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| 2. |
- Bergman, Marie-Louise, et al.
(författare)
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CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice
- 2001
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Ingår i: Journal of Autoimmunity. - : Elsevier. - 0896-8411 .- 1095-9157. ; 16:2, s. 105-113
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Tidskriftsartikel (refereegranskat)abstract
- The genes conferring susceptibility to autoimmune (insulin-dependent) diabetes mellitus (IDDM) are, in most cases, not defined. Among the loci so far identified as associated with murine IDDM (Idd1-19), only the nature of Idd1 has been assessed. Here we show that thymocytes and peripheral lymphocytes of the non-obese diabetic (NOD) mouse are relatively resistant to apoptosis induced by gamma-irradiation. By linkage analysis of F2 progeny mice, we map this trait to a locus on chromosome 1 containing the Idd5 diabetes susceptibility region. By the use of congenic mice, we confirm the linkage data and map this locus to a 6 cM region on proximal chromosome 1. Ctla4, being localized in this chromosomal region and mediating crucial functions in T cell biology, is a logical candidate gene in the Idd5 susceptibility region. In line with this, we demonstrate that T cells from Ctla4(-/-)deficient mice show a similar resistance to gamma-irradiation-induced apoptosis as observed in the NOD mice. This reinforces the notion that CTLA-4 contributes to the pathogenesis of autoimmune diabetes.
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| 4. |
- Colucci, Francesco, et al.
(författare)
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Apoptosis resistance of nonobese diabetic peripheral lymphocytes linked to the Idd5 diabetes susceptibility region
- 1997
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 94:16, s. 8670-8674
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Tidskriftsartikel (refereegranskat)abstract
- Defects in lymphocyte apoptosis may lead to autoimmune disorders and contribute to the pathogenesis of type 1 diabetes. Lymphocytes of nonobese diabetic (NOD) mice, an animal model of autoimmune diabetes, have been found resistant to various apoptosis signals, including the alkylating drug cyclophosphamide. Using an F2 intercross between the apoptosis-resistant NOD mouse and the apoptosis-susceptible C57BL/6 mouse, we define a major locus controlling the apoptosis-resistance phenotype and demonstrate its linkage (logarithm of odds score = 3.9) to a group of medial markers on chromosome 1. The newly defined gene cannot be dissociated from Ctla4 and Cd28 and in fact marks a 20-centimorgan region encompassing Idd5, a previously postulated diabetes susceptibility locus. Interestingly, we find that the CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) and the CD28 costimulatory molecules are defectively expressed in NOD mice, suggesting that one or both of these molecules may be involved in the control of apoptosis resistance and, in turn, in diabetes susceptibility.
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| 5. |
- Colucci, Francesco, et al.
(författare)
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Diabetes induction in C57BL/6 mice reconstituted with lymphocytes of nonobese diabetic C57BL/6 mouse embryo aggregation chimeras
- 1998
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Ingår i: Scandinavian Journal of Immunology. - : Wiley-Blackwell. - 0300-9475 .- 1365-3083. ; 48:6, s. 571-576
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Tidskriftsartikel (refereegranskat)abstract
- To determine whether the genetic background of the insulin-producing beta cells of the pancreas contributes to autoimmune diabetes susceptibility, we have used a model of the disease based on transferring spleen cells from nonobese diabetic (NOD) <--> C57BL/6 (B6) embryo aggregation (EA) chimeras into B6 and NOD irradiated mice. Insulitis and diabetes could be induced into both B6 and NOD hosts, albeit with low incidence. Cyclophosphamide (CY) treatment, known to accelerate diabetes in prediabetic NOD mice, was found to increase diabetes incidence up to 50-60% in both B6 and NOD mice reconstituted with chimeric splenocytes, while diabetes did not occur in CY-treated B6 mice reconstituted with B6 splenocytes. We conclude that the genetic make-up of the target organ does not affect the final stage of the pathogenesis of insulin-dependent diabetes mellitus.
