Dissertations / Theses: 'Islands of Langerhans – Transplantation'

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Ar'Rajab, Aamer. "Islet transplantation in the treatment of diabetes number of islets, functional regulation and metabolic control /." Lund : Dept. of Surgery, Lund University, 1991. http://catalog.hathitrust.org/api/volumes/oclc/38187937.html.

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Teague, Warwick J. "Mesenchyme-to-epithelial transition in pancreatic organogenesis." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670115.

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Wong, Jeffrey K. W. "Chemokines and chemokine receptors in islet xenograft rejection." Thesis, The University of Sydney, 2006. https://hdl.handle.net/2123/28055.

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This project investigates the role of chemokine and chemokine receptors in a model of CD4 T cell dependent cellular xenograft rejection, specifically the transplantation of fetal pig pancreas tissue to the renal subcapsular space of mice. Chemokines and chemokine receptor gene expression was assessed by cDNA arrays, and confirmed by multi-probe ribonuclease protection assay. Immunostaining for a selected chemokine, RANTES was performed to demonstrate upregulation at the protein level. These methods were applied to several different models to dissect the role Chemokines and their receptors in this process. Comparisons were made with: an allografi model, a model where indefinite xenograft survival could be achieved by short term costimulatory blockade with CTLA4-Fc and MR1, and an immunodeficient mouse recipient (RAG—1 KO, lacks B and T cells) that was reconstituted with either unfractionated leucocytes or purified CD4 T cells. The main findings were: 1. Allograft rejection and cellular xenografi rejection are THl type CD4 T cell dependent processes as shown by the common T cell chemokine genes (Ltn, IP-lO, and Mig) expressed in both models; however macrophages are the main effector cell in cellular xenografi rejection as evidenced by the selective upregulation of MCP-l and its receptor CCR2, as well as other macrophage markers 2. Of the Chemokines / receptors upregulated in this model of cellular xenograft rejection (Ltn, IP-lO, MCP-l, RANTES, MIP-lB, eotaxin) only MCP-l and IP-lO are CD4 T cell dependent, while Ltn expression is dependent upon a non-CD4 T cell leucocyte subset. 3. CTLA4-Fc and MR1 therapy resulted in indefinite fetal porcine islet survival and function in diabetic immune competent wild type C57BL/6 mice. This treatment suppresses the early upregulation of chemokines and chemokine receptors seen in untreated animals, and this corresponds with a significant reduction CD4 T cell and macrophage grafi infiltration at these time points, consistent with a role for select chemokine / receptors in the mechanism by which this therapy leads to indefinite graft survival. 4. In addition we studied the functioning of fetal porcine islet tissue in diabetic mice and found they developed and controlled glucose metabolism in a piglike manner, and different to normal mice, and thus conclude the development and function of fetal tissue in cross species transplantation is dependent upon the origins of the progenitor cells and not the xenogeneic environment i.e. nature not nurture (in this case anyway). We conclude that select chemokines and their receptors are important factors in the recruitment of effector cells mediating graft rejection in this model of cellular xenograft rejection and these chemokine pathways and networks may represent potential future therapeutic targets.

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Wang, Xiao Yang. "Approaches to induce islet allograft tolerance by liver allografting and to improve fetal pig islet function by gut hormones." Thesis, The University of Sydney, 1999. https://hdl.handle.net/2123/27740.

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This thesis examined (1) the effect of liver transplantation on tolerance induction to islet allografts; (2) the effects of gut hormones (CCK, GLP-1) on fetal pig islets. Liver allografts in tolerant strain combinations are unique in their ability to induce tolerance to other organ and skin grafts from the same donor strain in the absence of immunosuppression. Whether liver transplantation has the same effect on islet allografts is unknown. Studies in this thesis demonstrate that the protective effect of liver transplantation on islet allografts varies with the time of liver grafting. Islet allografts in the PVG —> DA combination were rapidly rejected. Rejection was delayed, but not prevented, when islets were transplanted simultaneously with the liver. Liver transplantation protected subsequently transplanted islet allografts from rejection and reversed ongoing rejection in previously placed islet grafts, in both cases leading to the tolerance of the islet allografts. There was a progressive increase of cell infiltration from day 2 to day 7 in both rejecting and tolerant islet allografts. The intensity of infiltration did not relate to the outcome of grafts. Islet rejection was characterised by an early dominance of monocytes/macrophages and CD25+ T cells in the infiltrate, a high incidence of apoptotic B cells in grafts, and a sensitised status in the MLR. Tolerance of islet allografts was associated with increased numbers of dendritic cells in the graft infiltrates, upregulation of FasL and prominent apoptosis of alloreactive leukocytes in the spleen and islet grafts, as well as donor-specific suppression in long—term survivors. It is suggested that islet allograft tolerance induced by liver transplantation is the result of an active immune regulation process which involves the deletion of donor-specific alloreactive lymphocytes by apoptosis. Transplantation of fetal pig pancreatic islets is capable of reversing diabetes in rodents, but several months are required to achieve this. During this time fetal [3 cells proliferate, differentiate and mature in their ability to secrete insulin when challenged with glucose. The study in Chapter 6 showed that CCK, GLP-l can induce the maturation and differentiation of fetal pig [5 cells during culture of fetal pig islet cell clusters (lCCs) in vitro. Two months after the ICCs were transplanted beneath kidney capsule of SCID mice, perfusion of the graft showed that ICCs previously exposed to CCK, GLP-1 for 4 days secreted insulin in response to glucose, whereas the control grafts remained glucose unresponsive. It is suggested that exposure of fetal pig lCCs to CCK, GLP-1 is likely to be advantageous in enhancing their ability to normalise blood levels when transplanted into diabetic recipients.

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Wilson, John Tanner. "Biomolecular strategies for cell surface engineering." Diss., Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/33846.

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Islet transplantation has emerged as a promising cell-based therapy for the treatment of diabetes, but its clinical efficacy remains limited by deleterious host responses that underlie islet destruction. In this dissertation, we describe the assembly of cell surface-supported thin films that confer molecular-level control over the composition and biophysicochemical properties of the islet surface with implications for improving islet engraftment. Specifically, the process of layer-by-layer (LbL) polymer self assembly was employed to generate nanothin films of diverse architecture with tunable properties directly on the extracellular surface of individual islets. Importantly, these studies are the first to report in vivo survival and function of nanoencapsulated cells, and have helped establish a conceptual framework for translating the diverse applications of LbL films to cellular interfaces. Additionally, through proper design of film constituents, coatings displaying ligands and bioorthogonally reactive handles may be generated, providing a modular strategy for incorporating exogenously derived regulators of host responses alongside native constituents of the islet surface. Towards this end, a strategy was developed to tether thrombomodulin to the islet surface in a site-specific manner, thereby facilitating local generation of the powerful anti-inflammatory agent, activated protein C. Collectively, this work offers novel biomolecular strategies for cell surface engineering with broad biomedical and biotechnological applications in cell-based therapeutics and beyond.

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Alves, Figueiredo Hugo Jorge. "Improving islet-graft revascularization." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/586309.

