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205. Clinical and experimental pancreatic islet transplantation to striated muscle: establishment of a vascular system similar to that in native islets.

Author

Christoffersson G, Henriksnäs J, Johansson L, Rolny C, Ahlström H, Caballero-Corbalan J, Segersvärd R, Permert J, Korsgren O, Carlsson PO, Phillipson M, Christoffersson, Gustaf, Henriksnäs, Johanna, Johansson, Lars, Rolny, Charlotte, Ahlström, Håkan, Caballero-Corbalan, José, Segersvärd, Ralf, Permert, Johan, and Korsgren, Olle

Abstract

Objective: Curing type 1 diabetes by transplanting pancreatic islets into the liver is associated with poor long-term outcome and graft failure at least partly due to inadequate graft revascularization. The aim of the current study was to evaluate striated muscle as a potential angiogenic site for islet transplantation.Research Design and Methods: The current study presents a new experimental model that is found to be applicable to clinical islet transplantation. Islets were implanted into striated muscle and intraislet vascular density and blood flow were visualized with intravital and confocal microscopy in mice and by magnetic resonance imaging in three autotransplanted pancreatectomized patients. Mice were rendered neutropenic by repeated injections of Gr-1 antibody, and diabetes was induced by alloxan treatment.Results: Contrary to liver-engrafted islets, islets transplanted to mouse muscle were revascularized with vessel densities and blood flow entirely comparable with those of islets within intact pancreas. Initiation of islet revascularization at the muscular site was dependent on neutrophils, and the function of islets transplanted to muscle was proven by curing diabetic mice. The experimental data were confirmed in autotransplanted patients where higher plasma volumes were measured in islets engrafted in forearm muscle compared with adjacent muscle tissue through high-resolution magnetic resonance imaging.Conclusions: This study presents a novel paradigm in islet transplantation whereby recruited neutrophils are crucial for the functionally restored intraislet blood perfusion following transplantation to striated muscle under experimental and clinical situations. [ABSTRACT FROM AUTHOR]

Published
2010
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206. Alloreactivity but Failure to Reject Human Islet Transplants by Humanized Balb/c/Rag2−/−gc−/− Mice.

Author

Jacobson, S., Heuts, F., Juarez, J., Hultcrantz, M., Korsgren, O., Svensson, M., Rottenberg, M., and Flodström-Tullberg, M.

Subjects
ISLANDS of Langerhans transplantation, DIABETES, IMMUNE system, IMMUNOSUPPRESSIVE agents, T cells, HEMATOPOIETIC stem cells
Abstract

A human islet transplant can cure patients with type 1 diabetes. A drawback of islet transplantation is the life-long immunosuppressive medication, often associated with severe side effects. Moreover, in spite of the immunosuppressive therapy, islets are lost in the majority of transplanted patients over time. An improved small animal model for studies on human islet allograft rejection mechanisms and the development of new measures for its prevention is clearly warranted. Here, we evaluated the potential of Balb/cRag2−/−γc−/− mice carrying a human-like immune system (so-called humanized mice) as a tool for studies on the rejection of transplanted human islets. Human T cells from Balb/cRag2−/−γc−/− mice, which as neonates had been transplanted with CD34+ human cord blood haematopoietic stem cells (HIS mice), proliferated in response to allogeneic human dendritic cells, but failed to reject a human islet allograft transplanted to the renal subcapsular space as assessed by immunohistochemistry and analysis of human serum C-peptide levels. Histological analysis revealed that few if any T cells had migrated to the grafted tissue. These observations question the usefulness of the HIS mouse model for studies on human islet allograft rejection mechanisms and highlight the need for further improvements. [ABSTRACT FROM AUTHOR]

Published
2010
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208. Formation of composite endothelial cell-mesenchymal stem cell islets: a novel approach to promote islet revascularization.

Author

Johansson U, Rasmusson I, Niclou SP, Forslund N, Gustavsson L, Nilsson B, Korsgren O, Magnusson PU, Johansson, Ulrika, Rasmusson, Ida, Niclou, Simone P, Forslund, Naomi, Gustavsson, Linda, Nilsson, Bo, Korsgren, Olle, and Magnusson, Peetra U

Abstract

Objective: Mesenchymal stem cells (MSCs) contribute to endothelial cell (EC) migration by producing proteases, thereby paving the way into the tissues for ECs. MSCs were added to our previously described composite EC islets as a potential means to improve their capacity for islet angiogenesis.Research Design and Methods: Human islets were coated with primary human bone marrow-derived MSCs and dermal microvascular ECs. The capacity of ECs, with or without MSCs, to adhere to and grow into human islets was analyzed. The survival and functionality of these composite islets were evaluated in a dynamic perifusion assay, and their capacity for angiogenesis in vitro was assessed in a three-dimensional fibrin gel assay.Results: ECs proliferated after culture in MSC-conditioned medium, and MSCs improved the EC coverage threefold compared with EC islets alone. Islet survival in vitro and the functionality of the composite islets after culture were equal to those of control islets. The EC-MSC islets showed a twofold increase in total sprout formation compared with EC islets, and vascular sprouts emanating from the EC-MSC-islet surface showed migration of ECs into the islets and also into the surrounding matrix, either alone or in concert with MSCs.Conclusions: EC proliferation, sprout formation, and ingrowth of ECs into the islets were enhanced by MSCs. The use of composite EC-MSC islets may have beneficial effects on revascularization and immune regulation. The technique presented allows for pretreatment of donor islets with recipient-derived ECs and MSCs as a means of improving islet engraftment. [ABSTRACT FROM AUTHOR]

Published
2008
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211. Cellular responses to cytomegalovirus in immunosuppressed patients: circulating CD8+ T cells recognizing CMVpp65 are present but display functional impairment.

Author

ENGSTRAND, M., LIDEHÄLL, A. K., TÖTTERMAN, T. H., HERRMAN, B., ERIKSSON, B.-M., and KORSGREN, O.

Subjects
T cells, CYTOMEGALOVIRUS diseases, IMMUNOSUPPRESSION
Abstract

SUMMARY The availability of tetrameric complexes of HLA class I molecules folded with immunodominant peptides makes it possible to utilize flow cytometry for rapid and highly specific visualization of virus specific CD8+ T cells. An alternate technique is to incubate whole blood with specific antigens and to subsequently detect and characterize responding T cells (e.g. by performing intracellular staining of interferon-gamma). By using an HLA-A2 tetramer construct folded with the same immunodominant CMV-peptide as that used for peptide pulsing, we monitored both the presence and functional capacity of CMV-specific CD8+ T cells. In addition T cell activation was assayed by determination of CD38 and CD69 expression. Twelve organ transplant patients and 31 healthy blood donors with latent CMV infection were investigated using CMV pp65 tetramer staining and intracellular staining of interferon-gamma after CMV pp65 peptide pulsing or CMV lysate pulsing. CMV-specific T cells were detected in similar absolute numbers as well as frequencies of T cells in the two groups investigated. However, the CMV-specific CD8+ T cells in immunosuppressed individuals showed a decreased functional response to the CMV-peptide, as evidenced by reduced interferon-gamma production when compared to healthy blood donors (19%; 42%, P < 0·005). In addition, CD38 expression was markedly higher in immunosuppressed patients compared to healthy blood donors (24%; 6%, P < 0·005). In a case report we demonstrate that reactivation of CMV can occur in an immunosuppressed patient with high number of CMV-specific T cells, but without functional capacity. Hence, these findings reflect impaired activation of cytotoxic T cells controlling latent CMV infection in immunosuppressed patients. [ABSTRACT FROM AUTHOR]

Published
2003
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212. The transplanted fetal endocrine pancreas undergoes an inherent sequential differentiation similar to that in the native pancreas. An ultrastructural study in the pig-to-mouse model.

