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- Korsgren, Magnus, et al.
(författare)
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Role of macrophage migration inhibitory factor (MIF) in allergic and endotoxin-induced airway inflammation in mice
- 2000
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Ingår i: Mediators of Inflammation. - : Hindawi Limited. - 0962-9351 .- 1466-1861. ; 9:1, s. 15-23
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Tidskriftsartikel (refereegranskat)abstract
- Macrophage migration inhibitory factor (MIF) has recently been forwarded as a critical regulator of inflammatory conditions, and it has been hypothesized that MIF may have a role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Hence, we examined effects of MIF immunoneutralization on the development of allergen-induced eosinophilic inflammation as well as on lipopolysaccharide (LPS)-induced neutrophilic inflammation in lungs of mice. Anti-MIF serum validated with respect to MIF neutralizing capacity or normal rabbit serum (NRS) was administered i.p. repeatedly during allergen aerosol exposure of ovalbumin (OVA)-immunized mice in an established model of allergic asthma, or once before instillation of a minimal dose of LPS into the airways of mice, a tentative model of COPD. Anti-MIF treatment did not affect the induced lung tissue eosinophilia or the cellular composition of bronchoalveolar lavage fluid (BALF) in the asthma model. Likewise, anti-MIF treatment did not affect the LPS-induced neutrophilia in lung tissue, BALF, or blood, nor did it reduce BALF levels of tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-1alpha (MIP-1alpha). The present data suggest that MIF is not critically important for allergen-induced eosinophilic, and LPS-induced neutrophilic responses in lungs of mice. These findings do not support a role of MIF inhibition in the treatment of inflammatory respiratory diseases.
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- Moberg, L, et al.
(författare)
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Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation
- 2002
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Ingår i: The Lancet. - 1474-547X. ; 360:9350, s. 2039-2045
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Tidskriftsartikel (refereegranskat)abstract
- Background Intraportal transplantation of pancreatic islets offers improved glycaemic control and insulin independence in type 1 diabetes mellitus, but intraportal thrombosis remains a possible complication. The thrombotic reaction may explain why graft loss occurs and islets from more than one donor are needed, since contact between human islets and ABO-compatible blood in vitro triggers a thrombotic reaction that damages the islets. We investigated the possible mechanism and treatment of such thrombotic reactions. Methods Coagulation activation and islet damage were monitored in four patients undergoing clinical islet transplantation according to a modified Edmonton protocol. Expression of tissue factor (TF) in the islet preparations was investigated by immunohistochemistry, immunoprecipitation, electron microscopy, and RT-PCR. To assess TF activity in purified islets, human islets were mixed with non-anticoagulated ABO-compatible blood in tubing loops coated with heparin. Findings Coagulation activation and subsequent release of insulin were found consistently after clinical islet transplantation, even in the absence of signs of intraportal thrombosis. The endocrine, but not the exocrine, cells of the pancreas were found to synthesise and secrete active TF. The clotting reaction triggered by pancreatic islets in vitro could be abrogated by blocking the active site of TF with specific antibodies or site-inactivated factor Vlla, a candidate drug for inhibition of TF activity in vivo. Interpretation Blockade of TF represents a new therapeutic approach that might increase the success of islet transplantation in patients with type 1 diabetes, in terms of both the risk of intraportal thrombosis and the need for islets from more than one donor.
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| 7. |
- Benda, B, et al.
(författare)
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Co-stimulatory molecules in islet xenotransplantation: CTLA4Ig treatment in CD40 ligand-deficient mice
- 2002
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Ingår i: Cell transplantation. - : SAGE Publications. - 0963-6897 .- 1555-3892. ; 11:7, s. 715-720
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Tidskriftsartikel (refereegranskat)abstract
- Previous work has demonstrated that short-term systemic administration of cytotoxic T lymphocyte antigen-4 (CTLA-4) Ig blocks human pancreatic islet xenograft rejection in mice and induces long-term, donor-specific tolerance, whereas studies on pig pancreatic islet rejection in mice have failed to demonstrate a role for CTLA4Ig in preventing rejection. Treatment with anti-CD40 ligand (L) monoclonal antibodies alone is somewhat effective in prolonging the survival of islet xenografts, but ineffective when applied to skin xenografts. However, simultaneous blockade of the CD28 and CD40 co-stimulatory pathways prolongs the survival of pig skin on recipient mice. To evaluate the role of CD28 and CD40 co-stimulatory pathways in pig islet-like cell cluster (ICC) xenograft rejection in mice, CD40L-deficient mice transplanted with fetal porcine ICCs were given posttransplant treatment with human (h) CTLA4Ig or a human IgG1 chimeric mAb (hL6). Xenografts were evaluated 6 or 12 days after transplantation. Fetal porcine ICC xenografts were protected from rejection in hCTLA4Ig-treated CD40L-deficient mice, whereas xenograft rejection persisted in untreated CD40L-deficient mice. Simultaneous blockade of the CD28 and CD40 co-stimulatory pathways is mandatory to inhibit ICC xenograft rejection in the pig-to-mouse model, because the CD28 and CD40 co-stimulatory pathways seem capable of efficiently substituting for one another.