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El trasplante de islotes ha sido reconocido como una prometedora opción de tratamiento de la diabetes tipo 1 (DT1) tras la introducción del protocolo de Edmonton, el cual enfatiza el requerimiento de un adecuado número de islotes donantes así como el uso de regímenes de inmunosupresores libres de esteroides. Además es un procedimiento quirúrgico menos invasivo y que conlleva menos complicaciones comparado con el trasplante de páncreas. A pesar de los importantes avances establecidos por el protocolo de Edmonton, el uso clínico del trasplante de islotes para el tratamiento de pacientes DT1 continúa siendo limitado, debido en gran parte a los retos post-trasplante. Tras el trasplante, los islotes son separados de su red vascular nativa, por lo que la funcionalidad y supervivencia del injerto dependerá del restablecimiento de nuevos vasos en el injerto para derivar el flujo sanguíneo al sistema vascular del huésped. Sin embargo, los estudios han demostrado que el grado de revascularización de los islotes trasplantados es considerablemente menor que el de la microvasculatura nativa de los islotes pancreáticos, incluso a los 9 meses del injerto . Ésta retrasada y insuficiente revascularización priva los nuevos islotes injertados de oxígeno y nutrientes, pudiendo provocar su muerte celular y el fallo temprano del injerto. En el estudio realizado, identificamos, por primera vez, la proteína tirosina fosfatasa 1B (PTP-1B) como una diana terapéutica, capaz de mejorar la revascularización de los injerto pancreáticos sin comprometer la masa ß-celular del injerto y la principal mediadora de la acción del tratamiento del tungstato sódico en la revascularización de islotes. Además hemos identificado el mecanismo por lo cual la PTP-1B induce la revascularización. Nuestros datos apuntan que en la ausencia de PTP-1B, los islotes pancreáticos expresan y secretan el factor de crecimiento del endotelio vascular A (VEGFA), una citoquina pro-angiogénica, mediante la activación de la PGC1 alpha y ERR-alpha de forma independiente de hipoxia. Finalmente hemos comprobado que éste mecanismo de inducción de VEGFA se conserva en islotes humanos. De ésta forma concluimos que PTP-1B es una diana prometedora en el desarrollo de nuevas terapias para la mejora de la revascularización de injertos de islotes.
Islet transplantation is considered a potentially curative treatment for type 1 diabetes, Despite the key important advances achieved by the establishment of the Edmonton protocol, islet transplantation remains clinically limited due to several challenges, which lead to massive islet loss or failure of the grafts. Therefore searching for new targets to facilitate islet revascularization may lead to improved future results in cell transplantation.Islets native architecture is characterized by a dense vessel network that, delivers oxygen, hormones, glucose, and nutrients to islet’s cells allowing them to function correctly. After transplantation, the survival and function of islet grafts must depend on the reestablishment of new vessels within the grafts to derive blood flow from the host vascular system. This vascular network is severed when islets are isolated for transplantation, and even though islets freely revascularize, they do not reach the levels of vascularization present in endogenous pancreatic islets, which results in the impairment of grafts function and survival. Altogether, the lack of a proper vascular network account as the primary responsible for early graft loss. Although the molecular mechanisms underlying islet revascularization remain elusive, a number of factors have been implicated, such as the vascular endothelial growth factor A (VEGFA), a key angiogenic molecule that acts to stimulate new vessel formation. VEGFA expression in transplanted islets is significantly impaired, which is further pronounced in prevailing hyperglycemia, and coincides with delayed and insufficient islet revascularization in diabetic mice In this thesis we identify for the first time, tyrosine phosphatase PTP-1B as a target for improving graft revascularization. We targeted PTP-1B, either by its inhibition, following a sodium tungstate treatment after transplantation, or by transplanting islets lacking PTP-1B, using a genetic model of PTP-1B knock-out, or following genetic silencing, using siRNA and shRNA Lentivirus particles. Following transplantation into the anterior chamber of the eye in diabetic mice, islet-grafts showed increased revascularization by inducing the expression of VEGF-A by ß-cells in the graft. This improved revascularization was followed by an improvement of islet-graft survival and function, as transplanted mice recovered normoglycemia and glucose tolerance. Furthermore, we demonstrated that PTP-1B induces VEGF-A expression and secretion in islets by upregulating HIF1A-independent PGC1α/ERRα signaling. Finally, we demonstrated that this regulatory mechanism is conserved in human islets. Together, these findings unravel the potential role of PTP-1B as a target for improving islet transplantation outcomes.

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Phelps, Edward Allen. "Bio-functionalized peg-maleimide hydrogel for vascularization of transplanted pancreatic islets." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/45899.

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Type 1 diabetes affects one in every 400-600 children and adolescents in the US. Standard therapy with exogenous insulin is burdensome, associated with a significant risk of dangerous hypoglycemia, and only partially efficacious in preventing the long term complications of diabetes. Pancreatic islet transplantation has emerged as a promising therapy for type 1 diabetes. However, this cell-based therapy is significantly limited by inadequate islet supply (more than one donor pancreas is needed per recipient), instant blood-mediated inflammatory reaction, and loss of islet viability/function during isolation and following implantation. In particular, inadequate revascularization of transplanted islets results in reduced islet viability, function, and engraftment. Delivery of pro-vascularization factors has been shown to improve vascularization and islet function, but these strategies are hindered by insufficient and/or complex release pharmacokinetics and inadequate delivery matrices as well as technical and safety considerations. We hypothesized that controlled presentation of angiogenic cues within a bioartificial matrix could enhance the vascularization, viability, and function of transplanted islets. The primary objective of this dissertation was to enhance allogenic islet engraftment, survival and function by utilizing synthetic hydrogels as engineered delivery matrices. Polyethylene glycol (PEG)-maleimide hydrogels presenting cell adhesive motifs and vascular endothelial growth factor (VEGF) were designed to support islet activities and promote vascularization in vivo. We analyzed the material properties and cyto-compatibility of these engineered materials, islet engraftment in a transplantation model, and glycemic control in diabetic subjects. The rationale for this project is to establish novel biomaterial strategies for islet delivery that support islet viability and function via the induction of local vascularization.

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Clayton, Heather Anne. "The encapsulation and transplantation of islets of Langerhans." Thesis, University of Leicester, 1992. http://hdl.handle.net/2381/34306.

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Although several clinical human islet transplants have been performed, allograft rejection has been a major problem. Encapsulation in sodium alginate/poly-l-lysine has been proposed as a method to protect the islets from rejection and autoimmune destruction. The aims of this project were to determine optimum capsule composition and to assess encapsulated islet function following transplantation using the spontaneously diabetic BioBreeding (BB/d) rat as a model of autoimmune insulin-dependent diabetes. The membrane integrity of islets, determined by microfluorometry, was not adversely affected by encapsulation. During perifusion, the stimulation increase of encapsulated islets was decreased relative to controls, but the stimulation index and response time were unaffected. Capsule composition did not affect these results. The biocompatibility of the capsules was related to their composition. The presence of an outer layer of alginate, and the preparation of alginate used, reduced the severity of pericapsular fibrosis. Capsules implanted in the peritoneal cavity provoked a more severe response than those placed in the renal subcapsular space. BB/d rats displayed a marked response to the capsules. Transplantation experiments demonstrated that 3000 non-encapsulated or 5000 encapsulated islets were the minimum number required to reverse streptozotocin-induced diabetes when transplanted into the peritoneal cavity. An intense pericapsular fibrosis led to failure of the encapsulated grafts. Further transplants into the BB/d rat were postponed to allow the cause of fibrosis to be investigated. The alginate was found to be contaminated with protein and this was removed by dialysis. In vitro experiments with the dialysed alginate demonstrated that treatment of the alginate did not affect the viability of encapsulated islets. Biocompatibility studies showed that capsules coated with dialysed alginate remained free from pericapsular fibrosis, even in the BB/d rat, when tested over the time interval which had resulted in the development of severe fibrosis of capsules coated with untreated alginate.

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Koulmanda, Maria. "Transplantation of organ cultured foetal islets of Langerhans in mice." Thesis, University of Leicester, 1997. http://hdl.handle.net/2381/29492.

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Foetal islets are functionally immature but retain their capacity for proliferation if harvested and cultured in an appropriate manner. Graft function was shown to depend largely on the gestational age and conditions of organ culture prior to transplantation. The required period of organ culture for optimal graft function was investigated for foetal mouse pancreas of different gestational ages. The growth of the graft in situ also depended on the diabetic state of the host, and chronic hyperglycaemia appeared to impair graft function. Subsequent studies using NOD recipient mice as a model for IDDM showed that recurrent autoimmune disease was seen in foetal islet isografts but rapid rejection of allografts and foetal pig xenografts also occurred. The striking differences seen between the allo-, and xenograft response was the presence of many eosinophils that dominated the infiltrate at the xenograft site. However, HAR was not a problem in this discordant xenograft and Gal(1-3)Gal expression, the major epitope for xenoreactive Ab, was not present on differentiated cells but was detectable on ductal cells. A brief treatment with a specific anti-CD4 MAb (GK1.5) had a profound effect in the survival of xenografts in NOD mice. There were consistent differences in xenograft survival and in the number of circulating T and B cells in other strains of mice, e.g. CBA, BALB/c, C57BL/6 compared to NOD mice. Prolongation of xenograft survival for up to 12 weeks was achieved with the use of peri-transplant and weekly treatment with anti-CD4 or anti-CD3 MAbs especially when the graft has been "immunomodulated" by using 90% O2 in organ culture. Using this protocol foetal pig xenografts maturing under the kidney capsule of spontaneously diabetic NOD mice reversed hyperglycaemia and appeared also to secrete growth factor(s) that induced regeneration of cells in the host pancreas.