Author

Lukinius, Agneta, Korsgren, Olle, Lukinius, A, and Korsgren, O

Subjects
ISLANDS of Langerhans, ANIMAL models of organ transplants
Abstract

This study examines, at the ultrastructural level, whether the fetal porcine endocrine pancreas (insulin, glucagon, somatostatin, and pancreatic polypeptide [PP]- and islet amyloid polypeptide [IAPP]-containing cells) develops normally after transplantation under the kidney capsule in athymic mice. We have thus used an in vivo pig-to-mouse model for the differentiation of the endocrine pancreas removed from its normal milieu. Islet-like cell clusters (ICCs) were prepared from the fetal porcine pancreas as previously described and transplanted under the renal capsule of athymic mice. At various times after transplantation, the endocrine pancreas was removed and the level of differentiation was compared with the native pancreas of the same biological age. At the ultrastructural level, several sequential steps could be identified based on the morphology and hormone content of the secretory granules of the endocrine cell examined. Applying this approach, we could demonstrate that the ontogeny of the transplanted fetal pig pancreas follows the same sequential differentiation as the native pancreas. The process seems to be under stringent control, apparently directly related to the biological age of the tissue, and independent not only of the new environment under the kidney capsule but also of the adult and xenogeneic milieu provided after transplantation to the athymic nude mouse. Therefore, all four major hormone-producing cells seem to develop normally after transplantation when compared with the development in the native pancreas. IAPP was produced by the pluripotent fetal endocrine cells as well as the adult alpha-, beta-, and delta-cell granules in the native pancreas; however, in the transplanted pancreas, IAPP expression was demonstrated only in beta-cells, delta-cells, and PP cells. No IAPP was found in granules of the alpha-cell lineage. The results suggest a sequential differentiation of all four major types of islet cells from a common pluripotent progenitor cell, which seems to be located in the pancreatic ducts. Therefore, the results presented strongly suggest that the ontogeny of the four major endocrine islet cells is determined by genetic information carried by the progenitor cells and not by the systemic or local environment. [ABSTRACT FROM AUTHOR]

Published
2001
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222. Functional and morphological differentiation of fetal porcine islet-like cell clusters after transplantation into nude mice.

Author

Korsgren, O., Jansson, L., Eizirik, D., and Andersson, A.

Abstract

By using a previously described culture technique for the midgestational fetal porcine pancreas, islet-like cell clusters with a Beta-cell frequency of approximately 5% have been produced in large numbers. These islet-like cell clusters were transplanted beneath the kidney capsule to either normoglycaemic or alloxan-treated nude mice. The grafts consistently failed to cure the alloxan-treated mice immediately after implantation, however, normoglycaemia was restored in a majority of the mice within 2 months after transplantation and in all animals after 4 and 6 months. Indeed, the insulin released from the transplanted fetal Beta cells was able to normalize the serum glucose concentration at porcine levels (4-5 mmol/l) rather than at the level maintained in mice (8-10 mmol/l). In the cured mice there was a normal secretory response to glucose in the grafts as evidenced by normal glucose profiles during intravenous glucose tolerance test and a biphasic insulin response to high glucose when perfusing the graft bearing kidney. On the other hand, in the normoglycaemic animals the second phase faded before the glucose stimulus had been withdrawn. Two months after transplantation the edocrine cells were arranged so that the endocrine non-Beta cells were randomly scattered among a majority of Beta cells. The cell replication of the Beta cells, measured by H-thymidine incorporation, was within the lower range of that seen in the native islets of adult mice. No major differences between the controls and the alloxan-treated animals were observed in this respect. Cultured islet-like cell clusters had high rates of glucose utilization, paralleled by low rates of glucose oxidation, compared with adult mouse islets. Following transplantation there was a progressive decrease in glucose utilization and an increase in glucose oxidation. It is concluded that after transplantation the epitheloid cells comprising the porcine islet-like cell clusters can develop into insulin-producing cells with the ability to cure diabetic nude mice. Provided the rejection problems can be overcome the fetal porcine pancreas may be suitable for future clinical xenogeneic transplantations. [ABSTRACT FROM AUTHOR]

Published
1991
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223. Large-Scale Comparison of Liberase HI and Collagenase NB1 Utilized for Human Islet Isolation

Author

Brandhorst, H., Friberg, A., Nilsson, B., Andersson, H. H., Felldin, M., Foss, A., Salmela, K., Tibell, A., Tufveson, G., Korsgren, O., and Brandhorst, D.

Abstract

For more than a decade Liberase HI was commonly used as the standard enzyme blend for clinical human islet isolation until enforced replacement by collagenase NB1 (NB1). This change resulted initially in a reduction in islet isolation outcome and transplant activities worldwide. This retrospective study was initiated to compare the efficiency of NB1 premium grade with Liberase in 197 human islet isolations. All pancreata were processed between January 2006 and June 2008 utilizing the same procedures for isolation and quality assessment except the administration of preselected lots of either Liberase (n= 101) or NB1 (n= 96). Utilizing Liberase, significantly more digested tissue and purified islet yield was produced compared to NB1. In contrast, the use of NB1 was associated with significantly higher purity and glucose stimulation index during dynamic perifusion. The expression of proinflammatory markers was almost identical except tissue factor expression, which was higher after utilization of Liberase. No difference was found in the percentage of pancreata fulfilling the criteria for clinical islet transplantation. The results suggest that Liberase is more efficient for pancreas dissociation than collagenase NB1 but seems to be more harmful to exocrine cells and islet tissue.

Published
2010
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224. Positron Emission Tomography in Clinical Islet Transplantation

Author

Eriksson, O., Eich, T., Sundin, A., Tibell, A., Tufveson, G., Andersson, H., Felldin, M., Foss, A., Kyllönen, L., Langstrom, B., Nilsson, B., Korsgren, O., and Lundgren, T.

Abstract

The fate of islets in clinical transplantation is unclear. To elude on this positron emission tomography combined with computed tomography (PET/CT) was performed for 60 min during islet transplantation in five patients receiving six transplants.

Published
2009
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225. Pig Pancreas Oxygenation at 20°C Increases Islet ATP Generation but Deteriorates Islet Function

Author

Iken, M., Brandhorst, H., Korsgren, O., and Brandhorst, D.

Abstract

Successful pancreas preservation during storage in oxygenated perfluorodecalin (PFD) is mainly related to oxidative ATP generation during storage. Increasing the storage temperature would accelerate this process essential for resuscitation of ischemically damaged pancreatic tissue. The present study aimed at comparing islet isolation outcome from adult pig pancreata preserved in oxygenated PFD by means of a one-layer method during storage on ice or at 20°C. Resected pancreata were intraductally flushed with cold UW solution and promptly processed (n= 6) or stored for 3 h in continuously oxygenated PFD at 4°C (n= 5) or 20°C (n= 7). Prior to digestion-filtration pancreata were intraductally injected with UW supplemented with Serva collagenase NB8 and neutral protease. Islet quality assessment determined viability, glucose stimulation index, mitochondrial activity, intracellular ATP content, and transplant function in diabetic nude mice. Pancreata oxygenated for 3 h at 20°C yielded islet numbers similar to organs oxygenated at 4°C. Compared to a storage temperature of 20°C, preservation at 4°C reduced islet ATP content (p< 0.05) as well as islet viability (p< 0.05). Nevertheless, PFD storage at 20°C decreased insulin response to glucose compared to unstored pancreata (p< 0.05). In contrast to unstored pancreata or cold-stored organs, transplantation of islets isolated after oxygenation at 20°C was characterized by an early loss of transplant function in 50% of recipients (p< 0.05). The present study demonstrates that PFD storage at 20°C enhances islet ATP synthesis within a short period of oxygenation but deteriorates islet function. We conclude that the present data reflect an equilibration between reduced depression of metabolic activity resulting in damage of islets and temperature-stimulated acceleration of ATP synthesis. Future studies are required to adjust the optimum storage temperature for pancreas oxygenation in different species.

