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  • 1.
    Alanentalo, Tomas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hörnblad, Andreas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nilsson, Anna Karin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sharpe, James
    Larefalk, Åsa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Quantification and 3-D imaging of the insulitis-induced destruction of β-cells in murine type 1 diabetes2010In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, no 7, p. 1756-1764Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to refine the information regarding the quantitative and spatial dynamics of infiltrating lymphocytes and remaining beta-cell volume during the progression of type 1 diabetes in the NOD mouse model of the disease.

    Research design and methods: Using an ex vivo technique, optical projection tomography (OPT), we quantified and assessed the 3D spatial development and progression of insulitis and beta-cell destruction in pancreas from diabetes prone NOD and non-diabetes prone congenic NOD.H-2b mice between 3 and 16 weeks of age.

    Results: Together with results showing the spatial dynamics of the insulitis process we provide data of beta-cell volume distributions down to the level of the individual islets and throughout the pancreas during the development and progression of type 1 diabetes. Our data provide evidence for a compensatory growth potential of the larger insulin(+) islets during the later stages of the disease around the time point for development of clinical diabetes. This is in contrast to smaller islets, which appear less resistant to the autoimmune attack. We also provide new information on the spatial dynamics of the insulitis process itself, including its apparently random distribution at onset, the local variations during its further development, and the formation of structures resembling tertiary lymphoid organs at later phases of insulitis progression.

    Conclusions: Our data provides a powerful tool for phenotypic analysis of genetic and environmental effects on type 1 diabetes etiology as well as for evaluating the potential effect of therapeutic regimes.

  • 2.
    Alanentalo, Tomas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lorén, Christina E
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Larefalk, Asa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Sharpe, James
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    High-resolution three-dimensional imaging of islet-infiltrate interactions based on optical projection tomography assessments of the intact adult mouse pancreas2008In: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 13, no 5, p. 054070-Article in journal (Refereed)
    Abstract [en]

    A predicament when assessing the mechanisms underlying the pathogenesis of type-1 diabetes (T1D) has been to maintain simultaneous global and regional information on the loss of insulin-cell mass and the progression of insulitis. We present a procedure for high-resolution 3-D analyses of regions of interest (ROIs), defined on the basis of global assessments of the 3-D distribution, size, and shape of molecularly labeled structures within the full volume of the intact mouse pancreas. We apply a refined protocol for optical projection tomography (OPT)-aided whole pancreas imaging in combination with confocal laser scanning microscopy of site-directed pancreatic microbiopsies. As such, the methodology provides a useful tool for detailed cellular and molecular assessments of the autoimmune insulitis in T1D. It is anticipated that the same approach could be applied to other areas of research where 3-D molecular distributions of both global and regional character is required.

  • 3. Fransen-Pettersson, Nina
    et al.
    Duarte, Nadia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. nstituto Gulbenkian de Sciencia, Oeiras, 2780–156 Oeiras, Portugal.
    Nilsson, Julia
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Larefalk, Åsa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Hannibal, Tine D.
    Hansen, Lisbeth
    Schmidt-Christensen, Anja
    Ivars, Fredrik
    Cardell, Susanna
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rozell, Bjoern
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. EMV Immunology, BMC, Lund University, Lund, Sweden; ISIM- Immunology, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark.
    A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 7, article id e0159850Article in journal (Refereed)
    Abstract [en]

    Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.

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  • 4.
    Johansson, Ann-Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Larefalk, Åsa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Eriksson, Björn
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Vierimaa, O
    Aittomaki, K
    Pukkala, E
    Launonen, V
    Aaltonen, L A
    Germ line insertions of moloney murine leukemia virus in the TLL mouse causes site-specific differences in lymphoma/leukemia frequency and tumor immunophenotype2006In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 26, no 4B, p. 2873-2878Article in journal (Refereed)
    Abstract [en]

    Background: Moloney murine leukemia virus (Mo-MLV) has proven valuable for studies of the pathogenesis of malignant lymphoma. Inoculation of newborn mice induces T cell lymphoma with 100% incidence. The TLL (T cell lymphoma/leukemia)-strain was previously established and was shown to spontaneously develop T cell lymphoma at high frequency.

    Materials and Methods: Differential screening of cDNA libraries was performed to discover an involvement of Mo-MLV and genomic sequencing was used to identify the chromosomal position of Mo-MLV proviral integration sites. Immunophenotypes of the tumors were established by flow cytometry. Disease frequency curves were created according to the Kaplan-Meier method.

    Results: Two independent Mo-MLV germ line integrations were characterized on chromosomes 2 and 14, giving rise to two substrains of mice denoted TLL-2 and TLL-14. The chromosomal position of the integrated provirus affected the frequency of disease, as well as the immunophenotype of the tumors.