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Rafael, Ehab. "Cell transplantation and immunoisolation : studies on a macroencapsulation device /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3883-0/.

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Coffey, Lane Claire Katherine. "Immune Cells, Inflammatory Molecules, and CD40 in Nonhuman Primate Islets of Langerhans." Scholarly Repository, 2009. http://scholarlyrepository.miami.edu/oa_dissertations/430.

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Type 1 Diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing beta cells in the pancreas. Amelioration of T1D and the prevention of its detrimental complications are possible through islet transplantation, wherein hormone-producing clusters of cells, islets of Langerhans (islets), are separated from the pancreas and transplanted into a diabetic patient. However, alterations due to the effects of organ recovery, cold ischemia time (CIT), and islet isolation may increase the inflammatory and immunogenic properties of these islets, thereby predisposing them to functional impairment and rejection in a transplant. Understanding the inflammatory properties of islets will allow for the development of strategies that decrease early islet loss and effectively enhance engraftment and long-term function. Therefore, the aims of this study were to 1) identify and characterize populations of antigen presenting cells (APC) and other immune cells in nonhuman primate (NHP) islets in situ and after isolation; and 2) characterize the expression and functional role of CD40 and the IFN alpha receptor in NHP islets, including their effects on islet immunogenicity. A surprising result of these studies was that half of the APC present in isolated NHP islets were B lymphocytes. We observed that the number of islet-resident immune cells increased with islet size, and described the localization pattern of these cells within islets. We characterized CD40 expression in NHP islets, demonstrating that multiple CD40 isoforms are expressed, and made the novel finding that functional CD40 is expressed on the somatostatin-producing δ cells. When CD40 was stimulated with its ligand, it induced downstream signaling changes, increased proinflammatory cytokine release, and increased islet immunogenicity. Based on our results, we have hypothesized a model of CD40 signaling in islet δ cells. Microarray analysis revealed expression changes in many inflammatory molecules integral to inflammation, the immune response, and apoptosis in islets that had endured increased CIT, demonstrating the unfavorable conditions created within islets following organ recovery, CIT, and islet isolation. Furthermore, we demonstrated that the IFN alpha receptor is present on isolated NHP islets, and that stimulation with IFN alpha leads to increased proinflammatory cytokine release, surface receptor upregulation, and a decrease in immunogenicity. In summary, in NHP islets we have defined the type and quantity of immune cells, the inflammatory molecules expressed, including CD40 and the IFN alpha receptor, and their downstream functional roles in an immune response.

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Breuer, Susanne. "Etablierung des Modells "Ratte-anti-Schwein" zur xenogenen Transplantation mikroverkapselter Langerhans-Inseln." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=976080583.

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King, Aileen. "Evaluation of Alginate Microcapsules for Use in Transplantation of Islets of Langerhans." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5113-6/.

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Axcrona, Ulrika Myrsén. "Expression and regulation of neuropeptide Y (NPY) in the Islets of Langerhans." Lund : Dept. of Physiology and Neuroscience, Section for Neuroendocrine Cellbiology, Lund University, 1997. http://books.google.com/books?id=Ew5rAAAAMAAJ.

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Edwin, Nalini. "Quantitative estimation of islet tissue of pancreas in Australian mammals (comparative histological study) /." Title page, contents and summary only, 1986. http://web4.library.adelaide.edu.au/theses/09PH/09phe269.pdf.

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Lefebvre, Jacques. "L'histiocytose x pulmonaire : a propos d'un cas avec transplantation bi-pulmonaire." Amiens, 1994. http://www.theses.fr/1994AMIEM085.

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Kulis, Michael D. "Islet neogenesis associated protein-related protein from gene to folded protein /." Available online, Georgia Institute of Technology, 2006, 2006. http://etd.gatech.edu/theses/available/etd-01112006-195113/.

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Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2006.
Shuker, Suzanne, Committee Chair ; Doyle, Donald, Committee Member ; Orville, Allen, Committee Member ; Barry, Bridgette, Committee Member ; McCarty, Nael, Committee Member.

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Blais, Debbie Lin Marie. "Becoming an islet cell allotransplant recipient." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq21258.pdf.

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Chodnevskaja, Irina. "Histo-morphologische Untersuchungen nach xenogener Transplantation mikroverkapselter Langerhans-Inseln im Modell "Schwein-auf-Ratte"." Diss., lmu, 2006. http://nbn-resolving.de/urn:nbn:de:bvb:19-58123.

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Mattsson, Göran. "Experimental studies on the vasculature of endogenous and transplanted islets of Langerhans /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3596.

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Johansson, Åsa. "Properties of Endothelium and its Importance in Endogenous and Transplanted Islets of Langerhans." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk cellbiologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-109713.

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Transplantation of insulin producing cells is currently the only cure for type 1 diabetes. However, even though the Edmonton protocol markedly increased the success rate of pancreatic islet transplantation, the long term insulin independence is still very poor. An adequate engraftment is critical for islet graft survival and function. In the present thesis, isolated islet endothelial cells were found to have a low proliferatory and migratory capacity towards vascular endothelial growth factor (VEGF), but this could be reversed by using neutralizing antibodies to the angiostatic factors thrombospondin-1, endostatin or alpha1-antitrypsin. In the adult islet endothelial cell, VEGF may act as a permeability inducer more than an inducer of angiogenesis. p38 MAP kinase activity has been shown to serve as a switch between these properties of VEGF. Inhibition of p38 MAP kinase by daily injections of SB203580 in the early posttransplantation phase lead to a redistribution of the islet graft blood vessels from the stroma into the endocrine tissue and this was accompanied by a higher oxygen tension. Besides transports of oxygen and nutrients, beta-cells may require signals from the endothelial cells for their growth and differentiation. It was demonstrated that islet endothelial cells secrete factors, including laminin, that have positive effects on beta-cell insulin release and insulin content. Our results suggest that improved revascularization of transplanted islets may be achieved by either inhibition of angiostatic factors, or by blocking p38 MAPkinase activity, in the implanted tissue. Islet endothelial cells have a supportive paracrine role for beta-cells that might be hampered by the normally poor revascularization.

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Cabrera, Over. "Autocrine/paracrine interactions modulating hormone release in the endocrine pancreas /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-378-8/.

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Yan, Mengyong. "Interaction of human papillomavirus-like particles with dendritic cells and Langerhans cells : involvement in uptake, activation and cross-presentation /." St. Lucia, Qld, 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17614.pdf.

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Beilke, Joshua Nathan. "NK cell involvement in the induction of allograft tolerance /." Connect to full text via ProQuest. IP filtered, 2005.

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Thesis (Ph.D. in Immunology) -- University of Colorado, 2005.
Typescript. Includes bibliographical references (leaves 133-151). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;

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Nyqvist, Daniel. "In vivo imaging of islet cells and islet revascularization /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-116-6/.

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Orti-Raduan, Érika Sinara Lenharo. "Análise quantitativa das células de Langerhans em mucosa bucal de pacientes submetidos ao transplante de medula óssea alogênico com doença enxerto contra hospedeiro crônica." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/25/25136/tde-15102007-092541/.

