The popliteal lymph node response to streptozotocin is under type 1, MHC class-I restricted, CD8+ T-cell control

Choquet-Kastylevsky, Geneviève; Tédone, R.; Ducluzeau, MT; Kehren, Jeanne; Nicolas, Jean‐François; Descotes, Jacques

doi:10.1016/s0300-483x(00)00155-4

Cited by 11 publications

(10 citation statements)

References 40 publications

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“…CD4 + T-cell depleted mice exhibited the expected PLN response after STZ injection (WI = 2.89±0.13). As previously shown (Choquet-Kastylevsky et al 2000), CD8 + T-cell depletion in STZ-treated C57 BL/6 mice resulted in PLN responses within the same range as in saline-treated mice (WI = 1.12±0.14 and 1.10±0.02, respectively). Conversely, neither CD4 + nor CD8 + T-cell depletion had any influence on the PLN responses to acetone or ethanol.…”

Section: Resultssupporting

confidence: 76%

“…The PLN assay was performed as previously described (Choquet-Kastylevsky et al 2000). Mice received an intradermal injection of 0.25 mg STZ, 50% ethanol or pure acetone on day 1 into the right hind footpad, and 50 ll of saline into the left hind footpad.…”

Section: Pln Assaymentioning

confidence: 99%

“…A quantitative reverse transcriptioncoupled polymerase chain reaction (RT-PCR) was used as previously described (Choquet-Kastylevsky et al 2000). PLNs were removed on day +8, weighted, and immediately frozen in liquid nitrogen and finally kept at À80°C before RNA extraction.…”

Section: Cytokine Quantificationmentioning

confidence: 99%

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Popliteal lymph node responses to acetone and ethanol differ from those induced by streptozotocin

Choquet-Kastylevsky¹,

Descotes²

2004

Arch Toxicol

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The popliteal lymph node (PLN) assay was proposed to detect the potential of immunotoxicants for inducing systemic autoimmune-like reactions, but also xenobiotics that are sensitizing or exert immunostimulatory properties. Results on over 100 chemicals, mostly pharmaceuticals, are available with the PLN assay and show many correlations between rodent data and the clinical experience. A major issue is that the mechanisms involved have not been fully elucidated. In order to provide mechanistic clues to improve the predictability of the PLN assay, the effects of streptozotocin (STZ) were compared to those of ethanol and acetone in normal C57Bl/6 mice as well as mice depleted in CD4+ or CD8+ T-cells by treatment with specific monoclonal antibodies. STZ, ethanol and acetone gave similar positive responses in normal mice. Neither CD4+ nor CD8+ T-cell depletion influenced the PLN responses to ethanol or acetone, whereas CD8+ in contrast to CD4+ T-cell depletion abolished the response to STZ. There was an increase in the production of IL-6 and IFN-gamma mRNAs measured by RT-PCR in STZ-, but not in ethanol- or acetone-treated normal mice. The production of TNFalpha, IL-1alpha, IL-1beta, IL-2R and IL-12 mRNAs was increased whatever the treatment, but increases were 2- to 3-fold greater after STZ than ethanol or acetone. These results suggest that PLN responses to primary irritants such as ethanol and acetone essentially reflect non-specific inflammation, whereas PLN responses to an autoimmunogenic compound such as STZ involve CD8+ T lymphocytes and the production of IFN-gamma and IL-6. These findings may prove useful to improve the predictability of the PLN assay.

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Section: Resultssupporting

confidence: 76%

Section: Pln Assaymentioning

confidence: 99%

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Popliteal lymph node responses to acetone and ethanol differ from those induced by streptozotocin

Choquet-Kastylevsky¹,

Descotes²

2004

Arch Toxicol

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“…+ or CD8 + T cells has been proposed as a method for the elimination of false-positive PLN responses to primary irritants (Choquet-Kastylevsky et al, 2000b). Subsequently, false-positive PLN responses to imipramine (Choquet-Kastylevsky et al, 2002), acetone and ethanol (Choquet-Kastylevsky and Descotes, 2004) were shown to reflect primary irritation using this experimental procedure.…”

Section: Refinement Of the Techniquementioning

confidence: 99%

“…In mice, streptozotocin induced a dramatic increase in interferon-γ (IFN-γ ) mRNA production that correlated with WI and CI increases, whereas there was no change in the production of interleukin 4 (IL-4) mRNA (Choquet-Kastylevsky et al, 2000a). Subsequently, streptozotocin was shown to induce a marked increase in the production of IL-6, IFN-γ, tumous neurosis factor alpha (TNF-α), IL-1α, IL-1β, IL-2R and IL-12 mRNA (Choquet-Kastylevsky et al, 2000b), whereas neither ethanol nor acetone induced changes in the production of IL-6 and IFN-γ mRNA (Choquet-Kastylevsky and Descotes, 2004). In addition, increases in the production of TNF-α, IL-1α, IL-1β, IL-2R and IL-12 mRNA were two to three times lower in mice treated with acetone or ethanol than with streptozotocin.…”