Published
2009
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226. Human Islet Separation Utilizing a Closed Automated Purification System

Author

Friberg, A. S., Ståhle, M., Brandhorst, H., Korsgren, O., and Brandhorst, D.

Abstract

A central step within the human islet isolation process is the separation of islets from contaminating exocrine tissue utilizing linear, continuous density gradients manufactured by means of manually controlled standard gradient makers (SGM). The present study was performed to develop a closed, automated purification system (APS) that customizes density gradient profiles aiming to standardize and optimize human islet purification. Digested human pancreata were pooled, split evenly, and incubated in UW solution according to our standard protocol (n = 11). Continuous density gradient centrifugation was performed in parallel in two refrigerated COBE 2991 cell separators loaded with light (1.076 g/ml) and heavy (1.097 g/ml) Ficoll utilizing either an SGM or two computer-controlled pumps connected to Ficoll-containing bags. Quality control included islet equivalent (IE) yield, purity, in vitro function, and islet cytokine expression. Gradient profiles demonstrated that the APS readily customizes linear and nonlinear gradients. In comparison to the SGM, the APS recovered a higher percentage of the expected volume of continuous gradients (90.0 ± 1.1% vs. 98.2 ± 2.0%, p < 0.05). Islet yield (120,468 ± 15,970 vs. 114,570 ± 15,313 IE, NS) and purity (51.7 ± 4.8% vs. 54.4 ± 4.9%, NS) were nearly identical utilizing the SGM or APS. Decreased MCP-1, IL-6, and IL-8 expression indicated that APS-purified islets were possibly exposed to less proinflammatory stress. Compared to standard procedures, similar success and gentle continuous density gradient separation of human islets is feasible utilizing the APS. The APS facilitates the standardization of this complex procedure according to cGMP standards.

Published
2008
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227. Intramuscular Autotransplantation of Pancreatic Islets in a 7-Year-Old Child: A 2-Year Follow-Up

Author

Rafael, E., Tibell, A., Rydén, M., Lundgren, T., Sävendahl, L., Borgström, B., Arnelo, U., Isaksson, B., Nilsson, B., Korsgren, O., and Permert, J.

Abstract

A 7‐year‐old girl with severe hereditary pancreatitis underwent total pancreatectomy. A total of 160 000 islet equivalents (6400 islet/kg) were transplanted to the brachioradialis muscle of the right forearm. Her plasma C‐peptide level was undetectable after pancreatectomy but increased to 1.37 ng/mL after 17 days; at this time point, her insulin requirement was 0.75 units of insulin/kg/day. At 5‐ and 27‐months, her hemoglobin A1c (HbA1c) and insulin requirements were 4.5 and 5.3% and 0.3 and 0.18 units/kg/day, respectively. Basal and stimulated C‐peptide levels were 0.67 ± 0.07 and 3.36 ± 1.37 ng/mL, respectively. Stimulated insulin levels were 30% higher in the islet‐bearing arm compared to the contralateral arm after glucagon stimulation. After surgery and islet transplantation, the quality of life improved dramatically and she gained 8 kg of weight. In summary, a normal HbA1c, a low insulin requirement and the absence of recurrent hypoglycemia and the gradient of insulin between the arms indicate that the intramuscularly transplanted islets contribute to a long‐term clinically significant metabolic control.

Published
2008
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228. Effects of Immunosuppressive Drugs on In Vitro Neogenesis of Human Islets: Mycophenolate Mofetil Inhibits the Proliferation of Ductal Cells

Author

Gao, R, Ustinov, J, Korsgren, O, and Otonkoski, T

Abstract

Assuming that neogenesis contributes to long-term function of islet grafts, it is important to study the effects of immunosuppressive drugs on precursor cell proliferation and differentiation. We examined the effects of low-dose immunosuppressive drugs on these processes in vitroImmunosuppressive drugs, including sirolimus, tacrolimus, mycophenolate mofetil (MMF), daclizumab and their combinations were tested in parallel culture wells through either the expansion phase (5–7 days) or the entire culture period (4–5 weeks). MMF, alone or in combination with sirolimus or tacrolimus, severely hampered duct-cell proliferation by 8-fold during the expansion period, and significantly reduced the total DNA content by about 40% after 5-week culture. After 4–5 week exposure to different drugs, only sirolimus and daclizumab showed no adverse effects on insulin content, whereas significant reductions of 30–60% in insulin content were seen in all other experimental groups. Only tacrolimus decreased the insulin content per DNA, as well as the proportion of insulin-positive cells. In conclusion, MMF has a potent inhibitory effect on neogenesis primarily through an antiproliferative effect on the precursors, whereas tacrolimus mainly affects beta-cell differentiation. Sirolimus and daclizumab have no adverse effects on these parameters. The immunosuppressive protocol may be an important determinant of long-term clinical islet graft function.

Published
2007
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229. Effects of Immunosuppressive Drugs on In VitroNeogenesis of Human Islets: Mycophenolate Mofetil Inhibits the Proliferation of Ductal Cells

Author

Gao, R., Ustinov, J., Korsgren, O., and Otonkoski, T.

Abstract

Assuming that neogenesis contributes to long-term function of islet grafts, it is important to study the effects of immunosuppressive drugs on precursor cell proliferation and differentiation. We examined the effects of low-dose immunosuppressive drugs on these processes in vitro. Immunosuppressive drugs, including sirolimus, tacrolimus, mycophenolate mofetil (MMF), daclizumab and their combinations were tested in parallel culture wells through either the expansion phase (5-7 days) or the entire culture period (4-5 weeks). MMF, alone or in combination with sirolimus or tacrolimus, severely hampered duct-cell proliferation by 8-fold during the expansion period, and significantly reduced the total DNA content by about 40 after 5-week culture. After 4-5 week exposure to different drugs, only sirolimus and daclizumab showed no adverse effects on insulin content, whereas significant reductions of 30-60 in insulin content were seen in all other experimental groups. Only tacrolimus decreased the insulin content per DNA, as well as the proportion of insulin-positive cells. In conclusion, MMF has a potent inhibitory effect on neogenesis primarily through an antiproliferative effect on the precursors, whereas tacrolimus mainly affects beta-cell differentiation. Sirolimus and daclizumab have no adverse effects on these parameters. The immunosuppressive protocol may be an important determinant of long-term clinical islet graft function.

Published
2007
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230. The ADP/ATP Ratio: A Novel Predictive Assay for Quality Assessment of Isolated Pancreatic Islets

Author

Goto, M., Holgersson, J., Kumagai-Braesch, M., and Korsgren, O.

Abstract

The current standard assays for islet product release criteria are unable to predict the outcome after clinical islet transplantation. Therefore, establishment of reliable and rapid assays enabling pre-transplantation prediction of islet potency is warranted. In the present study, we have evaluated the adenosine diphosphate (ADP)/adenosine triphosphate (ATP) test, the glucose-stimulated insulin release, the loss of islets during the first 24 h in culture, and the insulin/deoxyribonucleic acid as predictive assays for the ability of isolated porcine islets to cure athymic mice with streptozotocin-induced diabetes. From the results presented, it is concluded that the measurement of the ADP/ATP ratio was the only test that correlated with transplantation outcome. In summary, we propose that the ADP/ATP assay is worthwhile as applied to human islet transplantation and seek to validate it as a rapid and potent predictor of transplant outcome.