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A doença enxerto contra hospedeiro é uma complicação comum nos pacientes submetidos ao transplante de medula óssea alogênico. Com o objetivo de contribuir para o esclarecimento da participação das células de Langerhans na doença enxerto contra hospedeiro crônica (GVHDc) quando de sua ocorrência na mucosa bucal, foram analisados 40 pacientes oncohematológicos e hematológicos submetidos ao transplante de medula óssea alogênico no Hospital Amaral Carvalho, Jaú - SP. Cortes microscópicos de 3µm de espessura da mucosa jugal com padrão de normalidade (controle - 20 pacientes) e de pacientes transplantados com e sem GVHDc, foram avaliados em hematoxilina e eosina e pela técnica imuno-histoquímica padrão da estreptavidina-biotina-peroxidase utilizando-se o anticorpo monoclonal anti- CD1a. As células de Langerhans imunomarcadas foram quantificadas no epitélio da mucosa jugal, sendo o número médio destas células estatisticamente comparado entre os pacientes controle e os pacientes transplantados com e sem GVHDc. Os resultados demonstraram um maior número de células de Langerhans na mucosa jugal dos pacientes com GVHDc quando comparado aqueles sem GVHDc e ao grupo controle (p=0,001). Foi observado também, a presença de intenso infiltrado inflamatório crônico, justaepitelial, com desorganização das células da camada basal do epitélio, com vacuolização celular, satelitose, corpúsculos acidofílicos e ocorrência de clivagem entre e o epitélio e o tecido conjuntivo nos pacientes que desenvolveram GVHDc. Estes resultados sugerem que a células de Langerhans participa da doença enxerto contra hospedeiro crônica na mucosa jugal dos pacientes submetidos ao transplante de medula óssea alogênico, sendo provavelmente recrutadas pelo processo inflamatório e imunopatológico que caracteriza esta doença.
The graft versus host disease (GVHD) is a common complication in patients submited to alogeneic bone marrow transplantation. To understand the role of Langerhans cells in chronic GVHD (cGVHD) in oral mucosa, we analyzed 40 oncohematological or hematological patients who received alogeneic bone marrow transplantation at Hospital Amaral Carvalho, Jaú - SP. Slices of 3µm from normal oral mucosa (control - 20 patients) and transplanted patients with and without cGVHD were analyzed by hematoxylin-eosin technique and conventional immunohistochemistry of streptavidin-biotin peroxidase technique for monoclonal antibody anti-CD1a. The immunomarked Langerhans cells were quantified in the epithelium of oral mucosa; the average number of these cells was statistically significant when compared to the control group and patients with and without cGVHD. The results showed higher number of Langerhans cells in oral mucosa of cGVHD when we compared the control group and the group of patients with and without cGVHD (p=0,001). We also observed the presence of chronic juxtaepithelial inflammatory infiltrate, with basal layer epithelium desorganization, vacuolization, satellitosis, acidophilic bodies and presence of gap between epithelium and connective tissue of patients with cGVHD. These results suggest that Langerhans cells may have a role in cGVHD of oral mucosa in patients submited to alogeneic bone marrow transplantation, and they may be recruited by inflammatory and immunopathologic process that are characteristic in this disease.

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Moberg, Lisa. "The Role of Innate Immunity in Islet Transplantation : Clinical and Experimental Studies." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4260.

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Sörenby, Anne. "Strategies to improve macroencapsulated islet graft survival /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-304-7/.

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Cantarovich, Diego. "Xenogreffe d'ilots pancreatiques porcins et traitement immunosuppresseur sans corticosteroides avec du serum antithymocytaire apres transplantation renale et pancreatique (doctorat immunologie)." Nantes, 2001. http://www.theses.fr/2001NANT12VS.

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Hårdstedt, Maria. "Studies of Innate and Adaptive Immunity in Islet Transplantation." Doctoral thesis, Uppsala universitet, Klinisk immunologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-232863.

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Clinical islet transplantation is today an established alternative treatment for a selected group of type 1 diabetes patients. The predominant technique for transplantation is infusion of islets in the liver via the portal vein. Obstacles to advancing islet transplantation include limited engraftment resulting from an immediate blood-mediated inflammatory reaction (IBMIR), a life-long need for immunosuppression and the shortage of organs available. In this thesis, innate and adaptive immunity were explored in allogeneic and xenogeneic settings, with the long-term goal of preventing islet graft destruction. Methods for studying immune responses to islets in blood and engrafted islets in liver tissue (intragraft gene expression) were developed and refined. The innate response to human islets and exocrine tissue in ABO-compatible blood was characterized up to 48 h using a novel whole-blood model. Physiological changes in the blood during incubations were explored and adjusted to allow prolonged experiments. Increased production of chemokines targeting CXCR1/2, CCR2 and CXCR3 was observed, accompanied by massive intra-islet neutrophil infiltration. Notably, endocrine and exocrine tissue triggered a similarly strong innate immune response. Two studies of adult porcine islet transplantation to non-human primates (NHPs) were performed. Expression of immune response genes induced in liver tissue of non-immunosuppressed NHPs (≤72 h) was evaluated after porcine islet transplantation. Up-regulation of CXCR3 mRNA, together with IP-10, Mig, MIP-1α, RANTES, MCP-1 and cytotoxic effector molecule transcripts, was associated with T-cell and macrophage infiltration at 48-72 h. Long-term survival (>100 days) of adult porcine islets in a NHP model was later demonstrated using T-cell-based immunosuppression, including co-stimulatory blockade (anti-CD154 mAb). Graft failure was associated with increased levels of circulating, indirectly activated T cells, non-Gal pig-specific IgG and gene transcripts of inflammatory cytokines. Microarray analysis of the response to inflammatory cytokines in cultured porcine islets identified genes involved in cell death, immune responses and oxidative stress; this gene pattern coincided with physiological changes (decrease in insulin and ATP content). In summary, allogeneic whole-blood experiments and xenogeneic in vivo studies underscored the importance of preventing early inflammation and cell-recruitment to avoid islet graft loss in islet transplantation. Long-term survival of porcine islets in NHPs was shown to be feasible using T-cell-directed immunosuppression, including anti-CD154 mAb.

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Cabric, Sanja. "Pancreatic Islet Transplantation : Modifications of Islet Properties to Improve Graft Survival." Doctoral thesis, Uppsala University, Department of Oncology, Radiology and Clinical Immunology, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8333.

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During the past decade clinical islet transplantation has become a viable strategy for curing type 1 diabetes. The limited supply of organs, together with the requirement for islets from multiple donors to achieve insulin independence, has greatly limited the application of this approach.

The islets are infused into the liver via the portal vein, and once exposed to the blood, the grafted tissue has been shown to be damaged by the instant blood-mediated inflammatory reaction (IBMIR), which is characterized by coagulation and complement activation as well as leukocyte infiltration into the islets. Islet revascularization is a subsequent critical step for the long-term function of the transplanted graft, which may partially be impeded by the IBMIR.

In this thesis, we have explored novel strategies for circumventing the effects of the IBMIR and facilitating islet revascularization.

Systemic inhibitors of the IBMIR are typically associated with an increased risk of bleeding. We therefore evaluated alternative strategies for modulating the islets prior to transplantation. We demonstrated, using an adenoviral vector, that a high level of expression and secretion of the anticoagulant hirudin could be induced in human islets. An alternative approach to limiting the IBMIR was developed in which anticoagulant macromolecular heparin complexes were conjugated to the islet surface. This technique proved effective in limiting the IBMIR in both an in vitro blood loop model and an allogeneic porcine model of islet transplantation. An increased adhesion of endothelial cells to the heparin-coated islet surface was demonstrated, as was the capacity of the heparin conjugate to bind the angiogenic factors VEGF and FGF; these results have important implications for the revascularization process.

The outcome of the work in this thesis suggests that modulation of the islet surface is an attractive alternative to systemic therapy as a strategy for preventing the IBMIR. Moreover, the same techniques can be employed to induce revascularization and improve the engraftment of the transplanted islets. Ultimately, improved islet viability and engraftment will make islet transplantation a more effective procedure and increase the number of patients whose diabetes can be cured.

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Iovino, Giugetta. "The role of lipid peroxidation in pancreatic islet function and destruction in Type 1 diabetes mellitus." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ37131.pdf.

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Wu, Douglas Ching Gee. "Cellular therapeutic strategies for the treatment of Type 1 Diabetes Mellitus." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670111.

