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Cellular and genetic components in the development of IDDM in NOD mice.
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). (Department of Cell and Molecular Biology. University of Umeå)
1996 (English)Doctoral thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Umeå: Umeå universitet , 1996. , 80 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 464
Keyword [en]
non-obese diabetic, IgVh gene utilisation, immunoregulation, programmed cell death, genetic linkage analysis
National Category
Basic Medicine
Research subject
Immunology
Identifiers
URN: urn:nbn:se:umu:diva-87787ISBN: 91-7191-150-2 (print)OAI: oai:DiVA.org:umu-87787DiVA: diva2:711211
Public defence
1996-03-22, Institutionen för Mikrobiologi, föreläsningssalen, Umeå universitet, Umeå, 09:30
Supervisors
Available from: 2014-04-11 Created: 2014-04-09 Last updated: 2014-04-11Bibliographically approved
List of papers
1. Specific destruction of islet transplants in NOD‹–›C57BL/6 and NOD‹–›C3H/Tif embryo aggregation chimeras irrespective of allelic differences in beta-cell antigens
Open this publication in new window or tab >>Specific destruction of islet transplants in NOD‹–›C57BL/6 and NOD‹–›C3H/Tif embryo aggregation chimeras irrespective of allelic differences in beta-cell antigens
1995 (English)In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 8, no 3, 347-356 p.Article in journal (Refereed) Published
Abstract [en]

We have tested the hypothesis that allelic differences in the antigens expressed by the beta-cells of the islets of Langerhans influence the development of insulitis in the non-obese diabetic (NOD) mouse. Islets of Langerhans from NOD, C57BL/6 and C3H/Tif mice were transplanted under the kidney capsule of NOD<-->C57BL/6 and NOD<-->C3H/Tif embryo aggregation (EA) chimeras and the infiltration was scored 5-7 weeks later. Mononuclear cell infiltration of pancreatic islets was observed in 60% of the NOD<-->C57BL/6 and in 55% of the NOD<-->C3H/Tif EA chimeras. All transplanted EA chimeras that developed insulitis also displayed mononuclear cell infiltrates in the transplants, irrespective of the origin of the transplanted islets. In contrast, no infiltration of transplants was detected in EA chimeras scoring negative for insulitis. These results demonstrate that the specific destruction of islet transplants does not require the expression of NOD specific antigens by the islets. Moreover, the beta-cell destruction appears not to be restricted to NOD-MHC. The correlation between insulitis and transplant beta-cell destruction suggests the possibility that the development of insulitis is a prerequisite for transplant specific destruction. MHC restricted destruction may, therefore, precede the beta-cell destruction of transplanted islets. The chimerism among the mononuclear cells infiltrating the islet transplants was found to correlate with the overall haematopoetic chimerism in each of the individual EA chimeras. This observation suggests that NOD bone marrow, as well as non-NOD bone marrow, generates cells contributing to the beta-cell destruction process.

Place, publisher, year, edition, pages
Elsevier, 1995
National Category
Basic Medicine Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-87503 (URN)10.1006/jaut.1995.0027 (DOI)7575996 (PubMedID)
Available from: 2014-04-02 Created: 2014-04-02 Last updated: 2017-12-05Bibliographically approved
2. Analysis of VH gene utilisation in the non-obese diabetic mouse
Open this publication in new window or tab >>Analysis of VH gene utilisation in the non-obese diabetic mouse
1993 (English)In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 15, no 1, 11-18 p.Article in journal (Refereed) Published
Abstract [en]

The immunoglobulin (Ig) heavy chain variable (VH) gene complexity and the VH gene utilisation pattern of the non-obese diabetic (NOD) mouse were investigated. We found that the NOD mouse displays a VH gene complexity which appears to be identical to that of the C57BL/6 mouse. Thus, Southern hybridisation using probes specific for 9 of the murine VH gene families revealed identical restriction fragment length polymorphism (RFLP) patterns in both mouse strains. As indicated by immunofluorescence analysis using allotype specific monoclonal antibodies the NOD mice were also found to carry the IgCH-1b allele. Collectively, these data suggest that the NOD mice carry an IgVH locus identical to that carried by C57BL/6. In contrast to the apparent identity at the level of germline VH gene repertoires, the pattern of VH gene utilisation differed considerably between these two mouse strains. Thus, in NOD mice the neonatal preference of D-proximal VH genes was found to be more pronounced than in C57BL/6 mice. Moreover, in contrast to adult C57BL/6 mice a D-proximal bias was evident also in adult NOD mice. On the basis of these findings we discuss the possibility that the distorted development of B cell repertoires in the NOD mouse could be directly or indirectly related to the T cell mediated, autoimmune process in the NOD mouse.