    Conclusion: The data suggest that factors influencing the transcriptional activity of the chromosomal regions, leading to differences in proviral expression, could underlie the observed difference in tumor frequency.

  • 5.
    Johansson, Ann-Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Larefalk, Åsa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lindskog, Magnus
    Fish oil delays lymphoma progression in the TLL mouse2010In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 51, no 11, p. 2092-2097Article in journal (Refereed)
    Abstract [en]

    The objective was to investigate the effects of omega-3 fatty acids, known for their anti-inflammatory effects, on time to lymphoma progression and survival in the TLL mouse, a strain genetically prone to developing aggressive T-cell lymphoma. Compared to mice fed a standard diet, TLL mice fed omega-3 (menhaden fish oil) experienced a significant delay in disease progression and were more likely to remain alive and symptom free during the first 8 months of the study. In contrast, omega-6 supplementation (corn oil) did not significantly affect lymphoma progression. Irrespective of diet, all mice eventually progressed, and 1-year survival was not different between the groups. Immunological analysis demonstrated a significantly altered B-cell compartment and fewer NK cells in healthy C57Black6 mice fed omega-3, compared to controls. In conclusion, a diet rich in omega-3 fatty acids delays lymphoma development in the TLL mouse possibly by mechanisms that include complex effects on immune function.

  • 6.
    Johansson, Ann-Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Pawelzik, Sven-Christian
    Department of Medicine, Rheumatology Unit and Karolinska Biomics Centre, Karolinska Institutet, Stockholm, Sweden.
    Larefalk, Åsa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Jakobsson, Per-Johan
    Department of Medicine, Rheumatology Unit and Karolinska Biomics Centre, Karolinska Institutet, Stockholm, Sweden.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lindskog, Magnus
    Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
    Lymphoblastic T-cell lymphoma in mice is unaffected by Celecoxib as single agent or in combination with cyclophosphamide2009In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 50, no 7, p. 1198-1203Article in journal (Refereed)
    Abstract [en]

    Celecoxib, an inhibitor of cyclooxygenase-2, is a promising novel antitumor agent with pleitropic mechanisms of action. Whereas this drug induces growth arrest and apoptosis of B-lymphoma cells, its effect against aggressive T-cell neoplasms remains to be studied. We therefore evaluated Celecoxib therapy of immunocompetent mice transplanted with lymphoblastic T-cell lymphomas. Oral Celecoxib in clinically relevant and non-toxic doses did not affect the degree of hypersplenism or the number of viable lymphoma cells. The clinical deterioration of Celecoxib-treated mice was not different from untreated controls. The impact of adding Celecoxib (60 mg/kg) to cyclophosphamide (200 mg/kg x 1, i.p.) was assessed but showed no benefit compared to cyclophosphamide alone. Thus, Celecoxib lacks effect against lymphoblastic T-cell lymphoma in mice.

  • 7. Schmidt-Christensen, Anja
    et al.
    Hansen, Lisbeth
    Ilegems, Erwin
    Fransen-Pettersson, Nina
    Dahl, Ulf
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Gupta, Shashank
    Larefalk, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Hannibal, Tine D.
    Schulz, Alexander
    Berggren, Per-Olof
    Holmberg, Dan
    Imaging dynamics of CD11c(+) cells and Foxp3(+) cells in progressive autoimmune insulitis in the NOD mouse model of type 1 diabetes2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, no 12, p. 2669-2678Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to visualise the dynamics and interactions of the cells involved in autoimmune-driven inflammation in type 1 diabetes. We adopted the anterior chamber of the eye (ACE) transplantation model to perform non-invasive imaging of leucocytes infiltrating the endocrine pancreas during initiation and progression of insulitis in the NOD mouse. Individual, ACE-transplanted islets of Langerhans were longitudinally and repetitively imaged by stereomicroscopy and two-photon microscopy to follow fluorescently labelled leucocyte subsets. We demonstrate that, in spite of the immune privileged status of the eye, the ACE-transplanted islets develop infiltration and beta cell destruction, recapitulating the autoimmune insulitis of the pancreas, and exemplify this by analysing reporter cell populations expressing green fluorescent protein under the Cd11c or Foxp3 promoters. We also provide evidence that differences in morphological appearance of subpopulations of infiltrating leucocytes can be correlated to their distinct dynamic behaviour. Together, these findings demonstrate that the kinetics and dynamics of these key cellular components of autoimmune diabetes can be elucidated using this imaging platform for single cell resolution, non-invasive and repetitive monitoring of the individual islets of Langerhans during the natural development of autoimmune diabetes.

1 - 7 of 7
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