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Serra, Navarro Berta. "Implicació de la senyalització dependent de Gsα en l’establiment de la massa cel·lular β." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/667060.

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La regulación y potenciación de la proliferación de la célula β pancreática es un objetivo principal en la prevención y/o retardo de la diabetes. Su replicación se regula a través de un proceso dinámico, siendo muy elevada en el estado embrionario hasta el nacimiento y disminuyendo gradualmente durante la etapa posnatal, manteniéndose en niveles muy bajos durante la edad adulta. Las vías de señalización que regulan este descenso son poco conocidas. Este estudio pretende establecer el papel de las vías Gsα-dependientes que actúan a través del segundo mensajero AMPc en la regulación de la masa celular β durante la etapa postnatal temprana. Para esta tesis hemos generado ratones deficientes para Gsα en célula β (β-GsαKO). En primer lugar hemos realizado una caracterización fenotípica de este modelo animal tanto a nivel de la homeostasis de la glucosa como a nivel del compartimento β pancreático, mostrando una clara intolerancia la glucosa junto con una reducción en la masa celular β así como en los niveles de proliferación des de una etapa postnatal temprana. Por otro lado el estudio de los determinantes moleculares responsables de las alteraciones observadas en el establecimiento de la masa celular β, pone en manifiesto un defecto claro en la señalización Gs-AMPc/PKA así como en la señalización de la insulina/igf1. El defecto en la vía de la insulina se observa tanto a nivel de ligando como a nivel de receptor con una alteración en la distribución de las isoformas así como en la propia activación de la vía para estimular la proliferación de la célula β en respuesta a insulina. De hecho, hemos visto una relación sinérgica dependiente entre las dos vías de señalización Gs-AMPc/PKA y insulina en la potenciación de la proliferación en respuesta a diferentes mitogenos. Esta tesis revela la importancia de la señalización mediada por AMPc en el establecimiento de la masa de célula β durante la etapa posnatal temprana. Además, demuestra de forma preliminar la existencia de una conexión entre el AMPc y la señalización intracelular mediada por la insulina en la célula β.

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Bennet, William. "Isolated islets of Langerhans trigger an instant blood mediated inflammatory reaction : a finding with implications for intraportal islet transplantation /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4161-0/.

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Karsten, Véronique. "Etude du chimiotactisme des macrophages peritoneaux au cours de la transplantation d'ilots de langerhans dans un modele de pancreas bioartificiel." Université Louis Pasteur (Strasbourg) (1971-2008), 2000. http://www.theses.fr/2000STR13099.

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Le traitement du diabete par la transplantation d'ilots pancreatiques est limite par les reactions immunologiques de rejet et necessite le developpement de techniques d'immunoprotection basees sur l'encapsulation des ilots a l'aide de membranes artificielles. Chez la souris diabetique, la xenogreffe d'ilots pancreatiques de rat encapsules avec la membrane de dialyse renale an69 (societe hospal) s'accompagne d'une reaction macrophagique membranaire responsable de la destruction des ilots. En effet, les macrophages exercent un effet cytotoxique sur les ilots encapsules en induisant un stress oxydatif. Le but de ce travail est de determiner le role des ilots pancreatiques dans la reaction cellulaire membranaire par l'etude du chimiotactisme des macrophages et d'evaluer l'influence du transfert de genes d'enzymes anti-oxydantes aux ilots sur la migration macrophagique. Notre etude a mis en evidence que les ilots pancreatiques induisent l'attraction des macrophages par la secretion de substances chimiotactiques. Celles-ci sont de nature proteique, et se caracterisent par leur specificite immunologique. Par ailleurs, l'encapsulation permet de retenir une partie de ces produits chimiotactiques et diminue l'activation du chimiotactisme des macrophages peritoneaux observee lors de la greffe d'ilots libres confirmant ainsi le role immunoprotecteur de la membrane an69. Des etudes realisees in vitro sur une lignee de cellules (ins-1) ont montre que l'induction d'un stress oxydatif stimule la secretion de facteurs chimiotactiques. Le transfert des genes de la catalase ou de la superoxyde dismutase aux ins-1 permet d'ameliorer la viabilite des cellules stressees tout en limitant la liberation de substances chimiotactiques. La surexpression d'enzymes anti-oxydantes est une approche interessante pour ameliorer la survie des ilots encapsules et limiter la reaction de rejet induit par la transplantation. Par ailleurs, l'identification des substances chimiotactiques devrait contribuer a moduler le chimiotactisme macrophagique et ainsi prolonger l'efficacite de la transplantation d'ilots pancreatiques.

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Jackson, Andrew M. Naziruddin Bashoo. "Analysis of inflammatory changes in human pancreatic islet cells." Waco, Tex. : Baylor University, 2009. http://hdl.handle.net/2104/5344.

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Filiputti, Eliane. "Regulação da secreção de insulina em ilhotas de Langerhans de ratos submetidos a restrição proteica e suplementados com leucina." [s.n.], 2006. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314197.

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Orientador: Everardo Magalhães Carneiro
Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: Suspeita-se que a desnutrição intra-uterina e pós-natal produzam mudanças morfológicas e funcionais no pâncreas endócrino e em tecidos periféricos, que se traduzem em insulinopenia e resistência à insulina. Baseado nessas complicações avaliou-se neste trabalho a regulação da secreção de insulina em ilhotas de Langerhans de ratos e camundongos submetidos à restrição protéica e suplementados com leucina. A suplementação com leucina não modificou hábitos alimentares, ingestão hídrica e o peso corpóreo dos animais em estudo, mas alterou parâmetros bioquímicos importantes como glicose (G), ácidos graxos (AGL) em animais desnutridos. A fosforilação do receptor de insulina (IR) e de seu substrato (IRS-l) foi modificada em fígado e músculo levando a uma melhoria na homeostasia glicêmica em ratos desnutridos, a metabolismo de glicose em ilhotas de ratos controle e desnutridos teve redução após suplementação, a potencial de membrana das células B foi restaurado, o movimento de cálcio citoplasmático e a secreção de insulina estimulada por G e leucina apresentaram aumentados em ilhotas de ratos e camundongos desnutridos. Alterações ocorreram também no perfil eletroforético de proteínas citoplasmáticas após suplementação com leucina em ilhotas de ratos. Expressão gênica e protéica de proteínas chaves na cascata de sinalização de insulina como IR, IRS-l, PI3K, mTaR e S6K-l se alteraram em resposta à suplementação com leucina em ilhotas de ratos desnutridos, favorecendo vias de crescimento, em especial o aumento da PI3K a qual resultou em aumento de sua atividade em ilhotas de ratos controle e desnutridos. Por fim, podemos concluir que a suplementação com leucina promoveu modulação da sensibilidade periférica em fígado e músculo de maneira tecido específica. Isto confere uma regulação da homeostase glicêmica de maneira distinta entre animais controle e desnutridos suplementados. Além disso, direcionam para que os sinais metabólicos produzidos pela leucina devam promover seus efeitos, em ilhotas de Langerhans, via dois sensores: a GDH que controla a glutaminólise, e por outro lado está a PI3K que deve exercer seu papel, ativando vis envolvidas com a síntese protéica através da mTOR. Estes dois sensores devem atuar sinergicamente participando do rearranjo da concentração citosólica dos íons cálcio, principalmente em ilhotas de animais desnutridos que foram suplementados com leucina
Abstract: We think that intra-uterine mal nutrition and after birth produce morphological and changes in endocrine pancreas and in peripheric tissue that translate insulinopenia and insulin resistance. Based on these complications we have evaluated in this work the insulin secretion regulation in Langerhans islets from rats and mice fed a low protein diet and supplemented with leucine. The leucine supplementation hasn't changed the diet in the hybrid ingest and body weight but has changed important biochemistry standards as glucose (G) and FFA in malnutrition animals. The insulin receptor phosphorilation and its substract have been changed in liver and musc1e leading to an increase in glicemic homeostase in malnutrition rats. The glucose metabolism in control and malnutrition rats' islets had one reduction after supplementation. B cells potential membranes were restored; the citoplasmatic ca1cium movement and insulin secretion were stimulated by glucose and leucine. They have showed an increased in islets of control and malnourished rats and mice islets. Some alterations have also occurred in the citoplasmatic protein eletrophoretic profile after leucine supplementation in rats islets. The genetic and protein expression from key enzymes in the insulin cascade signalization as: IR; IRS-l; PI3K; mTOR and S6K-l have altered in leucine supplementation answer in malnutrition islets rats favoring growth pathways specially PI3K increase which resulted in an increasement of control and malnutrition rats islets activity. In the end we can conc1ude that the leucine supplementation has promoted peripheric sensibilization in liver and muscle in specific tissue manner. This confirms one glicemic homeostase regulation in distinct manner among control and malnutrition both supplemented animals. Furthermore they lead the metabolic signals produced by leucine should promote their effects in Langerhans islets throw sensor ways: GDH which controls glutaminolisis and on the otherhand is PI3K that should do its role activating growth pathways throw mTOR. These two sensors should work in synergism participating in citosolic concentration changes of ca1cium ions mainly in malnutrition animals' islets, which were supplemented.
Doutorado
Fisiologia
Doutor em Biologia Funcional e Molecular