Published
2006

231. Low Molecular Weight Dextran Sulfate: A Strong Candidate Drug to Block IBMIR in Clinical Islet Transplantation

Author

Johansson, H., Goto, M., Siegbahn, A., Elgue, G., Korsgren, O., and Nilsson, B.

Abstract

The instant blood-mediated inflammatory reaction (IBMIR) is triggered in clinical islet transplantation when human pancreatic islets come in contact with blood and may explain the initial tissue loss associated with this procedure. Low molecular weight dextran sulfate (LMW-DS; MM 5000), today available for clinical use, inhibits both complement and coagulation activation. In a tubing loop model, LMW-DS at concentrations ranging from 0.01 to 1 g/L showed a dose-dependent inhibition of IBMIR with an inhibition of coagulation and complement activation and less consumption of platelets and other blood cells. In blood or plasma APTT was demonstrated to be an excellent method for monitoring the LMW-DS concentration both in vitro and in vivo in a nonhuman primate model. The toxicity was assessed using a glucose challenge test and the pharmacokinetics was tested in the nonhuman primate model. Here, we present a tentative protocol for using LMW-DS in clinical islet transplantation.

Published
2006
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232. IMPORTANCE OF THE GAL 1–3 GAL ANTIGEN IN DISCORDANT ISLET XENOTRANSPLANTATION IMMUNOSUPPRESSION, WHICH INHIBITS PORCINE ISLET XENOGRAFT REJECTION IN ORDINARY MICE, IS EQUALLY EFFECTIVE IN GAL-KNOCKOUT MICE

Author

WENNBERG, L., SONG, Z., BENNET, W., SANDBERG, J. O., SUNDBERG, B., THALL, A., and KORSGREN, O.

Abstract

Islet xenotransplantation will most likely be performed in diabetic patients treated with immunosuppressive drugs. The importance of the galactosyl alpha(1–3) galactose (Gal1–3Gal) antigen in immunosuppressed islet xenograft recipients has not been studied.

Published
2004
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233. Interleukin-6 in islet xenograft rejection

Author

Benda, Birgitta and Korsgren, O.

Abstract

Abstract: Earlier work on primate cardiac xenotransplantation has demonstrated a correlation between interleukin (IL)-6 levels and severity of vascular rejection. IL-6 was originally identified as a lymphokine inducing final maturation of B lymphocytes into antibody-secreting cells. The present study aimed to evaluate the role of IL-6 in fetal porcine islet-like cell cluster (ICC) xenograft rejection. Moreover, other authors have reported that eosinophils dominate the cellular response following discordant islet xenograft transplantation. Here, a technique for specific detection of eosinophils was applied. IL-6-deficient mice and wild-type controls were implanted with fetal porcine ICCs under the kidney capsule and killed 4-, 7-, and 10 days after transplantation. Xenografts were histologically evaluated, and serum samples were analyzed for IgM and IgG antibodies against ICC membrane antigens. IL-6-deficient mice and wild-type controls readily rejected the xenograft. On day 7 after transplantation, abundant numbers of F4/80+ and Mac-1+ cells were found distributed throughout the collapsing graft accompanied by small amounts of eosinophils and peripherally accumulated CD3+ T cells (predominantly CD4+). Significantly lower serum levels of IgM and IgG antibodies against ICC membrane antigens were observed in IL-6-deficient mice on day 4 or 7 after transplantation when compared to wild-type controls. No significant differences were seen on day 10 after transplantation. In both experimental groups, specific IgM and IgG antibody levels remained stable over time. In the pig-to-mouse model, IL-6 seems to be of minor importance to fetal porcine ICC xenograft rejection. Macrophages, and not eosinophils, dominate the cellular response associated with this process.

Published
2001
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234. Neural Tissue Xenotransplantation: What is Needed Prior to Clinical Trials in Parkinson's Disease?

Author

Barker, Roger A., Kendall, A. Lisa, Widner, Håkan, Widner, H., Larsson, L., Czech, K. A., Anderson, P., Mirza, B., Dunnett, S. B., Kendall, A. L., Annett, L.E., Barker, R., Torres, E., Rosser, A. E., Watts, C., Zimmer, J., Finsen, B. R., Dahl-Jørgensen, A., Pedersen, E. B., Brevig, T., Meyer, M., Holgersson, J., Korsgren, O., Breimer, M., Gjedde, A., and Danielsen, E.

Abstract

Embryonic allografted human tissue in patients with Parkinson's disease has been shown to survive and ameliorate many of the symptoms of this disease. Despite this success, the practical problems of using this tissue coupled to the ethical restrictions of using aborted human fetal tissue have lead to an exploration for alternative sources of suitable material for grafting, including xenogeneic embryonic dopaminergic-rich neural tissue. Nevertheless, xenografted neural tissue itself generates a number of practical, ethical, safety, and immunological issues that have to be addressed prior to any clinical xenotransplant program. In this article we review these critical issues and set out the criteria that we consider need to be met in the development of our clinical xenotransplantation research programs. We advocate that these, or similar, criteria should be adopted and made explicit by other centers contemplating similar clinical trials.

Published
2000
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235. The diagnosis of insulitis in human type 1 diabetes.

Author

Campbell-Thompson, M., Atkinson, M., Butler, A., Chapman, N., Frisk, G., Gianani, R., Giepmans, B., Herrath, M., Hyöty, H., Kay, T., Korsgren, O., Morgan, N., Powers, A., Pugliese, A., Richardson, S., Rowe, P., Tracy, S., and In't Veld, P.

Published
2013
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236. Allogeneic and xenogeneic islets are rejected by different and specific mechanisms: A study in rodents using a mixed allogeneic‐xenogeneic islet transplantation model

Author

Wennberg, L., Rafael, E., Liu, J., Sundberg, B., Wernersson, A., and Korsgren, O.

Abstract

Abstract: Indirect evidence suggests that islet alio‐ and xeno‐graft rejections are two qualitatively, and not simply quantitatively, different processes. This, however, has never been clearly shown and a direct in vivo comparison of cell‐mediated alio‐ and xeno‐graft rejections has never been made. Therefore, Lewis rats were transplanted with either Wistar‐Furth rat islets or fetal porcine islet‐like cell clusters (ICC) under the kidney capsule. Other Lewis rats were transplanted with Wistar‐Furth rat islets and fetal porcine ICC, which were mixed together into one single graft. Animals were left untreated or were treated with cyclosporin A (CyA, 20 mg/kg b.w., p.o.) daily. Twelve days following transplantation, islet alio‐ and xeno‐graft survival was evaluated morphologically and any cellular infiltration into the grafts was characterized immunohistochemically. In untreated animals, both allogeneic and xenogeneic islets were destroyed by massive cellullar infiltration. The main infiltrating cells in islet allograft rejection were TCR a/(i‐positive T‐cells. In contrast, the main infiltrating cells in islet xenograft rejection were EDI‐ and ED2‐positive macrophages. In islet xenograft rejection, only a few T‐cells were found. In islet allografts removed from rats treated with CyA, many morphologically intact rat islets were found. Only a few infiltrating cells were detected and these were both EDI‐positive macrophages and TCR a/p‐positive T‐cells. In CyA‐treated rats transplanted with porcine ICC, we noted a massive infiltration with EDI‐ and ED2‐positive macrophages and TCR a/p‐positive T‐cells, similar to that observed in untreated animals. No endocrine cells were present. In mixed allogeneic‐xenogeneic islet grafts transplanted into CyA‐treated rats, many morphologically intact rat islets were found, as evidenced by positive staining for rat MHC class I. However, no porcine ICC remained. The xenogeneic islets in these mixed grafts were destroyed by massive cellular infiltration, similar to that observed after transplantation of xenogeneic islets alone. Obviously, the xenogeneic islets in these mixed grafts were rejected by a cell‐mediated process qualitatively different from that of cell‐mediated allograft rejection.

