid antibodies are increased, as well as induced, after grafting pig organs into humans/NHP. Non-Gal antibodies does not cause hyperacute xenorejection but can be cytotoxic and cause xenoorgan damage. If humans sensitized to HLA antigens are at a higher risk of rejecting pig xenograft compared with non-sensitized individuals is not fully clarified. Clinical trials are needed to evaluate the relevance of non-Gal antigens/antibodies and for the xenofield to advance.
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