| 1. |
- Bergman, Marie-Louise, et al.
(författare)
-
Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains
- 2003
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 52:7, s. 1677-1682
-
Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes in the nonobese diabetic (NOD) mouse is a multifactorial and polygenic disease. The NOD-derived genetic factors that contribute to type 1 diabetes are named Idd (insulin-dependent diabetes) loci. To date, the biological functions of the majority of the Idd loci remain unknown. We have previously reported that resistance of NOD immature thymocytes to depletion by dexamethazone (Dxm) maps to the Idd6 locus. Herein, we refine this phenotype using a time-course experiment of apoptosis induction upon Dxm treatment. We confirm that the Idd6 region controls apoptosis resistance in immature thymocytes. Moreover, we establish reciprocal Idd6 congenic NOD and B6 strains to formally demonstrate that the Idd6 congenic region mediates restoration of the apoptosis resistance phenotype. Analysis of the Idd6 congenic strains indicates that a 3-cM chromosomal region located within the distal part of the Idd6 region controls apoptosis resistance in NOD immature thymocytes. Together, these data support the hypothesis that resistance to Dxm-induced apoptosis in NOD immature thymocytes is controlled by a genetic factor within the region that also contributes to type 1 diabetes pathogenesis. We propose that the diabetogenic effect of the Idd6 locus is exerted at the level of the thymic selection process.
|
|
| 2. |
- Duarte, Nadia, et al.
(författare)
-
Prevention of diabetes in nonobese diabetic mice mediated by CD1d-restricted nonclassical NKT cells.
- 2004
-
Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 173:5, s. 3112-3118
-
Tidskriftsartikel (refereegranskat)abstract
- A role for regulatory lymphocytes has been demonstrated in the pathogenesis of type 1 diabetes in the NOD mouse but the nature of these cells is debated. CD1d-restricted NKT lymphocytes have been implicated in this process. Previous reports of reduced diabetes incidence in NOD mice in which the numbers of NKT cells are artificially increased have been attributed to the enhanced production of IL-4 by these cells and a role for classical NKT cells, using the Valpha14-Jalpha18 rearrangement. We now show that overexpression in NOD mice of CD1d-restricted TCR Valpha3.2(+)Vbeta9(+) NKT cells producing high levels of IFN-gamma but low amounts of IL-4 leads to prevention of type 1 diabetes, demonstrating a role for nonclassical CD1d-restricted NKT cells in the regulation of autoimmune diabetes.
|
|
| 3. |
- Lundholm, Marie, 1974-, et al.
(författare)
-
Defective induction of CTLA-4 in the NOD mouse is controlled by the NOD allele of Idd3/IL-2 and a novel locus (Ctex) telomeric on chromosome 1
- 2006
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 55:2, s. 538-544
-
Tidskriftsartikel (refereegranskat)abstract
- Cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), or CD152, is a negative regulator of T-cell activation and has been shown to be associated with autoimmune diseases. Previous work has demonstrated a defect in the expression of this molecule in nonobese diabetic (NOD) mice upon anti-CD3 stimulation in vitro. Using a genetic approach we here demonstrate that a novel locus (Ctex) telomeric on chromosome 1 together with the Idd3 (Il-2) gene confers optimal CTLA-4 expression upon CD3 activation of T-cells. Based on these data, we provide a model for how gene interaction between Idd3 (IL-2), Ctex, and Idd5.1 (Ctla-4) could confer susceptibility to autoimmune diabetes in the NOD mouse. Additionally, we showed that the Ctex and the Idd3 regions do not influence inducible T-cell costimulator (ICOS) protein expression in NOD mice. Instead, as previously shown, higher ICOS levels in NOD mice appear to be controlled by gene(s) in the Idd5.1 region, possibly a polymorphism in the Icos gene itself.
|
|
| 4. |
- Rolf, Julia, et al.
(författare)
-
The enlarged population of marginal zone/CD1d(high) B lymphocytes in nonobese diabetic mice maps to diabetes susceptibility region Idd11.