Place, publisher, year, edition, pages
Harwood Academic, 1993
Keyword
NOD mouse, Type 1 diabetes, IgVH gene complexity
National Category
Basic Medicine
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-87488 (URN)10.3109/08916939309004834 (DOI)8105987 (PubMedID)
Available from: 2014-04-02 Created: 2014-04-02 Last updated: 2017-12-05Bibliographically approved
3. Induction of diabetes in NOD‹–›C57BL/6 embryo aggregation chimeras by cyclophosphamide through preferential depletion of C57BL/6 lymphocytes
Open this publication in new window or tab >>Induction of diabetes in NOD‹–›C57BL/6 embryo aggregation chimeras by cyclophosphamide through preferential depletion of C57BL/6 lymphocytes
Show others...
1996 (English)In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 9, no 4, 493-499 p.Article in journal (Refereed) Published
Abstract [en]

The majority of embryo aggregation (EA) mouse chimeras between non-obese diabetic (NOD) mice and C57BL/6 (B6) mice show clear signs of insulitis frequently accompanied by beta-cell destruction. Less than 5% of these chimeras, however, spontaneously progress to autoimmune diabetes, an incidence far lower than observed in NOD mice. The resistance in chimeras can be accounted for by the target organ chimerism and/or the immune system chimerism. To investigate the mechanism(s) controlling diabetes resistance in these mice, we studied a total of 92 NOD<-->B6 EA chimeras that showed overt lymphoid chimerism and treated 34 chimeras with cyclophosphamide (CY), a compound known to precipitate an acute form of insulin-dependent diabetes mellitus (IDDM) in pre-diabetic NOD mice, by interfering with regulatory mechanisms. We found that CY-treated EA chimeras displayed an increase in the NOD:B6 lymphocyte ratio and 32% of them developed diabetes that could be adoptively transferred to irradiated NOD or NOD-rag-2-/- mice. These findings suggest that lymphocyte chimerism rather than beta-cell chimerism accounts for diabetes resistance in NOD<-->B6 EA chimeras and that the susceptibility to CY-induced diabetes may be related to the proportion of NOD versus B6 lymphoid cells.

Place, publisher, year, edition, pages
Elsevier, 1996
Keyword
immunoregulation, organ-specific autoimmunity, IDDM, NOD mouse
National Category
Basic Medicine
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-87684 (URN)10.1006/jaut.1996.0066 (DOI)8864824 (PubMedID)
Available from: 2014-04-07 Created: 2014-04-07 Last updated: 2017-12-05Bibliographically approved
4. Non-obese diabetic (NOD) mice display enhanced immune responses and prolonged survival of lymphoid cells
Open this publication in new window or tab >>Non-obese diabetic (NOD) mice display enhanced immune responses and prolonged survival of lymphoid cells
1994 (English)In: International Immunology, ISSN 0953-8178, E-ISSN 1460-2377, Vol. 6, no 2, 339-345 p.Article in journal (Refereed) Published
Abstract [en]

We report that lymphoid cells originating from the non-obese diabetic (NOD) autoimmune prone mouse strain are resistant to several signals known to induce programmed cell death. In vitro culturing of lymphoid cells of splenic or lymph node origin showed that B cells and T cells of both CD4+ and CD8+ phenotypes from NOD mice display extended survival in vitro. By cytofluorimetric analysis, immature CD4+ CD8+ NOD thymocytes were shown to partially resist in vivo treatment with corticosteroids. Finally, immunization with protein antigens induced enhanced and prolonged immune responses in NOD mice compared with normal C57BL/6, BALB/c, and C3H/Tif control mice. We conclude that the NOD mouse displays a defect in the mechanism(s) mediating programmed cell death in T and B lymphocytes. These findings provide a novel explanation for the B cell aberrations observed in the NOD mouse and may have implications for the understanding of the autoimmune pathogenesis in this mouse strain.

Place, publisher, year, edition, pages
Oxford: Oxford University Press, 1994
National Category
Basic Medicine
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-87591 (URN)10.1093/intimm/6.2.339 (DOI)8155606 (PubMedID)
Available from: 2014-04-04 Created: 2014-04-04 Last updated: 2017-12-05Bibliographically approved
5. Type 1 diabetes and the control of dexamethazone-induced apoptosis in mice maps to the same region on chromosome 6
Open this publication in new window or tab >>Type 1 diabetes and the control of dexamethazone-induced apoptosis in mice maps to the same region on chromosome 6
1995 (English)In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 28, no 3, 398-404 p.Article in journal (Refereed) Published
Abstract [en]

Quantitative trait loci mapping was used to identify the chromosomal location of genes that contribute to increase the resistance to apoptosis induced in immature CD4+8+ thymocytes. An F2 intercross of the nonobese diabetic (NOD) mouse (displaying an apoptosis-resistance phenotype) and the C57BL/6 mouse (displaying a nonresistance phenotype) was phenotypically analyzed and genotyped for 32 murine microsatellite polymorphisms. Maximum likelihood methods identified a region on the distal part of chromosome 6 that is linked to dexamethazone-induced apoptosis (lod score = 3.46) and accounts for 14% of the phenotypic variation. This chromosomal region contains the diabetes susceptibility locus Idd6, suggesting that the apoptosis-resistance phenotype constitutes a pathogenesis factor in IDDM of NOD mice.

Place, publisher, year, edition, pages
Elsevier, 1995
National Category
Basic Medicine
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-87505 (URN)10.1006/geno.1995.1167 (DOI)7490073 (PubMedID)
Available from: 2014-04-02 Created: 2014-04-02 Last updated: 2017-12-05Bibliographically approved

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