Alterations of in vitro interleukin 1 and 2 in diabetic children

Interleukin 1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF-alpha) may be pathogenetically important in insulin-dependent diabetes mellitus (IDDM), which is associated with genes of the HLA region. Since a regulatory role of HLA region genes on monokine production may exist, we looked for an association between the monokine and prostaglandin E2 (PGE2) responses of monocytes (Mo) from 20 healthy males (18-50 years) with HLA-DR types relevant for IDDM susceptibility and resistance (DR1,2, DR1,3, DR1,4, DR3,4). Monokine assays were established and evaluated and the secretions of IL-1 beta, TNF-alpha, and PGE2 measured in Mo cultures (2h, 6h, 20h) prepared by endotoxin-free techniques and stimulated by low-dose E. coli lipopolysaccharides (LPS). There were no significant associations between Mo responses and HLA-DR phenotype. Likewise, Mo from DR2 (n = 5) and DR4 (n = 5) homozygous healthy males demonstrated no significant differences in monokine and PGE2 responses of Mo. In the HLA class III region a diallelic TNF-beta gene NcoI polymorphism consisting of alleles of 5.5 kb and 10.5 kb was recently described and associated with susceptibility to autoimmune diseases including IDDM. We report that IL-1 beta and TNF-alpha responses of Mo from TNF-beta 10.5 kb homozygous healthy individuals were significantly higher than for TNF-beta 5.5/10.5 kb heterozygotes. IL-1 beta and TNF-alpha responses of Mo from males (18-35 years) with newly diagnosed (n = 10) and long-standing IDDM (n = 10) and from age- and HLA-DR-matched healthy males (n = 10) were studied. LPS, gamma interferon (IFN), and TNF-alpha-stimulated Mo cultures were investigated. No significant differences were found between Mo responses of IDDM patients and controls. IFN (1000 U/ml) in the presence of LPS significantly potentiated LPS-stimulated Mo TNF-alpha secretion and reduced the levels of IL-1 beta immunoreactivity in Mo lysates. IFN and TNF-alpha did not have any effects on LPS-stimulated Mo secretion of IL-1 beta immunoreactivity. We conclude that Mo IL-1 beta and TNF-alpha production is normal in patients with recent-onset and long-standing IDDM. The interindividual differences in monokine responses may be accounted for by the diallelic human TNF-beta gene polymorphism rather than by HLA class II genes. This observation may be important for understanding the association of certain HLA haplotypes with autoimmune phenomena and disease.

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“…Monokine secretory patterns have been reported to be highly variable in autoimmune diseases [2,45,46,60] including IDDM [29,30,48].…”

Section: Discussionmentioning

confidence: 99%

Monocyte Function in IDDM Patients and Healthy Individuals

et al. 1990

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“…DCs may be altered in NOD mice as a result of underlying genetics or inflammation associated with diabetes pathogenesis, which can result in the release of endogenous TLRL and inflammatory cytokines [2,11,12,45]. Therefore, we transferred BDC2.5 T cells to NOD mice lacking the signaling molecule MyD88 (NOD.MyD88Ϫ/Ϫ), which is necessary for most TLR and IL-1R signaling.…”

Section: T Cell Tolerance Induction Is Not Rescued In Recipients Thatmentioning

confidence: 99%

“…These genetic susceptibilities interact with environmental influences to allow for autoreactive T cell stimulation and ␤ cell destruction. For example, both NOD mice and type 1 diabetes patients have IL-1 signatures associated with disease [11][12][13]. Inflammation plays a role in disease initiation and progression, possibly by altering DC number or phenotype that then increases autoreactive T cell stimulation [14].…”

Section: Introductionmentioning

confidence: 99%

CD8+ dendritic cell-mediated tolerance of autoreactive CD4+ T cells is deficient in NOD mice and can be corrected by blocking CD40L

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Beauchamp

Rahir

et al. 2013

Journal of Leukocyte Biology

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DCs are important mediators of peripheral tolerance for the prevention of autoimmunity. Chimeric αDEC-205 antibodies with attached antigens allow in vivo antigen-specific stimulation of T cells by CD8(+) DCs, resulting in tolerance in nonautoimmune mice. However, it is not clear whether DC-mediated tolerance induction occurs in the context of ongoing autoimmunity. We assessed the role of CD8(+) DCs in stimulation of autoreactive CD4(+) T cells in the NOD mouse model of type 1 diabetes. Targeting of antigen to CD8(+) DCs via αDEC-205 led to proliferation and expansion of β-cell specific BDC2.5 T cells. These T cells also produced IL-2 and IFN-γ and did not up-regulate FoxP3, consistent with an activated rather than tolerant phenotype. Similarly, endogenous BDC peptide-reactive T cells, identified with I-A(g7) tetramers, did not become tolerant after antigen delivery via αDEC-205: no deletion or Treg induction was observed. We observed that CD8(+) DCs from NOD mice expressed higher surface levels of CD40 than CD8(+) DCs from C57BL/6 mice. Blockade of CD40-CD40L interactions reduced the number of BDC2.5 T cells remaining in mice, 10 days after antigen targeting to CD8 DCs, and blocked IFN-γ production by BDC2.5 T cells. These data indicate that the ability of autoreactive CD4(+) T cells to undergo tolerance mediated by CD8(+) DCs is defective in NOD mice and that blocking CD40-CD40L interactions can restore tolerance induction.

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“…The role of lymphokines, especially interfer on-gamma, interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a) in the pathogenesis of autoimmune dia betes has recently received increasing attention [2][3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Low Serum Levels of Tumor Necrosis Factor-Alpha in Insulin-Dependent Diabetic Children

et al. 1995

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We measured serum levels of tumor necrosis factor-α (TNF-α) in 48 children with insulin-dependent diabetes mellitus (IDDM), divided into two groups according to disease duration (group I < 6 months and group II > 3 years): group I 15 patients, aged 2.2-13.7 years, and group II 33 patients, aged 4.5-25.5 years. Thirty-six age- and sex-matched healthy subjects served as controls. TNF-α levels were measured by immunoradiometric assay. We found that TNF-α levels were lower in all IDDM patients (29.65 ± 3.83 pg/ml) than in controls (74.74 ± 10.17 pg/ml) (p < 0.0001), as well as in group I (24.07 ± 3.65 pg/ml) and group II (32.16 ± 5.29 pg/ml) as compared to controls (p < 0.001). TNF-α levels were significantly lower in patients with antibodies than in those without antibodies and in controls. Similar results were found in longstanding IDDM patients. No correlation was found between serum TNF-α and chronologic age, duration of disease, metabolic control, insulin requirement and HLA typing. During a 1-year follow-up study in 12 group I patients no significant variations in TNF-α levels were observed. It has been reported that the administration of exogenous TNF suppresses the development of diabetes in nonobese diabetic mice, low producers of endogenous TNF. The results suggest that aberrant TNF-α synthesis may contribute to immune dys-regulation thus favoring the development of autoimmune diseases.

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Alterations of in vitro interleukin 1 and 2 in diabetic children

Cited by 16 publications

References 10 publications

Monocyte Function in IDDM Patients and Healthy Individuals

Monocyte Function in IDDM Patients and Healthy Individuals

CD8+ dendritic cell-mediated tolerance of autoreactive CD4+ T cells is deficient in NOD mice and can be corrected by blocking CD40L

Low Serum Levels of Tumor Necrosis Factor-Alpha in Insulin-Dependent Diabetic Children

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