Type 1 Diabetes and the Control of Dexamethazone-Induced Apoptosis in Mice Maps to the Same Region on Chromosome 6

Penha‐Gonçalves, Carlos; Leijon, Kristina; Persson, Linda; Holmberg, Dan

doi:10.1006/geno.1995.1167

Cited by 43 publications

(25 citation statements)

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“…However, we found no structural or quantitative polymorphism of the Bcl-2 protein to support a role for the Bcl-2 gene itself in the NOD apoptotic phenotype (our unpublished data), which otherwise, is influenced by a locus on chromosome 6 [34]. Our observation of a dysregulated expression of Bcl-x in NOD activated lymphocytes in response to IL-2 withdrawal (Fig.…”

Section: Discussionmentioning

confidence: 61%

Resistance of T-cells to apoptosis in autoimmune diabetic (NOD) mice is increased early in life and is associated with dysregulated expression of Bcl-x

et al. 1998

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Section: Discussionmentioning

confidence: 61%

Resistance of T-cells to apoptosis in autoimmune diabetic (NOD) mice is increased early in life and is associated with dysregulated expression of Bcl-x

et al. 1998

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“…It has already been shown that NOD lymphocytes are highly resistant to various apoptotic signals, such as CY and dexamethasone [20][21][22][23]. A resistance and/or earlier recovery of effectors after CY in the NOD model probably explains the diabetogenic potential of CY.…”

Section: Discussionmentioning

confidence: 98%

“…Transgenic mice expressing bcl-2, an apoptosisinhibiting gene, have impaired apoptosis which leads to the development of an autoimmune phenomenon depending on their genetic background [15][16][17][18][19]. Also, NOD lymphocytes appear to be resistant to apoptotic signals, such as CY and dexamethasone [20][21][22][23], and it might be hypothesized that this mechanism is involved in the accumulation of autoimmune effector cells in NOD mice. Since it is known that 1,25(OH) 2 D 3 can induce apoptosis in phytohaemagglutinin (PHA)-stimulated lymphocytes, HL60 leukaemic cells and MCF 7 breast cancer cells [24][25][26], the protection against diabetes in NOD mice by 1,25(OH) 2 D 3 might also involve a better elimination of autoimmune effector cells by increasing their sensitivity to apoptosis.…”

Section: Introductionmentioning

confidence: 99%

1,25-Dihydroxyvitamin D3 restores sensitivity to cyclophosphamide-induced apoptosis in non-obese diabetic (NOD) mice and protects against diabetes

Casteels¹,

Waer

Bouillon³

et al. 1998

Clinical and Experimental Immunology

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SUMMARYThe activated form of vitamin D, 1,25(OH) 2 D 3 , and its analogues can prevent type I diabetes in NOD mice. Protection is achieved without signs of systemic immunosuppression and is associated with a restoration of the defective immune regulator system of the NOD mice. The aim of the present study was to investigate whether this restoration of regulator cell function is the only mechanism in the prevention of diabetes by 1,25(OH) 2 D 3 . We tested therefore if 1,25(OH) 2 D 3 could prevent cyclophosphamideinduced diabetes, since diabetes occurring after cyclophosphamide injection is believed to be due to an elimination of suppresser cells. NOD mice treated with 1,25(OH) 2 D 3 (5 mg/kg every 2 days) from the time of weaning were clearly protected against diabetes induced by cyclophosphamide (200 mg/kg body wt at 70 days old) (2/12 (17%) versus 36/53 (68%) in control mice, P < 0·005). By co-transfer experiments it was demonstrated that cyclophosphamide had indeed eliminated the suppresser cells present in 1,25(OH) 2 D 3 -treated mice. Since cyclophosphamide injection did not break the protection offered by 1,25(OH) 2 D 3 , it was clear that diabetogenic effector cells were affected by 1,25(OH) 2 D 3 treatment as well. This was confirmed by the finding that splenocytes from 1,25(OH) 2 D 3 -treated mice were less capable of transferring diabetes in young, irradiated NOD mice, and by the demonstration of lower Th1 cytokine levels in the pancreases of 1,25(OH) 2 D 3 -treated, cyclophosphamide-injected mice. This better elimination of effector cells in 1,25(OH) 2 D 3 -treated mice could be explained by a restoration of the sensitivity to cyclophosphamide-induced apoptosis in both thymocytes and splenocytes, in normally apoptosis-resistant NOD mice. Altogether, these data indicate that the protection against diabetes offered by 1,25(OH) 2 D 3 may be independent of the presence of suppresser cells, and may involve increased apoptosis of Th1 autoimmune effector cells.

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“…AF118263) and detect a polymorphism in the promoter region of the TGFb2 at the position 830 bp. All genotypes were detected by conventional protocols (28).…”

Section: Methodsmentioning

confidence: 99%

Identification of two cerebral malaria resistance loci using an inbred wild-derived mouse strain

Bagot

Campino

Penha‐Gonçalves

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Malaria is a complex infectious disease in which the host͞parasite interaction is strongly influenced by host genetic factors. The consequences of plasmodial infections range from asymptomatic to severe complications like the neurological syndrome cerebral malaria induced by Plasmodium falciparum in humans and Plasmodium berghei ANKA in rodents. Mice infected with P. berghei ANKA show marked differences in disease manifestation and either die from experimental cerebral malaria (ECM) or from hemolytic anemia caused by hyperparasitemia (HP). A majority of laboratory mouse strains so far investigated are susceptible to ECM; however, a number of wild-derived inbred strains show resistance. To evaluate the genetic basis of this difference, we crossed a uniquely ECM-resistant, wild-derived inbred strain (WLA) with an ECM susceptible laboratory strain (C57BL͞6J). All of the (WLA ؋ C57BL͞6J) F 1 and 97% of the F2 progeny displayed ECM resistance similar to the WLA strain. To screen for loci contributing to ECM resistance, we analyzed a cohort of mice backcrossed to the C57BL͞6J parental strain. A genome wide screening of this cohort provided significant linkage of ECM resistance to marker loci in two genetic regions on chromosome 1 ( 2 ‫؍‬ 18.98, P ‫؍‬ 1.3 ؋ 10 ؊5 ) and on chromosome 11 ( 2 ‫؍‬ 16.51, P ‫؍‬ 4.8 ؋ 10 ؊5 ), being designated Berr1 and Berr2, respectively. These data provide the first evidence of loci associated with resistance to murine cerebral malaria, which may have important implications for the search for genetic factors controlling cerebral malaria in humans.

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Type 1 Diabetes and the Control of Dexamethazone-Induced Apoptosis in Mice Maps to the Same Region on Chromosome 6

Cited by 43 publications

References 0 publications

Resistance of T-cells to apoptosis in autoimmune diabetic (NOD) mice is increased early in life and is associated with dysregulated expression of Bcl-x

Resistance of T-cells to apoptosis in autoimmune diabetic (NOD) mice is increased early in life and is associated with dysregulated expression of Bcl-x

1,25-Dihydroxyvitamin D3 restores sensitivity to cyclophosphamide-induced apoptosis in non-obese diabetic (NOD) mice and protects against diabetes

Identification of two cerebral malaria resistance loci using an inbred wild-derived mouse strain

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