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39

Mattsson, Göran. "Experimental Studies on the Vasculature of Endogenous and Transplanted Islets of Langerhans." Doctoral thesis, Uppsala University, Department of Medical Cell Biology, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3596.

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The blood vessels of the pancreatic islets are of crucial importance for oxygen and metabolite supply as well as dispersal of secreted hormones. In addition to this, endothelial cells have an important role in the revascularization process after islet transplantation. Previous studies have reported signs of poor engraftment of transplanted islets, presumably due to impaired revascularization. The aims of this thesis were to investigate the revascularization process of transplanted islets and to examine the role of islet endothelial cells. In this context, the lectin Bandeiraea simplicifolia was found to stain endothelium of both endogenous and transplanted pancreatic islets. By using this lectin we investigated the vascular density of both endogenous and islets transplanted syngeneically beneath the renal capsule, into the spleen or intraportally into the liver of normoglycemic C57BL/6 mice. One month post-transplantation, a time point when the grafts are assumed to be completely revascularized, the vascular density was decreased at all three implantation sites when compared to endogenous islets. Furthermore, most of the blood vessels were located in the graft connective tissue stroma. Similar results were obtained when islet transplant vascular density was determined six months post-transplantation and in cured diabetic animals after one month. In order to evaluate the function of intraportally transplanted islets, we developed a method to retrieve such islets. We treated the implantation organ (liver) first enzymatically (collagenase) and then mechanically, thereafter we could re-isolate the transplanted islets for further in vitro studies. The retrieved islets had a decreased insulin relase, insulin content and glucose oxidation rate when compared to non-transplanted control islets. To understand the role of islet endothelium in the revascularization of transplanted islets we performed angiogenesis GEArray studies on islet endothelial cells, from non-cultured, cultured and transplanted islets. We found that the islet endothelium expressed mRNA for both inhibitors and inducers of angiogenesis, and that this expression differed with time. The functional consequences of this remain to be determined. In summary, the results presented above provide a useful platform for future studies of the morphology and function of islet endothelial cells, especially with a view for elucidating changes induced by islet transplantation.

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Arantes, Vanessa Cristina. "Acido graxo aumenta a secreção de insulina e modula a expressão de genes envolvidos na biossintese de insulina em ilhotas de ratos submetidos a desnutrição proteica." [s.n.], 2006. http://repositorio.unicamp.br/jspui/handle/REPOSIP/313938.

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Orientador: Antonio Carlos Boschero
Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: Em animais, a desnutrição intra-uterina exerce efeitos marcantes sobre o desenvolvimento fetal e pós-natal. Sabe-se que animais desnutridos apresentam níveis elevados de ácidos graxos plasmáticos e esses, por sua vez, são responsáveis por alterar a secreção de insulina. Neste trabalho, verificamos a expressão do fator de transcrição PDX-1, da p38/SAPK2, o metabolismo da glicose e a secreção de insulina em ilhotas de ratos mantidos durante o período fetal e da lactação com uma dieta normoprotéica (17% de proteína) ou hipoprotéica (6% de proteína). Cultivamos as ilhotas por 48 horas em meio de cultura contendo 5.6 mM/L de glicose, na ausência ou presença de0.6 mM/L de ácido palmítico. A secreção de insulina em ilhotas isoladas em resposta 16,7 mmol/L de glicose foi reduzida em ratos desnutridos, no entanto, quando na presença de ácido graxo, observou-se um aumento. Em 2.8 mmol glicose/L,houve diminuição do metabolismo da glicose em ilhotas de desnutridos .Entretanto, quando estimuladas com 16.7 mmol/L de glicose, tanto as ilhotas de desnutridos como as do controle, apresentaram acentuada redução na oxidação da glicose, na presença de ácido graxo. Os níveis de mRNA do PDX-1 e da insulina aumentaram significativamente quando na presença de ácido graxo em ambos os grupos. O efeito do ácido palmítico sobre a expressão protéica de PDX-1 e da p38/SAPK2 apresentou-se similar em ambos os grupos, mas o aumento foi muito mais evidente em ilhotas de desnutridos. Esses resultados demonstram a complexa relação entre nutrientes no controle da secreção de insulina e mostram queos ácidos graxos desempenham um papel importante na homeostasia da glicose, por afetar mecanismos moleculares e as vias de acoplamentsecreção de insulina
Abstract: A severe reduction in insulin release in response to glucose is consistently noticed in protein-deprived rats and is attributed partly to the chronic exposure to elevated levels of free fatty acids. Since the pancreatic and duodenal transcription factor homeobox 1 (PDX-1) is important for the maintenance of B-cell physiology, and since PDX-1 expression is altered in the islets of rats fed a low protein diet, we assessed PDX-1 and insulin mRNA expression, as well as PDX-1 and p38/SAPK2 protein expression, in islets from young rats fed low (6%; LP) or normal (17%; C) protein diets and maintained for 48 h in culture medium containing 5.6 mmol glucose/L with or without 0.6 mmol palmitic acid/L. We also measured glucoseinduced insulin secretion and glucose metabolism. Insulin secretion by isolated islets in response to 16.7 mmol glucose/L was reduced in LP compared to C rats. In the presence of free fatty acids, there was an increase in insulin secretion in both groups At 2.8 mmol glucose/L, the metabolism of this sugar was reduced in LP islets, regardless of the presence of this fatty acid. However, when challenged with 16.7 mmol glucose/L, LP and C islets showed a severe reduction in glucose oxidation in the presence of free fatty acid. The PDX-1 and insulin mRNA were significantly higher when free fatty acid was added to the culture medium in both groups of islets.The effect of palmitic acid on PDX-1 and p38/SAPK2 protein levels was similar in LP and C islets, but the increase was much more evident in LP islets. These results demonstrate the complex interrelationship between nutrients in the control of insulin release and support the view that fatty acids play an important role in glucose homeostasis by affecting molecular mechanisms and stimulus/secretion coupling pathways
Doutorado
Fisiologia
Doutor em Biologia Funcional e Molecular

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41

Quallio, Silvana. "Avaliação da função e plasticidade celuar de ilhotas pancreaticas em modelo de resistencia a insulina induzida por dexametosa em ratos." [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314399.