- 2005
-
Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 174:8, s. 4821-4827
-
Tidskriftsartikel (refereegranskat)abstract
- The NOD mouse is an important experimental model for human type 1 diabetes. T cells are central to NOD pathogenesis, and their function in the autoimmune process of diabetes has been well studied. In contrast, although recognized as important players in disease induction, the role of B cells is not clearly understood. In this study we characterize different subpopulations of B cells and demonstrate that marginal zone (MZ) B cells are expanded 2- to 3-fold in NOD mice compared with nondiabetic C57BL/6 (B6) mice. The NOD MZ B cells displayed a normal surface marker profile and localized to the MZ region in the NOD spleen. Moreover, the MZ B cell population developed early during the ontogeny of NOD mice. By 3 wk of age, around the time when autoreactive T cells are first activated, a significant MZ B cell population of adult phenotype was found in NOD, but not B6, mice. Using an F2(B6 x NOD) cross in a genome-wide scan, we map the control of this trait to a region on chromosome 4 (logarithm of odds score, 4.4) which includes the Idd11 and Idd9 diabetes susceptibility loci, supporting the hypothesis that this B cell trait is related to the development of diabetes in the NOD mouse.
|
|
| 5. |
- Andersson, Christer, et al.
(författare)
-
Acute-phase proteins in response to tumor growth.
- 1993
-
Ingår i: The Journal of surgical research. - : Elsevier BV. - 0022-4804. ; 55:6, s. 607-14
-
Tidskriftsartikel (refereegranskat)abstract
- This study has evaluated the relationship between tumor growth and induction of acute-phase proteins. It has also determined whether an intact cellular immunity is obligatory for a fully expressed acute-phase plasma protein response in the presence of a highly antigenic tumor. Quantitatively, acute-phase responses (protein synthesis, plasma concentrations, hepatic RNA content, anorexia) were proportional to tumor burden. Anti-inflammatory drugs (indomethacin 1 micrograms/g body wt, dexamethasone 0.5 micrograms/g body wt) had no direct effect on the attenuation of the systemic acute-phase responses, but did affect them indirectly by decreasing tumor growth. Immune suppression (cyclosporine A at 20 or 60 micrograms/g body wt) had no effect on either acute-phase reactions or local tumor growth. In endotoxin-stimulated (lipopolysaccharide) normal mice, immune suppression aggravated anorexia and caused high mortality, while dexamethasone partly reversed these effects in endotoxin-stimulated mice. Plasma levels of acute-phase proteins correlated to circulating levels of IL-6 in untreated tumor-bearing mice, but this relationship was not obvious in either drug-treated tumor-bearing or endotoxin-stimulated mice. Tumor tissue induced the synthesis of different acute-phase proteins compared to endotoxin. However, disintegrated normal liver tissue induced the synthesis of serum amyloid protein to the same extent as the growing tumor. This effect was primarily associated with the mitochondrial/lysosomal and microsomal liver cell fractions. In conclusion, the overall acute-phase protein response is not a modulating factor of tumor growth.(ABSTRACT TRUNCATED AT 250 WORDS)
|
|
| 6. |
- Andersson, Christer, et al.
(författare)
-
Identification of tissue sites for increased albumin degradation in sarcoma-bearing mice.
- 1991
-
Ingår i: The Journal of surgical research. - 0022-4804. ; 50:2, s. 156-62
-
Tidskriftsartikel (refereegranskat)abstract
- Plasma albumin concentration declines in both experimental and clinical cancer. Previous investigations have demonstrated that this is partly explained by increased breakdown of albumin. The present study has identified the tissue sites for increased albumin degradation in a nonmetastasizing sarcoma mouse (C57/BL6J) model. Results have been compared to nontumor-bearing animals either freely fed or food restricted (pair-weighed) so that their body composition was similar to tumor-bearing animals. Tumor-bearing mice had increased albumin degradation (0.13 +/- 0.02 mg/hr/g bw) compared to both freely fed (0.09 +/- 0.007) and pair-weighed control animals (0.05 +/- 0.008). Radioactivity from circulating [3H]raffine aldehyde labeled albumin appeared with maximum peak values in lysosomes isolated from both tumor and nontumor tissues at 48 hr following iv injection. The intralysosomal accumulation of radioactivity was two- to threefold higher in tumor tissue compared to liver tissue, although the specific activity of protease(s) for albumin degradation measured in vitro was not higher in tumor tissue (30.4 +/- 3.6 mg/hr/g tissue) compared to normal liver tissue (36.9 +/- 1.7). Accounting for the entire tumor the proteolytic capacity for albumin breakdown was however much larger in the tumor (161.6 +/- 32.6 mg/organ) compared to both normal liver (37.5 +/- 2.3) and tumor-host liver (56.4 +/- 2.8). Pepstatin inhibited 78 +/- 6% of the proteolytic activity in the tumor measured by 125I-labeled undenatured mouse albumin as the substrate. Leupeptin inhibited 49 +/- 6%. There was a significantly decreased breakdown of albumin in both skeletal muscles and the gastrointestinal tract from tumor-bearing animals.(ABSTRACT TRUNCATED AT 250 WORDS)
|
|
| 7. |
- Andersson, Christer, et al.
