Increased In Vitro Interleukin-12 Production by Peripheral Blood in High-Risk IDDM First Degree Relatives

Szelachowska, Małgorzata; Krętowski, Adam; Kinalska, I

doi:10.1055/s-2007-979014

Cited by 29 publications

(15 citation statements)

References 10 publications

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“…The following CBA-NOD recombinant congenic strains that have unique sets of Idd loci (12) were a gift from Dr. E. Leiter (The Jackson Laboratory): NOcCB-1 (Idd1, 2,4,5,6,7,8,13,14,15,16), CBcNO6 (Idd1, 2,6,8,9,11,13,15,16), CBcNO7-C (Idd1, 6,7,9,15,16), and CBcNO7-D (Idd1, 6,7,9,10,13,15,16,17). Breeding pairs of the following C57BL/6 mice congenic for Idd loci were also a gift from Dr. E. Leiter and bred in-house: B6.NODc17 (B6.NODIdd1), D17MIT21-D17MIT10, 19 cM interval; B6.NODc11 (B6.NODIdd4), D11Mit20-D11Mit42, 52 cM interval; B6.NODc17/c11 (B6.NODIdd1/Idd4), D17Mit21-D17Mit10, 19 cM interval, D11Mit20-D11Mit42, 52 cM interval; B6.NODc17/c1c (B6.NODIdd1/Idd5), D17Mit21-D17Mit10, 19 cM interval, D1Mit3-BclII, 44 cM interval; B6.NODc17/c6 (B6.NODIdd1/Idd6), D17MIT21-D17MIT10, 19 cM interval, D6MIT54-D6MIT14, 24 cM interval; B6.NODc17/c3 (B6.NODIdd1/Idd3/Idd10), D17Mit21-D17Mit10, 19 cM interval, D3Mit132-Tshb, 43 cM interval; B6.NODc2 (B6.NODIdd13), D2Mit17-D2Mit48, 32 cM interval (13).…”

Section: Animalsmentioning

confidence: 99%

Cutting Edge: Diabetes-Associated Quantitative Trait Locus, Idd4, Is Responsible for the IL-12p40 Overexpression Defect in Nonobese Diabetic (NOD) Mice

Simpson

Mistry

Maki

et al. 2003

The Journal of Immunology

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APCs of the nonobese diabetic (NOD) mouse have a genetically programmed capacity to overexpress IL-12p40, a cytokine critical for development of pathogenic autoreactive Th1 cells. To determine whether a diabetes-associated NOD chromosomal locus (i.e., Idd) was responsible for this defect, LPS-stimulated macrophages from several recombinant congenic inbred mice with Idd loci on a C57BL/6 background or with different combinations of NOD and CBA genomic segments were screened for IL-12p40 production. Only macrophages from the congenic strains containing the Idd4 locus showed IL-12p40 overproduction/expression. Moreover, analysis of IL-12p40 sequence polymorphisms demonstrated that the Idd4 intervals in these strains contained the IL-12p40 allele of the NOD, although further analysis is required to determine whether the IL-12p40 allele itself is responsible for its overexpression. Thus, the non-MHC-associated Idd4 locus appears responsible for IL-12p40 overexpression, which may be a predisposing factor for type 1 diabetes in NOD mice.

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Section: Animalsmentioning

confidence: 99%

Cutting Edge: Diabetes-Associated Quantitative Trait Locus, Idd4, Is Responsible for the IL-12p40 Overexpression Defect in Nonobese Diabetic (NOD) Mice

Simpson

Mistry

Maki

et al. 2003

The Journal of Immunology

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“…13 Also, in vitro studies have demonstrated that high-risk first-degree relatives produce significantly higher levels of IL-12 compared to age-and sex-matched controls. 14 In the present study we have investigated if the 3 0 UTR polymorphism in the IL12B gene is associated with early-onset type 1 diabetes in the Northern Ireland population employing both case-control and familybased association studies involving a total of 120 cases, 330 healthy controls, and 307 trio families comprising both parents and an affected offspring. The probands were Caucasian and derived from a population-based register of individuals with type 1 diabetes diagnosed before their 15th birthday.…”

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confidence: 99%

The IL12B 3′ untranslated region DNA polymorphism is not associated with early-onset type 1 diabetes