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Orientador: Jose Roberto Bosqueiro
Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: Introdução e objetivos: O aumento nos níveis de glicose circulante é o principal estímulo para a secreção de insulina. A insulina se liga a receptores de membrana desencadeando diversas respostas celulares. Qualquer alteração na sensibilidade à insulina pode levar a disfunções fisiológicas como a resistência à insulina observada em pacientes diabéticos tipo 2 (T2DM). Experimentalmente, essa condição patológica pode ser mimetizada pela administração de altas doses de glicocorticóides, provendo assim um bom modelo para seu estudo. O objetivo do presente trabalho foi avaliar a plasticidade das ilhotas pancreáticas submetidas à variação na necessidade secretória de insulina por indução de resistência periférica ao hormônio por tratamento com dexametasona e posterior interrupção do tratamento. Métodos: Ratos wistar com 90 dias de vida foram tratados com dexametasona (1mg/kg, ip) por 5 dias consecutivos (DEX). Em outro grupo (DEX10), os animais foram tratados da mesma maneira e avaliados 10 dias após o último dia da administração de dexametasona. Ratos controle (CTL) receberam administração de NaCl 0,9% apenas. As ilhotas foram isoladas pelo método da colagenase. A expressão de proteínas foi feita por immunoblotting. As análises morfométricas foram realizadas microscopicamente. Resultados: O grupo DEX exibiu marcante resistência periférica à insulina, que foi revertida após o período de 10 dias no grupo DEX10. As ilhotas do grupo DEX apresentaram alterações funcionais e morfológicas como aumento da secreção de insulina estimulada por secretagogos, da área, da densidade e tendência de aumento na massa de células ß ao contrário do grupo DEX10. O conteúdo de proteínas relacionadas ao ciclo celular como a CD2 e CDK4 e a fosforilação da AKT aumentou em ilhotas do grupo DEX, mas retornou aos níveis do CTL em ilhotas DEX10. Conclusão: Estes resultados mostram a plasticidade do pâncreas endócrino haja vista a habilidade de se adaptar a situações que exigem maior ou menor demanda de insulina
Abstract: Introduction and aims: Insulin binds to plasma membrane receptors leading to a variety of cellular responses. Malfunction in any of the insulin cell signalling pathways in target tissues may lead to several conditions and diseases, like hyperglycemia, insulin resistance and type 2 diabetes mellitus (T2DM). These effects may be experimentally reproduced using high doses of glucocorticoids, providing thus a good model for the study of T2DM. The aims of this study were to evaluate the plasticity of pancreatic islets subject to variation on the need for insulin secretory induction of peripheral resistance to the hormone by treatment with dexamethasone and subsequent treatment interruption. Methods: Male wistar rats (90 days old) were treated with dexamethasone (1mg/kg, ip) for 5 consecutive days (DEX). In another group (DEX10), the animals were treated in the same way and assessed 10 days after the last day of administration. Control rats (CTL) received equivalent volume of vehicle. Protein expression was assayed trough immunoblotting. Morphometric analyses were done using a optical microscope and specific digital analysis programs. Results: DEX group showed marked peripheral insulin resistance, reverted after the recovering period in the DEX10 group. DEX islets showed functional and morphological changes, like increased insulin secretion, superficial area, population density, and a tendency for increase in the total mass content of beta cell. Cell cycle proteins CD2 and CDK4 and AKT phosphorylation were increased in the DEX group when compared to CTL group. All these effects were reverted in the group DEX10. Conclusions: These results show that the endocrine pancreas possess a plasticity regarding the capacity of pancreatic islets to adapt themselves to situations where a higher or lower demand for insulin is needed.
Mestrado
Fisiologia
Mestre em Biologia Funcional e Molecular

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42

Johansson, Helena. "Mechanisms and Therapeutic Interventions of Instant Blood-Mediated Inflammatory Reaction (IBMIR)." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7786.

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43

Lindeborg, Ellinor. "Immunity against porcine islet xenografts in man /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-628-6657-5/.

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44

Grapensparr, Liza. "Auxiliary Cells for the Vascularization and Function of Endogenous and Transplanted Islets of Langerhans." Doctoral thesis, Uppsala universitet, Integrativ Fysiologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-327314.

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Type 1 diabetes develops through the progressive destruction of the insulin-producing beta-cells. Regeneration or replacement of beta-cells is therefore needed to restore normal glucose homeostasis. Presently, normoglycemia can be achieved by the transplantation of whole pancreas or isolated islets of Langerhans. Islet transplantation can be performed through a simple laparoscopic procedure, but the long-term graft survival is low due to poor revascularization and early cell death. This thesis examined the possibility of using different auxiliary cells (Schwann cells, endothelial progenitor cells, and neural crest stem cells) to improve the engraftment and function of endogenous and transplanted islets. Co-transplantation of Schwann cells with islets improved islet graft function early after transplantation, and caused an increased islet mass at one month posttransplantation. However, the vascular densities of these grafts were decreased, which also related to an impaired graft function. Islet grafts containing endothelial progenitor cells had a superior vascular density, with functional chimeric blood vessels and substantially higher blood perfusion and oxygen tension than control transplants. By culturing and transplanting islets together with neural crest stem cells it was found that islets exposed to these cells had a higher beta-cell proliferation compared with control islets. At one month posttransplantation, the grafts with neural crest stem cells also had a superior vascular- and neural density. The potential of intracardially injected neural crest stem cells to home to the pancreas and ameliorate hyperglycemia in diabetic mice was investigated. During a three-week period after such cell treatment blood glucose concentrations decreased, but were not fully normalized. Neural crest stem cells were present in more than 10% of the pancreatic islets at two days postinjection, at which time the beta-cell proliferation was markedly increased when compared with islets of saline-treated diabetic animals. Three weeks later, a doubled beta-cell mass was observed in animals receiving neural crest stem cells. In summary, islets can easily be transplanted together with different auxiliary cells. Some of these cells provide the possibility of improving vascular- and neural engraftment, as well as beta-cell growth and survival. Systemic administration of neural crest stem cells holds the potential of regenerating the endogenous beta-cells.

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Orti-Raduan, Érika Sinara Lenharo. "Doença enxerto contra hospedeiro crônica em mucosa bucal: relação da concentração de células de Langerhans com a expressão da quimiocina CCL20 e de seu receptor CCR6." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/25/25150/tde-18012012-104510/.

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A doença enxerto contra hospedeiro (GVHD) é uma complicação comum nos pacientes submetidos ao transplante de células-tronco hematopoiéticas (TCTH), sendo considerada a maior causa de morbidade e mortalidade nesses pacientes. O principal objetivo do presente estudo foi relacionar a concentração de células de Langerhans em mucosa bucal de pacientes com GVHDc bucal com a expressão da quimiocina CCL20 e de seu receptor CCR6 no epitélio bucal, a fim de elucidar os mecanismos biológicos envolvidos no recrutamento das células de Langerhans na GVHDc. Foram selecionados fragmentos obtidos por biópsia de mucosa bucal de 60 pacientes onco-hematológicos e hematológicos submetidos previamente ao transplante de células tronco hematopoiéticas no Hospital Amaral Carvalho, Jaú SP, onde 30 pacientes desenvolveram GVHDc em mucosa bucal (Grupo 1) e 30 não desenvolveram GVHDc (Grupo 2). Amostras obtidas a partir de 30 biópsias de lesões não inflamatórias em mucosa bucal constituíram o Grupo Controle (Grupo 3). Cortes microscópicos foram avaliados em coloração de rotina Hematoxilina e Eosina, e submetidos à técnica imuno-histoquímica, utilizando-se anticorpos monoclonais anti-CD1a e anti-CCR6, e anticorpos policlonais anti-CCL20. As células de Langerhans CD1a+ foram quantificadas no epitélio da mucosa bucal, e os resultados demonstraram um maior número destas células nos pacientes com GVHDc quando comparados àqueles sem GVHDc e ao Grupo Controle (p<0,001). A análise da imunomarcação das moléculas CCR6 e CCL20 foi subjetiva com aplicação de escores. Quanto à molécula CCR6, houve maior expressão no Grupo 1 (p<0,001) em comparação aos outros Grupos; porém, quanto à expressão de CCL20, não houve diferença estatística entre os três Grupos (p=0,108). Estes resultados sugerem que o aumento das células de Langerhans, na doença enxerto contra hospedeiro crônica, em mucosa bucal, pode estar associado a maior expressão do receptor CCR6. Possivelmente, o maior recrutamento de células de Langerhans até a mucosa bucal, em pacientes transplantados de medula óssea, colabora para o desenvolvimento da GVHDc bucal.
The graft versus host disease (GVHD) is a common complication in patients undergoing hematopoietic stem cell transplantation (HSCT), and considered a major cause of morbidity and mortality in these patients. The main objective of this study was to compare the concentration of Langerhans cells in oral mucosa of patients with oral chronic GVHD (GVHDc) with the expression of the chemokine CCL20 and its receptor CCR6 in oral epithelium, in order to clarify the biological mechanisms involved in the recruitment of Langerhans cells in GVHDc. We selected 60 biopsies of oral mucosa from onco-hematological and hematological patients submitted to prior hematopoietic stem cell transplantation at Hospital Amaral Carvalho, Jaú - SP from which 30 patients developed GVHDc in the oral mucosa (Group 1) and 30 did not develop GVHDc (Group 2). The Control Group (Group 3) was obtained from 30 biopsies of non-inflammatory lesions of oral mucosa. Microscopic sections were evaluated in routine Hematoxylin and Eosin staining, and submitted to immunohistochemistry using anti-CD1a and anti-CCR6 monoclonal antibodies, and anti-CCL20 polyclonal antibody. The Langerhans cells (CD1a+) were quantified in the epithelium of the oral mucosa, and the results showed a greater number of these cells in patients with GVHDc compared to those without GVHDc and the Control Group (p<0.001). Analysis of immunostaining of molecules CCL20 and CCR6 were subjective with application of scores. The expression of CCR6 molecule was more significant in Group 1 (p<0.001) compared to other groups, but in relation to CCL20 expression, there was no statistical difference between the three groups (p=0.108). These results suggest that the increase of Langerhans cells in GVHDc affecting oral mucosa may be associated with increased expression of the receptor CCR6. We suggest that the increased recruitment of Langerhans cells to the oral mucosa in patients with transplanted bone marrow contributes to the development of oral GVHDc.