Published
1997
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237. Transplantation of porcine fetal pancreas to diabetic patients.

Author

Groth, C.G. and Korsgren, O.

Subjects
*TRANSPLANTATION of organs, tissues, etc., *TREATMENT of diabetes
Abstract

Examines the therapeutic value of the transplantation of porcine fetal pancreatic tissues to diabetic patients. Insufficiency of human tissue supply; Percutaneous kidney-core biopsies; Intraportal injection of islet-like cell clusters; Human islet transplantation.

Published
1994
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238. Evidence of xenograft function in a diabetic patient grafted with porcine fetal pancreas

Author

Cg, Groth, Korsgren O, Andersson A, Hellerström C, Bjöersdorff A, Tibell A, Tollemar J, Jan Bolinder, Ostman J, and Kumagai M

Subjects
Adult, Glycated Hemoglobin, C-Peptide, Swine, Transplantation, Heterologous, Antibodies, Heterophile, Kidney Transplantation, Diabetes Mellitus, Type 1, Immunoglobulin M, Fetal Tissue Transplantation, Animals, Humans, Diabetic Nephropathies, Female, Lymphocytes, Pancreas Transplantation, Immunosuppressive Agents

239. Immune response of diabetic patients against transplanted porcine fetal islet cells

Author

Kumagai Braesch M, Cg, Groth, Korsgren O, Andersson A, Hellerström C, Bjöersdorff A, Tibell A, Tollemar J, Jan Bolinder, and Ostman J

Subjects
Adult, Swine, Transplantation, Heterologous, Antibody-Dependent Cell Cytotoxicity, Islets of Langerhans Transplantation, Antibodies, Heterophile, Kidney Transplantation, Diabetes Mellitus, Type 1, Immunoglobulin M, Fetal Tissue Transplantation, Immunoglobulin G, Antibody Formation, Animals, Humans, Female

240. Transplantation of porcine fetal pancreas to a diabetic patient

Author

Korsgren O, Cg, Groth, Andersson A, Hellerström C, Tibell A, Tollemar J, Jan Bolinder, Ostman J, Kumagai M, and Möller E

Subjects
Adult, Diabetes Mellitus, Type 1, Treatment Outcome, Fetal Tissue Transplantation, Swine, Transplantation, Heterologous, Animals, Humans, Female, Pancreas Transplantation, Monitoring, Physiologic

242. 40 EASD Annual Meeting of the European Association for the Study of Diabetes : Munich, Germany, 5-9 September 2004