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| 6. |
- Colucci, Francesco, et al.
(författare)
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Induction of diabetes in NOD‹–›C57BL/6 embryo aggregation chimeras by cyclophosphamide through preferential depletion of C57BL/6 lymphocytes
- 1996
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Ingår i: Journal of Autoimmunity. - : Elsevier. - 0896-8411 .- 1095-9157. ; 9:4, s. 493-499
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Colucci, Francesco, et al.
(författare)
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Programmed cell death in the pathogenesis of murine IDDM : resistance to apoptosis induced in lymphocytes by cyclophosphamide
- 1996
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Ingår i: Journal of Autoimmunity. - : Elsevier. - 0896-8411 .- 1095-9157. ; 9:2, s. 271-276
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Tidskriftsartikel (refereegranskat)abstract
- The non-obese diabetic (NOD) mouse displays several immune related defects, each of which could potentially contribute to the immunopathogenesis of diabetes that spontaneously develops in these mice. The reported resistance of NOD-lymphocytes to several apoptosis-inducing signals constitutes one such factor. Apoptosis plays a key role in the homeostasis of the immune system, as a means of selecting lymphocyte repertoires both in primary lymphoid organs and in the periphery; distortions in the apoptotic machinery may therefore be hypothesized to be implicated in the pathogenesis of autoimmune disorders. We now report that cyclophosphamide constitutes an apoptosis signal to peripheral lymphocytes and we provide evidence that NOD B cells as well as both CD4 and CD8 T cells display resistance to cyclophosphamide-induced apoptosis. These observations support the notion that apoptosis resistance in NOD mice exists at various levels, and suggest that the CY-sensitive lymphoid population, believed to play an important role in inhibiting the disease in diabetes resistant NOD mice (particularly males), may be controlled by mechanisms that are mediated by apoptosis.
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| 8. |
- Colucci, Francesco, et al.
(författare)
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Taming killer cells may halt diabetes progression
- 2010
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Ingår i: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 11:2, s. 111-112
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Preclinical studies in mice suggest that the natural killer cell receptor NKp46 may be a new molecular target for delaying the progression of type 1 diabetes by interfering with unexpected natural killer cell-mediated recognition of pancreatic beta cells.
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| 9. |
- Wikström, Ingela, et al.
(författare)
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E2-2 regulates the expansion of pro-B cells and follicular versus marginal zone decisions.
- 2006
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Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 177:10, s. 6723-6729
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Tidskriftsartikel (refereegranskat)abstract
- The E-proteins E2A, HeLa E-box binding protein, and E2-2 constitute a class of basic helix-loop-helix transcription factors that differentially affect B cell development. E2A is by far the most investigated and appears to operate at several levels during B cell ontogeny. Less is known concerning the role of the other E-proteins. To address the role of E2-2, we have performed transfers of fetal liver (FL) cells into irradiated Rag-deficient mice. Although the transfer of E2-2-deficient cells alone can reconstitute all B cell subpopulations, albeit with a moderate reduction in cellularity, E2-2-deficient cells have a disadvantage when transferred together with wild-type cells. Cultivation of E2-2(-/-) day 14.5 FL cells on stromal cells and IL-7 revealed a reduced frequency of responding B cell progenitors despite normal IL-7Ralpha surface expression. Real-time PCR analysis revealed that E2-2 mRNA expression is high at the pro-B cell stage and drops sharply at the pre-B cell stage, consistent with a role for E2-2 in pro-B cells. In contrast, E2A mRNA was most abundant in pre-B cells. Analysis of the peripheral repertoire revealed that mice reconstituted with E2-2(-/-) FL cells had an increased proportion of marginal zone (MZ) B cells. Interestingly, E2-2 mRNA was elevated approximately 2-fold (p < 0.01) in follicular compared with MZ B cells. Although E2A mRNA showed a similar tendency, the difference was not significant. Collectively, our findings indicate that E2-2 is required for optimal expansion of pro-B cells, and also influences the follicular vs MZ decision.
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