McCormack¹,

Maxwell²,

Carson³

et al. 2002

Genes Immun

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A recent study employing Australian and UK type 1 diabetes families has demonstrated significant transmission bias to affected offspring of a polymorphism (1188A allele; termed allele 1) in the 3 0 untranslated region (3 0 UTR) of the interleukin 12B (IL12B) gene which encodes the IL-12p40 subunit of the pro-inflammatory cytokine IL-12. However, results from replication studies in other populations have been controversial. We performed both case-control (n ¼ 120 cases; n ¼ 330 controls) and familybased (n ¼ 307 families) association studies, using the transmission disequilibrium test, to investigate if allele 1 is associated with early-onset type 1 diabetes in Northern Ireland. No association was observed between allele 1 and type 1 diabetes in either case-control (80.8% vs 80.8%; P ¼ 0.98) or family-based (49.7% transmissions; P ¼ 0.94) studies. Our results do not support earlier reports of an association between allele 1 in the 3 0 UTR of the IL12B gene and type 1 diabetes.

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“…Increased IL-12 production is found in high-risk first-degree relatives oy Type I diabetic people [27]. Gene expression of IL-12 in islets correlate with beta-cell destruction in NOD mice [28].…”

Section: Discussionmentioning

confidence: 99%

Cyclophosphamide inhibits the development of diabetes in the diabetes-prone BB rat

et al. 2000

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Biobreeding (BB) diabetes-prone rats have been extensively used as an animal model for human Type I (insulin-dependent) diabetes mellitus. These rats spontaneously develop diabetes after autoimmune destruction of beta cells [1,2]. As in human Type I diabetes, the pathogenesis of the disease in the diabetes-prone BB rat is through a cell-mediated autoimmune process characterized by lymphocytic infiltration of the islets and the presence of serum anti-islet cytotoxic antibodies [3,4]. In addition, depressed suppressor cell activity is thought to play an important part in the development of diabetes in humans and the BB rat [5,6,7].Cyclophosphamide is an alkylating agent with many immunological properties and has been used Abstract Aims/hypothesis. Cyclophosphamide has been shown to augment the diabetic process in NOD mouse and BB rat models of Type I (insulin-dependent) diabetes mellitus. Because cyclophosphamide has, however, been shown to increase immunoregulatory cell activity, we examined if cyclophosphamide treatment increases immunoregulatory cell activity and inhibits the diabetic process in BB rats. Methods. The development of insulitis and diabetes was explored in BB rats treated with saline and cyclophosphamide (60 to 175 mg/kg body weight). Subsets of spleen cells were assessed by flow cytometry and cytokine gene expression by RT-PCR. To determine if cyclophosphamide induces immunoregulatory cell activity, the development of diabetes was assessed in BB rats injected with spleen cells from rats treated with saline and cyclophosphamide. Results. All dosages of cyclophosphamide decreased the development of diabetes. The degree of insulitis was lower in pancreata from 55-day-old rats treated with cyclophosphamide than those from controls. Cyclophosphamide caused no alterations in the numbers of NK cells, T-cell subsets, or RT6.1 + T cells. The adoptive transfer of spleen cells from cyclophosphamide-treated rats to BB rats inhibited the development of diabetes. Cyclophosphamide treatment decreased IL-12, IL-1b, IL-2, IFN-g and TNF-a gene expressions in mononuclear spleen cells but IL-4 gene expression increased. Conclusion/interpretation. These findings show that cyclophosphamide treatment decreases the development of diabetes by inhibiting the development of insulitis. This inhibitory action of cyclophosphamide on the diabetic process seems to be mediated by the induction of immunoregulatory cell activity. The suppression of cytokines that promote Th1 cell differentiation by cyclophosphamide treatment could also play a part in the diabetes sparing effect of cyclophosphamide. [Diabetologia (2000) 43: 986±994]

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Increased In Vitro Interleukin-12 Production by Peripheral Blood in High-Risk IDDM First Degree Relatives

Cited by 29 publications

References 10 publications

Cutting Edge: Diabetes-Associated Quantitative Trait Locus, Idd4, Is Responsible for the IL-12p40 Overexpression Defect in Nonobese Diabetic (NOD) Mice

Cutting Edge: Diabetes-Associated Quantitative Trait Locus, Idd4, Is Responsible for the IL-12p40 Overexpression Defect in Nonobese Diabetic (NOD) Mice

The IL12B 3′ untranslated region DNA polymorphism is not associated with early-onset type 1 diabetes

Cyclophosphamide inhibits the development of diabetes in the diabetes-prone BB rat

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