(författare)
-
Isolation of radiopure plasma and hepatic albumin in acute phase conditions.
- 1994
-
Ingår i: Clinical nutrition (Edinburgh, Scotland). - 0261-5614. ; 13:1, s. 35-41
-
Tidskriftsartikel (refereegranskat)abstract
- It is essential to obtain biochemically and radioactively pure albumin in studies on albumin metabolism and kinetics in stress and nutrition related conditions. However, published work on albumin metabolism, in both animals and man with acute phase reactions has usually been based on inadequate chemical methods for isolation of homogeneous albumin free from acute phase proteins and other contaminants. Applications of conventional antibody precipitating techniques was usually either not sufficient to give radiopure albumin, or did not allow determination of the true specific radioactivity during in vivo experiments. Thus, the lack of applicable methods to achieve radiopure albumin from small plasma and tissue samples for subsequent analyses and determination of the true specific radioactivity in albumin initiated the present method development. The combination of HPLC ionchromatography (DEAE-sepharose), affinity chromatography (Blue sepharose CL-6B, Con A sepharose) and HPLC based size exclusion chromatography (Protein PAK 300 SW, Waters) was applied. By this procedure we obtained radiopure albumin from both plasma and hepatic samples from individual mice with acute phase response as confirmed by two-dimensional electrophoresis and immune precipitation.
|
|
| 8. |
- Antonsson, Malin, 1986, et al.
(författare)
-
Using a Discourse Task to Explore Semantic Ability in Persons With Cognitive Impairment.
- 2021
-
Ingår i: Frontiers in aging neuroscience. - : Frontiers Media SA. - 1663-4365. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- This paper uses a discourse task to explore aspects of semantic production in persons with various degree of cognitive impairment and healthy controls. The purpose of the study was to test if an in-depth semantic analysis of a cognitive-linguistic challenging discourse task could differentiate persons with a cognitive decline from those with a stable cognitive impairment. Both quantitative measures of semantic ability, using tests of oral lexical retrieval, and qualitative analysis of a narrative were used to detect semantic difficulties. Besides group comparisons a classification experiment was performed to investigate if the discourse features could be used to improve classification of the participants who had a stable cognitive impairment from those who had cognitively declined. In sum, both types of assessment methods captured difficulties between the groups, but tests of oral lexical retrieval most successfully differentiated between the cognitively stable and the cognitively declined group. Discourse features improved classification accuracy and the best combination of features discriminated between participants with a stable cognitive impairment and those who had cognitively declined with an area under the curve (AUC) of 0.93.
|
|
| 9. |
- Arner, P., et al.
(författare)
-
Circulating Carnosine Dipeptidase 1 associates with weight loss and poor prognosis in gastrointestinal cancer
- 2015
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:4
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Cancer cachexia (CC) is linked to poor prognosis. Although the mechanisms promoting this condition are not known, several circulating proteins have been proposed to contribute. We analyzed the plasma proteome in cancer subjects in order to identify factors associated with cachexia. Design/Subjects: Plasma was obtained from a screening cohort of 59 patients, newly diagnosed with suspected gastrointestinal cancer, with (n = 32) or without (n = 27) cachexia. Samples were subjected to proteomic profiling using 760 antibodies (targeting 698 individual proteins) from the Human Protein Atlas project. The main findings were validated in a cohort of 93 patients with verified and advanced pancreas cancer. Results: Only six proteins displayed differential plasma levels in the screening cohort. Among these, Carnosine Dipeptidase 1 (CNDP1) was confirmed by sandwich immunoassay to be lower in CC (p = 0.008). In both cohorts, low CNDP1 levels were associated with markers of poor prognosis including weight loss, malnutrition, lipid breakdown, low circulating albumin/IGF1 levels and poor quality of life. Eleven of the subjects in the discovery cohort were finally diagnosed with non-malignant disease but omitting these subjects from the analyses did not have any major influence on the results. Conclusions: In gastrointestinal cancer, reduced plasma levels of CNDP1 associate with signs of catabolism and poor outcome. These results, together with recently published data demonstrating lower circulating CNDP1 in subjects with glioblastoma and metastatic prostate cancer, suggest that CNDP1 may constitute a marker of aggressive cancer and CC.
|
|
| 10. |
|
|