Author

Veitenhansl, M., Stegner, K., Hierl, F-X, Dieterle, C., Feldmeier, H., Gutt, B., Landgraf, R., Garrow, A. P., Vileikyte, L., Findlow, A., Waterman, C., Boulton, A. J. M., Shankhdhar, K., Shankhdhar, L., Shankhdhar, U., Petrova, N. L., Foster, A. V. M., Edmonds, M. E., Ferraresi, R., Caravaggi, C., Giglio, R., Cavaiani, P., Pogliaghi, I., Sommariva, E., Katz, I. A., Harlan, A., Miranda-Palma, B., Prieto-Sanchez, L., Armstrong, D. G., Bowker, J. H., Mizel, M. S., Cernea, S., Wohlgelernter, J., Kidron, M., Modi, P., Raz, I., Arbit, E., Nosek, L., Kapitza, C., Beckett, P., Gelfand, R., Goldberg, M., Heise, T., Testa, M. A., Turner, R. R., Hayes, J. F., Scranton, R. E., Simonson, D. C., Yang, Y-W, Hsu, Y-J, Naujok, O., Francini, F., Jorns, A., Tiedge, M., Lenzen, S., Abdel-Wahab, Y. H. A., Marenah, L., Orr, D. F., Shaw, C., Flatt, P. R., Chokkalingam, K., Mansell, P. I., Clausen, P., Ekbom, P., Damm, P., Feldt-Rasmussen, U., Nielsen, B., Mathiesen, E. R., Feldt-Rasmussen, B., Dewan, S., Da Silva, N., Ternan, P. Mc, Leong, K. S., Wilding, J. P. H., Asatiani, N., Kurashvili, R., Dundua, M., Shelestova, E., Pagava, K., Ramazashvili, M., Hod, M., Smirnov, S., Petersen, J. L. A., Justesen, T. I., Ringholm Nielsen, L., Muller, C., Hojlund, K., Wensaas, A., Kase, E. T., Aas, V., Rustan, A. C., Thoresen, G. H., Levin, K., Beck-Nielsen, H., Gaster, M., Im, S-S, Kang, S-Y, Kim, S-Y, Ahn, Y-H, Lihn, A. S., Schmoll, D., Werner, T., Kienitz, A., Meyer, M., Barthel, A., Ailett, F., Sutherland, C., Walther, R., Grempler, R., Sasson, S., Reich, R., Tenenbaum, T., Alpert, E., Anfossi, G., Russo, I., Traversa, M., Massucco, P., Mattiello, L., Doronzo, G., Trovati, M., Lally, S., Tan, C. Y., Owens, D., Tomkin, G. H., Porchay, I., Pean, F., Bellili, N., Betoulle, D., Balkau, B., Tichet, J., Marre, M., Fumeron, F., Group D.E.S.I.R., Chatellier, G., Alhenc-Gelas, F., Diabhycar, Study Group, Nichols, G. A., Brown, J. B., Hayes, R. P., Bowman, L., Drexel, H., Saely, C. H., Marte, T., Benzer, W., Langer, P., Hoefle, G., Moll, W., Aczel, S., Karagiannis, E., Lubben, G., Urquhart, R., Edwards, G., Bruce, S., Howlett, H. S. C., Cugnardey, N., Turner, K. C., Park, J-S, Fiedorek, F. T., Avogaro, A., Gallo, A., Pinton, P., Rizzuto, R., Murphy, E., Ceolotto, G., Caterson, I., Guy-Grand, B., Hill, J., Barone, M., Aiello, A., Allochis, G., Borzi, V., Cannata, F., Caronna, S., D Avanzo, A., Elli, R., Formoso, G., Paroli, A., Scardapane, R., Sorichetti, P., Tatti, P., Viviani, G., Santeusanio, F., Italian Repaglinide Study Group, Manzella, D., Grella, R., Abbatecola, A. M., Paolisso, G., Sondergaard, L. G., Monster, T. B. M., Johnsen, S. P., Olsen, M. L., Mclaughlin, J. K., Sorensen, H. T., Lervang, H. H., Rungby, J., Lyssenko, V., Fredriksson, J., Almgren, P., Anevski, D., Orho-Melander, M., Sjogren, M., Tuomi, T., Groop, L., Jaziri, R., Aubert, R., Tuomilehto, J., Hu, G., Jousilahti, P., Peltonen, M., Lindstrom, J., Laina, A., Alevizaki, M., Philippou, G., Souvatzoglou, A., Anastasiou, E., Alba, S., Metcalf, B. S., Voss, L. D., Jeffery, A. N., Wilkin, T. J., Gluimer, C., Colagiuri, S., Vistisen, D., Borch-Johnsen, K., Haynes, A., Bower, C., Bulsara, M. K., Jones, T. W., Davis, E. A., Mortensen, H. B., Hougaard, P., Holl, R., Swift, P., Pociot, F., Knip, M., Hansen, L., Szadkowska, A., Pietrzak, I., Zmyslowska, A., Wyka, K., Bodalski, J., Holl, R. W., Swift, R., Hougaard, R., Gerstl, E-M, Engelsberger, I., Rabl, W., Rosenbauer, J., Grobe, H., Hofer, S. E., Krause, U., DPV-Wiss-Study Group, Dabelea, D., Morgan, T., Pettitt, D. J., Dolan, L., Mayer-Davis, E. J., Pihoker, C., Hillier, T. A., Imperatore, G., Ruggiero, A., Hamman, R. E., Stylianou, A., Tentolouris, N., Perrea, D., Tselepis, A. D., Lourida, E., Kitsou, E., Katsilambros, N., Vedovato, M., Dodesini, A. R., Lepore, G., Tiengo, A., Trevisan, R., Penno, G., Miccoli, R., Pucci, L., Lucchesi, D., Bandinelli, S., Fotino, C., Triscornia, S., Baldassari, E., Del Prato, S., Reboldi, P., Santeusanio, E., Fuller, J., Langham, R. G., Gow, R. M., Zhang, Y., Kelly, D. J., Christensen, P. K., Parving, H-H, Gilbert, R. E., Chibalin, A. V., Zhong, Z., Kotova, O., Davidescu, A., Ehren, I., Ekberg, K., Wahren, J., Wassef, L., Buckley, A. J., Rooney, K. B., Briody, J., Thompson, M., Ozanne, S. E., Thompson, C. H., Chamson-Reig, A., Summers, K., Arany, E. J. R., Hill, D. J., Solerte, S. B., Gazzaruso, C., Locatelli, E., Precerutti, S., Schifino, N., Ferrari, E., Fioravanti, M., Phenekos, C. V., Ginis, A., Fragaki, I., Chalkiadaki, M., Tzioras, C., Powell, L. A., Mcguire, G. M., Jewhurst, V., Trimble, E. R., Rasmussen, B. M., Vessby, B., Uusitupa, M., Berglund, L., Pedersen, E., Riccardi, G., Rivellese, A. A., Tapsell, L., Hermansen, K., Kanwu, Study Group, Da Silva Xavier, G., Rutter, J., Rutter, G. A., Briaud, I. M., Lingohr, M. K., Dickson, L. M., Mccuaig, J. R., Lawrence, J. C., Rhodes, C. J., Wikstrom, J. D., Katzman, S. M., Shirihai, O. S., Yang, J., Deng, S., Wang, X., Hessner, M. J., Wu, J., Wong, R. K., Sukumvanich, S., Markman, J. F., Naji, A., Wolf, B. A., Gao, Z., Rubi, B., Del Arco, A., Satrustegui, J., Maechler, P., Del Guerra, S., Lupi, R., Bugliani, M., Sbrana, S., Torri, S., Boggi, U., Vistoli, F., Mosca, F., Marchetti, P., Rennings, A. J. M., Smits, P., Stewart, M. W., Tack, C. J. J., Li, L., Nystrom, T., Gutniak, M., Ahren, B., Holst, J., Sjoholm, A., Gomes, M. B., Cailleaux, S., Tibirica, E., Albertini, J-P, Chen, H., Mather, R., Valensi, P. E., Chisalita, S. I., Arnqvist, H. J., Kraenkel, N., Adams, V., Linke, A., Gielen, S., Schuler, G., Humbrecht, R., Cipollone, F., Iezzi, A., Fazia, M., Pini, B., Cucurullo, C., Cesare, D., Schmidt, A. M., Mazurek, T., Zang, L. F., Mannion, J., Diehl, J., Martin, J., Martella, A., Zalewski, A., Shi, Y., Otter, W., Winter, M., Doering, W., Standi, E., Schnell, O., Kragelund, C., Kober, L., Faber, J., Hildebrandt, P., Steffensen, R., Pankowska, E., Szypowska, A., Lipka, M., Herwig, J., Scholl-Schilling, G., Bohles, H., Robertson, K. J., Schonle, E., Gucev, Z., Mordhorst, L., Tamer, S. C., Gall, M-A, Ludvigsson, J., Hoogma, R. P. L., Hammond, P. J., Gomis, R., Kerr, D., Bruttomesso, D., Bouter, P., Wiefels, K. J., La Calle, H., Schweitzer, D. H., Pfohl, M., Torlone, E., Krinelke, L. G., 205-Nations Study Group, Conget, I., Storms, F., Rodriguez, J., Leperlier, C., Davies, M., At Lantus, Study Group, Peter, R., Luzio, S. D., Dunseath, G., Miles, A., Hare, B., Backx, K., Pauvaday, V., Owens, D. R., Caselli, A., Marfia, G. A., Battista, C., Veves, A., Spallone, V., Uccioli, L., Gonzalez, J. S., Peyrot, M. F., Rubin, R. R., Leventhal, H., Scheffler, N., Ulbrecht, J. S., Cavanagh, P. R., Boulton, A. J., Perrin, N. A., Oglesby, A., Bastyr, E. J., Ziegler, D., Siekierka-Kleiser, E., Meyer, B., Schweers, M., Selvarajah, D., Wilkinson, I. D., Emery, C. J., Shaw, P. J., Griffiths, P. D., Tesfaye, S., Obrosova, I. G., Arezzo, J., Phillips, K., Fidarestat Study Group, Gribble, F. M., Williams, L., Reimann, F., Iakoubov, R., Whiteside, C., Brubaker, P. L., Acitores, A., Gonzalez, N., Sancho, V., Valverde, I., Villanueva-Penacarrillo, M. L., Martin-Duce, A., Trigo, M. V., Arnes, L., Burkart, V., Ichino, N., Ohashi, A., Klein, B. S., Paxian, S., Schmid, R., Karlsen, A. E., Heding, P. E., Frobose, H., Ronn, S. G., Kruhoffer, M., Orntoft, T. F., Nerup, J., Mandrup-Poulsen, T., Billestrup, N., Cardozo, A. K., Ortis, F., Feng, Y-M, Rasschaert, J., Eylen, F., Storling, J., Herchuelz, A., Eizirik, D. L., Wang, H., Kouri, G., Wollheim, C. B., Ribaux, P., Hammar, E., Parnaud, G., Rouiller, D., Bosco, D., Halban, P., Midthjell, K., Carlsson, S., Grill, V., Lau, C., Farch, K., Glumer, C., Tetens, I., Jorgensen, T., Tillin, T., Forouhi, N., Mckeigue, P., Chaturvedi, N., Zethelius, B., Hales, C. N., Berne, C., Coleman, R. L., Stevens, R. J., Holman, R. R., Christensen, J. O., Sandbak, A., Lauritzen, T., Irwin, N., Gault, V. A., Green, B. D., Harriott, P., O Harte, F. P. M., Bouman, S. D., Urso, B., Brand, C. L., Rolin, B., Ribel, U., Schaffer, L., Maggs, D. G., Ceriello, A., Frias, J. P., Wang, Y., Ruggles, J. A., Kolterman, O. G., Piconi, L., Weyer, C., Want, L. L., Ratner, R. E., Uwaifo, G. I., Thornberry, N. A., Eiermann, G., Kim, D., Lankas, G., Leiting, B., Li, Z., Lyons, K., Petrov, A., Sinha Roy, R., Woods, A., Woods, J., Zhang, B. B., Fisher, M., Moller, D. E., Weber, A. E., Dreyer, M., Bellin, C., Schmitz, V., Roesen, R., Nescheret, A. P., Bose, A. K., Mocanu, M. M., Carr, R. D., Yellon, D. M., Manolopoulos, K., Born, S., Wagner, A., Jeziorska, M., Ben Drief, A., Bashir, M., Tomlinson, D., Malik, R. A., Zeymer, U., Schwarzmaier-D Assie, A., Petzinna, D., Chiasson, J-L, Stratton, I. M., Af