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- Kobayashi, T, et al.
(författare)
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Lack of antibody production against Hanganutziu-Deicher (H-D) antigens with N-glycolylneuraminic acid in patients with porcine exposure history.
- 2000
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Ingår i: Xenotransplantation. - : Wiley. - 0908-665X. ; 7:3, s. 177-80
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Tidskriftsartikel (refereegranskat)abstract
- The significance of non-alphagalactosyl antigens remains unclear in pig-to-primate xenotransplantation. Hanganutziu-Deicher (H-D) antigens with terminal N-glycolylneuraminic acid (NeuGc) are widely expressed on endothelial cells of mammalian species, with the exception of humans. As baboons and monkeys also express H-D antigens, a pig-to-non-human primate experimental model cannot resolve the question of whether H-D antigens can elicit a potent humoral response in human recipients. The purpose of this study was to elucidate the clinical significance of H-D antigens by examining the sera from patients who have been previously exposed to porcine tissue. After the digestion of porcine aortic endothelial cells (PAEC) by neuraminidase, NeuGc and N-acetylneuraminic acid (NeuAc) were quantitated by HPLC. IgG and IgM antibody levels against H-D antigens were measured by NeuGc-GM3-coated ELISA plates in the sera of patients who had undergone ex vivo kidney perfusion 1 to 3 weeks and 2 years previously (n=2) or had been injected with fetal porcine islets 2 months previously (n= 10). HPLC determined that 9.7x 10(7) NeuAc and 6.3x 10(7) NeuGc residues per cell were released from PAEC by neuraminidase, while 25.7x 10(7) NeuAc and an undetectable level of NeuGc were released from human aortic endothelial cells (HAEC). No significant elevation of IgG or IgM antibody levels against NeuGc-GM3 was observed in sera from patients with a history of porcine exposure. Considering the active production of antibody against the foreign galactosyl antigens after pig-to-human xenotransplantation, some production of antibodies against the equally foreign H-D antigens would be expected, because large amounts of NeuGc terminated saccharides are present in the pig endothelial cell surface. However, no production of antibodies directed to H-D antigens could be found in patients exposed to porcine tissue. Further studies are warranted to explain why H-D antigens do not elicit a significant antibody production.
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- Strokan, V, et al.
(författare)
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Distribution of the Galalpha1-3Gal antigen in cultured adult and fetal porcine pancreatic islet cells: an immunoelectron microscopic study.
- 2000
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Ingår i: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337. ; 70, s. 846-
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Tidskriftsartikel (refereegranskat)abstract
- The distribution of the Galalpha1-3Gal antigen (Galalpha) in cultured adult porcine islets (API) and fetal porcine pancreatic islet-like cell clusters (ICC) was studied using immunoelectron microscopy. API and ICC were cultured for 1 and 5 days, respectively, and immunogold labeled using human affinity isolated anti-Galalpha1-3Gal antibody, GS-IB4 lectin and antibodies against islet pancreatic hormones, vimentin, and von Willebrand factor. Differentiated endocrine cells were Gala-negative, but, in ICC, some immature endocrine cells were slightly Gala-positive. The Gala-expression in API was much weaker compared to ICC. In both API and ICC, the Gala antigen was expressed on duct epithelial cells, acinar cells, and endothelial cells. In ICC, strong Gala expression was observed on flattened cells covering their surfaces. These cells were identified as centroacinar cells originating from intra-islet ducts. In conclusion, although mature endocrine cells of cultured API and ICC lack the Gala-xenoantigen, several other cellular compounds are strongly Gala positive, which may contribute to xenorejection of these grafts.
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