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Johansson, Ulrika. "Formation of Composite Islet Grafts A novel strategy to promote islet survival and revascularization /." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-102788.

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47

Hubert, Thomas. "Thérapie cellulaire du diabète : influence des caractéristiques du donneur et du prélèvement pancréatique sur l'isolement des îlots de Langerhans." Lille 2, 2006. http://www.theses.fr/2006LIL2S054.

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Depuis les résultats de l'équipe d'Edmonton publiés en 2000, la greffe d'îlots de Langerhans connaît un essor particulier avec plus de 500 patients diabétiques traités par cette thérapeutique dans le monde. Malgré ces progrès réels, les freins demeurent la nécessité d'un traitement immunosuppresseur prolongé, la rareté des pancréas disponibles et le caractère imprévisible des résultats de l'isolement des îlots. Après un bref rappel et un historique de la greffe d'îlots de Langerhans, nous avons présenté les techniques actuelles du prélèvement pancréatique ainsi que les résultats de l'isolement des îlots dans notre équipe. Nous avons ensuite montré l'influence de la nature du liquide de conservation sur les résultats de l'isolement. Nous avons également démontré chez le Porc le caractère prédictif de la masse endocrine évaluée in vivo chez le donneur sur le rendement de l'isolement. Dans un second temps, ces résultats ont été confirmés chez l'Homme et ont permis d'envisager une sélection rationnelle des donneurs en vue de l'isolement d'îlots
Since the publication of clinical results in 2000 by the Edmonton team, islet transplantation has been on the rise where more than 500 diabetic patients have received this new therapy around the world. Despite this real progress, drawbacks remain such as the use of a prolonged immunosuppressive regimen, scarce organ availability for isolation and the unpredictable nature of isolation methods. Following a brief historical overview of the islet transplantation, we presented the current techniques of pancreas procurement and our islet isolation results. We then showed the influence of the conservation solution on the results of islet isolation. We were also able to establish in the pig model the predictive value of the pancreatic endocrine mass assessed in vivo in the donor on the isolation outcome. Secondly, we confirmed these results in man allowing us to consider a rational selection of donors prior to islet isolation

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Eriksson, Olof. "Imaging Islets of Langerhans by Positron Emission Tomography : Quantification of Beta-Cell Mass in the Native Pancreas and the Islet Graft." Doctoral thesis, Uppsala universitet, Enheten för radiologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-136372.

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Type 1 and 2 Diabetes Mellitus are a growing health problem throughout the world. There is an increasing need for methodologies, which are both reliable and non-invasive to measure the amount of insulin-producing tissue (Beta-cell mass, or BCM), as well as rapidly quantify changes in the BCM due to the onset of disease, beta-cell replacement therapy, or other treatments. Positron Emission Tomography (PET) is a non-invasive, quantitative functional imaging technique which can be used to study dynamical or static processes inside the body. In this thesis, we present a study protocol for in vivo imaging of the most common form of beta- cell replacement therapy; islet transplantation. Islets were labeled with the PET tracer, 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG), and administered intra-portally, while the recipient was monitored by PET/CT. The hepatic distribution of the islets was highly heterogeneous, and around 25% (human) or 50% (porcine) of the administered islets could not be found in the liver after completed transplantation, confirming previous reports of considerable cell injury during the procedure leading to low hepatic engraftment. Native BCM in the pancreas can potentially be quantified using a PET tracer with sufficiently high specificity, but the major obstacle is the relative low amounts of insulin producing tissue (only 1-2% of the pancreatic volume). Two tetrabenazine analogues, [18F]FE-(+)-DTBZ and [18F]FE-(+)-DTBZ-d4, are ligands to VMAT2, which is expressed in islet tissue. Both analogues were investigated and characterized as potential BCM imaging agents both in vitro and in vivo. Both tracers exhibited high preferential binding to islet tissue compared to exocrine pancreatic tissue. However, the specificity was not high enough to overcome the obscuring exocrine signal in vivo (7-10% of the signal originating from specific islet tracer uptake). This thesis demonstrates that it is possible to quantitatively assess islet transplantation by PET imaging. In vivo determination of native pancreatic BCM is, in theory, possible with both [18F]FE-(+)-DTBZ and [18F]FE-(+)-DTBZ-d4, but tracer analogues with higher islet specificity is needed for quantification of smaller BCM changes with physiological impact.

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Atla, Goutham. "Dissecting genetic regulatory mechanisms in human pancreatic islets to gain insights into type 2 diabetes pathophysiology." Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/672647.

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Diabetes mellitus is a heterogeneous group of metabolic diseases characterized by impaired blood glucose homeostasis that affects more than 415 million people worldwide and is a leading cause of mortality. The most prevalent form of diabetes is Type 2 Diabetes (T2D) that accounts for 90% of diabetes cases. An interplay of environmental and genetic risk factors contributes to etiology of T2D via a progressive loss of pancreatic beta cell function coupled with insulin resistance. Genome Wide Association Studies (GWAS) identified more than 400 independent genetic loci associated with T2D risk, although the molecular mechanisms underlying these genetic signals remain poorly understood. A comprehensive understanding of gene regulation in human pancreatic islets and identifying the role of T2D risk variants on different components of gene regulation will enlighten our insights into T2D etiology. In this work, we performed an in-depth characterization of human pancreatic islets transcriptional regulatory elements, attaining a greater granularity at transcriptional enhancers. We further identified glucose responsive enhancers which regulate glucose-dependent gene expression programs via three-dimensional chromatin interactions. This allowed us to gain insights into human islet transcriptional gene regulation and how glucose, a primary physiological stimulant of pancreatic islets, modulates human islet genome function. We also generated comprehensive transcriptome annotations in human islets using short- and long-read sequencing data along with accurate maps of transcriptional start sites. This revealed islet-specific promoters, transcript isoforms and novel coding sequences. This underscored the importance of generating transcript models in disease relevant tissue to progress in the understanding of gene regulation. Finally, these parallel efforts allowed us to create pioneer maps of genetic effects on human alternative splicing that revealed for the first time the noteworthy contribution of human islet mRNA splicing to T2D pathophysiology. These results have thus the potential to blossom in the discovery of novel T2D drug targets.

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Vantyghem, Marie-Christine. "Allogreffe intraportable d'ilôts pancréatiques endocrines dans le diabète de type I : aspects qualitatifs et quantitatifs de l'isolement ; résultats cliniques préliminaires." Lille 2, 2000. http://www.theses.fr/2000LIL2MT14.

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Dissertations / Theses on the topic 'Islands of Langerhans – Transplantation'

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