Bjorkesten, C-G, Fagerudd, J., Rosengard-Barlund, M., Forsblom, C., Pettersson-Fernholm, K., Waden, J., Saraheimo, M., Ronnback, M., Thorn, L., Groop, P-H, Mollsten, A., Svensson, M., Kockum, I., Rudberg, S., Brismar, K., Dahlquist, G., Hovind, P., Hansen, T. K., Tarnow, L., Thiel, S., Jensen, B. R., Flyvbjerg, A., Kankova, K., Hertlova, M., Krusova, D., Schwenke, S., Ott, J., Thom, S. A. M., Mistry, P., Sjolie, A., Larsen, B., Witt, N., Hughes, A. D., Samira, H. H., Lahiry, S., Howlader, S. R., Parveen, S., Azad Khan, A. K., Clarke, P. M., Gray, A., Stevens, R., Holman, R., Phillips, L., Phillips, P. J., Chittleborough, C., Baldock, K., Taylor, A., North West Adelaide Health Study Team, Davis, W. A., Davis, T. M. E., Knuiman, M. W., Hendrie, D., Worthley, D., Nicolucci, A., Pellegrini, F., Berardis, G., Franciosi, M., Belfiglio, M., Rossi, M. C. E., Sacco, M., Valentini, M., Richardson, C. C., Jones, P., Persaud, S., Hussain, K., Clark, A., Christie, M. R., Gniuli, D., Hribal, M. L., Accili, D., Khan, M., Zervou, S., Cheung, L., Abouna, S., Ifandi, V., Pelengaris, S., Luco, R. F., Ferrer, J., Ma, D., Shield, J. P. H., Dean, W., Leclerc, I., Knauf, C., Burcelin, R., Kelsey, G., Powers, A. C., Shostak, A., Ferrara, N., Poffenberger, G., Jerome, W. G., Brissova, M., Geloneze, S. R., Tambascia, M. A., Pareja, J. C., Chaim, E., Silveira, H. V., Geloneze, B., Ravikumar, B., Carey, P. E., Snaar, J. E., Dheelchand, D., Cook, D. B., Neely, D., Taylor, G., Morris, P. G., Taylor, R., Stears, A. J., Masding, M. G., Wootton, S. A., Sandeman, D. D., Klimes, I., Wein, S., Gasperikova, D., Ukropec, J., Wiernsperger, N., Sebokova, E., Manco, M., Mingrone, G., Granato, L., Greco, A. V., Nanni, G., Castagneto, M., Vidal, H., Calvani, M., Ferrannini, E., Alvarsson, M., Sundkvist, G., Lager, I., Henricsson, M., Berntorp, K., Fernqvist-Forbes, E., Steen, L., Orn, T., Shutler, S., Bianchi-Biscay, M., Rosenstock, J., Sugimoto, D., Strange, P., Stewart, J., Soltes Rak, E., Dailey, G., Kloos, C., Muller, U., Samann, A., Femerling, M., Risse, A., Jecht, M., Haak, T., Garg, R., Lawrence, I. G., Akinsola, M. O., Davies, M. J., Mcnally, P. G., Garber, A. J., Kim, H., Draeger, E., Aydin, L., Sengul, A., Kurklu, A., Ucak, S., Basat, O., Seber, S., Altuntas, Y., Jin, J., Yu, Y., Yu, H., Zhang, X., Mattoo, V., Eckland, D., Widel, M., Duran, S., Fajardo, C., Strand, J., Knight, D., Oakley, D., Tan, M., Sato, A., Nagao, M., Aki, N., Nakagami, T., Iwamoto, Y., Zhou, Z., Li, X., Huang, G., Yan, X., Yang, L., Peng, J., Wang, J., Tan, S., Tang, W., Furnsinn, C., Brunmair, B., Wagner, L., Gras, F., Artwohl, M., Zierhut, B., Waldhausl, W., Shine, B. L., Hopkins, D., Anand, V., Lim, E., Raval, U., Sharp, P., Corder, R., Lipkin, D., Lahiri, A., Bartnik, M., Ryden, L., Ferrari, R., Malmberg, K., Pyorala, K., Simoons, M. L., Standl, E., Soler-Soler, J., Ohrvik, J., Euro Heart Survey Investigators, Bruce, D. G., Starkstein, S. E., Schauer, U. J. W., Astrup, A. S., Pietraszek, L., Nielsen, F. S., Rossing, P., Ali, S., Smidt, U. M., Yokoyama, H., Pavkov, M. E., Knowler, W. C., Bennett, P. H., Nelson, R. G., Lopez-Alba, A., Morcillo, L., Caballero, A., Montoya, L., Jimenez, A., Maceira, B., Lewis, J. B., Ravid, M., Wajman, A., Tadgell, C., Remuzzi, G., Hunsicker, L. G., Wessman, M., Taskinen, M-R, FinnDiane Study Group, Pugliese, G., Amadio, L., Menini, S., Oddi, G., Ricci, C., Iacobini, C., Pricci, F., Sorcini, M., Pesce, C., Migliaccio, E., Giorgio, M., Pelicci, P., Di Mario, U., Lassila, M., Jandeleit-Dahm, K., Seah, K. K., Calkin, A. C., Allen, T. J., Cooper, M. E., Lopes Faria, J. M., Cavakcanti, T. C., Silva, K. C., Ferrari, A. L., Lopes Faria, J. B., Cellek, S., Foxwell, N. A., Cotter, M. A., Cameron, N. E., Tennagels, N., Jordan, H., Stahl, P., Voss, M. D., Welte, S., Werner, U., Lehmann, R., Moeschel, K., Baumgartner, F., Oeckinghaus, A., Beck, A., Weigert, C., Hennige, A., Schleicher, E. D., Haring, H. U., Mussig, K., Staiger, H., Haring, H-U, Natalicchio, A., Laviola, L., Tullio, C., Renna, L., Giorgino, R., Giorgino, F., Falasca, M., Maffucci, T., Park, D., Kang, S., Song, J., Lee, D., Lee, Y., Hariharan, N., Kunselman, L., Gu, L., Sasseville, V., Harrity, T., Cheng, P. T. W., Pratley, R. E., Schweizer, A., Mills, D., Kim, T-H, Song, X-L, Poelje, P. D., Potter, S. C., Dang, Q., Fujitaki, J. M., Linemeyer, D. L., Landau, B. R., Erion, M. D., Pankop, M., Golay, A., Despres, J., Sjostrom, L., Lawlor, D. L., Legg, K. T., Ur, E., Houweling, S. T., Kleefstra, N., Meyboom-De Jong, B., Bilo, H. J. G., Schlomer, G. J., Meyer, G., Kasper, J., Muhlhauser, I., Young, B., Taylor, J., Friede, T., Hollis, S., Mason, J., Long, A., Gambling, T., Pauline, L., Burns, E., New, J., Gibson, M., Betteridge, D. J., Leiter, L. A., Audit, Investigators, Whitty, P. M., Eccles, M. P., Hawthorne, G., Grimshaw, J., Steen, I. N., Vanoli, A., Wood, L., Speed, C., Mcdowell, D., Rewers, M., Maahs, D., Wadwa, R., Eckel, R., Tracy, R., Pfutzner, A., Strotmann, H-J, Schulze, J., Hohberg, C., Pahler, S., Forst, T., Ambery, P. D., Sydall, H., Cooper, C., Dennison, E., Sayer, A. Aihie, Barker, D., Phillips, D., Lalic, N. M., Ostojic, M., Lalic, K., Zamaklar, M., Jotic, A., Ilic, M., Rajkovic, N., Lukic, L., Milicic, T., Verges, B., Zeller, M., Steg, P. G., Beer, J. C., Brisard, C., Brindisi, M. C., Dentan, G., Laurent, Y., Janin-Manificat, L., Makki, H., Ravisy, J., Cottin, Y., Ajjan, R. A., Grant, P. J., Futers, T. S., Brown, J. M., Carter, A. M., Rasmussen, M. S., Bruun, J. M., Pedersen, S. B., Richelsen, B., Dietze-Schroeder, D., Sell, H., Koenen, M., Eckel, J., Delporte, M-L L., Bauche, I. B., Brichard, S. M., Ait El Mkadem, S., Rezsohazy, R., Tsiotra, P. C., Tsigos, C., Gatsiou, C., Raptis, S. A., Walker, C. G., Bryson, J. M., Hancock, D. P., Caterson, I. D., Takahashi, N., Hatakeyama, H., Kasai, H., Gauthier, B. R., Iezzi, M., Fukuda, M., Duhamel, D. L., Ravier, M. A., Dufer, M., Neye, Y., Krippeit-Drews, P., Hennige, A. M., Sausbier, U., Arntz, C., Sausbier, M., Neuhuber, W., Ruth, P., Drews, G., Beauvois, M. C., Rolland, J-F, Jonas, J-C, Merezak, C., Henquin, J-C, Gilon, P., Jabin Gustafsson, A., Dzabic, M., Islam, M. S., Vaxillaire, M., Cheyssac, C., Dina, C., Vasseur-Delannoy, V., Lepretre, F., Siddiq, A., Froguel, P., Neve, B., Fernandez-Zapico, M. E., Ashkenazi-Katalan, V., Urrutia, R., Melloul, D., Froguel, R., Poulsen, P., Wojtaszewski, J., Richter, E., Vaag, A., Granhall, C., Renstrom, E., Luthman, H., Isomaa, B., Gloyn, A. L., Edghill, E. L., Pearson, E. R., Mackay, D. J. G., Temple, I. K., Noyes, K., Freedenberg, D., Gillespie, K. M., Lambert, A. P., Gale, E. A., Ellard, S., Hattersley, A. T., Fanelli, C. G., Porcellati, F., Rossetti, P., Busciantella, N. R., Billi, C., Burrin, D. G., Bolli, G. B., Bingham, E. M., Dunn, J., Sutcliffe-Goulden, J., Marsden, P., Amiel, S., Davis, R. E., Kennedy-Martin, T., Peters, J. R., Wittrup-Jensen, K. U., Mcewan, P., Morrissey, M., Currie, C. J., Akram, K., Pedersen-Bjergaard, U., Thorsteinsson, B., Pibernik-Okanovic, M., Peros, K., Begic, D., Szabo, S., Metelko, Z., Vlaiculescu, M. V., Calota, I., Busila, T., Bruckner, I., Giannakopoulou, D. F., Lindner, H. D., Hrachovinova, T., Fejfarova, V., Csemy, L., Malcomson, J., Campbell, M., Pandolfi, A., Giardinelli, A., Di Tomo, P., Di Silvestre, S., Di Fulvio, P., Capani, F., Consoli, A., Roesen, P., Patruno, A., Grilli, A., Capani, R., Felaco, M., Boner, G., Mccarroll, K., Brenner, B. M., Zeeuw, D., Kowey, P., Shahinfar, S., Crow, R. S., Iso, K., Kuboki, K., Tada, H., Yoshino, G., Schjoedt, K. J., Andersen, S., Distiller, L. A., Degenhardt, T. P., Szabo, J. R., Khalifah, R. G., Schotzinger, R. J., Achenbach, P., Knopff, A., Naserke, H., Ziegler, A. G., Bonifacio, E., Valera, L., Jardin, B., Roche, S., Lampasona, V., Pugniere, M., Roquet, F., Granier, C., Laune, D., Afifiyan, F., Cheung, R., Yantha, J., Jackowski, G., Dosch, H-M, Nakanishi, K., Kogawa, N., Komatsu, Y., Fontes, G., Imamura, T., Ilic, C., Puech, C., Ktorza, A., Bataille, D., Dalle, S., Sorensen, H., Fosgerau, K., Gelling, R. W., Nishimura, E., Andersen, B., Madsen, P., Lau, J., Streicher, R., Wagner, K., Vettermann, R., Potterat, O., Renard, E., Panteleon, A. E., Kolopp, M., Rebrin, K., Steil, G., Steil, G. M., Hariri, F., Darwin, C., Saad, M. F., Buckingham, B., Kunselman, B., Wong, L., Istoc, E., Leach, J., Purvis, R., Monfre, S. L., Fischer, J. S., Garg, S., Ahmann, A. J., Ruchti, T. L., Gandhi, G. Y., Nuttall, G. A., Mullany, C. J., Schaff, H. 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243. Transplantation of porcine fetal islet-like cell clusters to three diabetic patients

Author

Andersson A, Cg, Groth, Korsgren O, Tibell A, Tollemar J, Kumagai M, Möller E, Jan Bolinder, Ostman J, and Bjöersdorff A

Subjects
Adult, C-Peptide, Platelet Count, Swine, Transplantation, Heterologous, Islets of Langerhans Transplantation, Fibrinogen, Alanine Transaminase, Kidney Transplantation, Diabetes Mellitus, Type 1, Fetal Tissue Transplantation, Animals, Humans, Insulin, Female, Aspartate Aminotransferases

246. Mesenchymal stromal cells support endothelial cell interactions in an intramuscular islet transplantation model

Author

Fransson Moa, Brännström Johan, Duprez Ida, Essand Magnus, Le Blanc Katarina, Korsgren Olle, and Magnusson Peetra U.

Subjects
Mesenchymal stromal cell, Islets of Langerhans, Transplantation, Endothelial cells, Medicine
Abstract

Background: Mesenchymal stromal cells (MSC) have been under investigation for a number of therapies and have lately been in focus as immunosuppressive actors in the field of transplantation. Herein we have extended our previously published in vitro model of MSC-islets in an experimental setting of islet transplantation to the abdominal muscle. Human islets coated with luciferase-GFP transduced human MSC were transplanted to the abdomen muscle tissue of NOD-scid ILR2γnull mice and cellular interactions were investigated by confocal microscopy. Result: The MSC reduced fibrotic encapsulation and facilitated endothelial cell interactions. In particular, we show a decreased fraction of αSMA expressing fibrotic tissue surrounding the graft in presence of MSC-islets compared to islets solely distributed into the muscle tissue. Also, in the presence of MSC, human islet endothelial cells migrated from the center of the graft out into the surrounding tissue forming chimeric blood vessels with recipient endothelial cells. Further, in the graft periphery, MSC were seen interacting with infiltrating macrophages. Conclusion: Here, in our experimental in vivo model of composite human islets and luciferase-GFP-transduced human MSC, we enable the visualization of close interactions between the MSC and the surrounding tissue. In this model of transplantation the MSC contribute to reduced fibrosis and increased islet endothelial cell migration. Furthermore, the MSC interact with the recipient vasculature and infiltrating macrophages.

Published
2015
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249. Photochemical pathogen inactivation of human serum enables its large-scale application in clinical cell transplantation.

Author

Ståhle, M., Carlsson, B., Le Blanc, K., Korsgren, O., and Knutson, F.

Subjects
TRANSPLANTATION of organs, tissues, etc., CELL culture, PHOTOCHEMICAL oxidants, PATHOGENIC microorganisms, CELLULAR therapy
Abstract

The article comments on a study, according to which, human serum provides a solution to regulatory problem in modern cell therapy and suggested for its safer use of products in clinical cell culture and transplantation. Thus, the termination of photochemical pathogen of human serum allows its large scale application in clinical cell transplantation. It also mentions that photochemical treatment of infection is shown to inactivate any pathogen of RNA and DNA origin.

Published
2010
Full Text
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