Section: Refinement Of the Techniquementioning

confidence: 99%

Popliteal lymph node assay: facts and perspectives

Ravel¹,

Descotes²

2005

J. Appl. Toxicol.

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The popliteal lymph node assay (PLNA) derives from the hypothesis that some supposedly immune-mediated adverse effects induced by certain pharmaceuticals involve a mechanism resembling a graft-versus-host reaction. The injection of many but not all of these compounds into the footpad of mice or rats produces an increase in the weight and/or cellularity of the popliteal lymph node in the treated limb (direct PLNA). Some of the compounds known to cause these adverse effects in humans, however, failed to induce a positive PLNA response, leading to refinements of the technique to include pretreatment with enzyme inducers, depletion of CD4(+) T cells or additional endpoints such as histological examination, lymphocyte subset analysis and cytokine fingerprinting. Alternative approaches have been used to improve further the predictability of the assay. In the secondary PLNA, the test compound is injected twice in order to illicit a greater secondary response, thus suggesting a memory-specific T cell response. In the adoptive PLNA, popliteal lymph node cells from treated mice are injected into the footpad of naive mice; a marked response to a subsequent footpad challenge demonstrates the involvement of T cells. Finally, the reporter antigens TNP-Ficoll and TNP-ovalbumin are used to differentiate compounds that induce responses involving neo-antigen help or co-stimulatory signals (modified PLNA). The PLNA is increasingly considered as a tool for detection of the potential to induce both sensitization and autoimmune reactions. A major current limitation is validation. A small inter-laboratory validation study of the direct PLNA found consistent results. No such study has been performed using an alternative protocol. Other issues include selection of the optimal protocol for an improved prediction of sensitization vs autoimmunity, and the elimination of false-positive responses due to primary irritation. Finally, a better understanding of underlying mechanisms is essential to determine the most relevant endpoints. The confusion resulting from use of the PLNA to predict autoimmune-like reactions as well as sensitization should be clarified. Interestingly, most drugs that were positive in the direct PLNA are also known to cause drug hypersensitivity syndrome in treated patients. This observation is expected to open new avenues of research.

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Granulocyte macrophage‐colony stimulating factor (GM‐CSF) recruits immune cells to the pancreas and delays STZ‐induced diabetes

Krakowski

Abdelmalik

Mocnik

et al. 2001

The Journal of Pathology

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Granulocyte macrophage-colony stimulating factor (GM-CSF) is one of the most widely used growth factors for enhancing immune responses and is known to recruit and activate antigen-presenting cells (APCs). This study hypothesized that overexpression of this cytokine within the pancreatic beta-cells would recruit, expand, and activate APCs. The question was whether this would lead to tolerance or autoimmunity to pancreatic antigens. This possibility was tested by preparing transgenic mice (ins-GM-CSF) whose islets expressed murine GM-CSF. By 6-8 weeks of age, these mice developed a profound mononuclear cell infiltration that often overwhelmed the exocrine pancreas, although no changes in enzyme or hormone function were apparent. The majority of the mononuclear infiltrate within the pancreas was identified as F4/80+ macrophages. Transgenic ins-GM-CSF mice had splenomegaly due to a massive increase in the macrophage population. Additionally, mononuclear cells were found within the livers of transgenic mice, with F4/80+ cells also identified within the infiltrate, indicating that GM-CSF-activated mononuclear cells circulated to organs other than the pancreas. To assess the disease potential, this study tested whether macrophage recruitment to the pancreas might accelerate or protect the islets from diabetes. It was found that the induction of diabetes by low-dose streptozotocin (STZ) was delayed and reduced within ins-GM-CSF transgenic mice, in comparison with negative littermates. Together, these data highlight the role of GM-CSF in recruiting APCs such as macrophages. Advanced cellular infiltration does not overtly harm, and may even protect, pancreatic function, as seen with the delay in chemically induced diabetes.

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The popliteal lymph node response to streptozotocin is under type 1, MHC class-I restricted, CD8+ T-cell control

Cited by 11 publications

References 40 publications

Popliteal lymph node responses to acetone and ethanol differ from those induced by streptozotocin

Popliteal lymph node responses to acetone and ethanol differ from those induced by streptozotocin

Popliteal lymph node assay: facts and perspectives

Granulocyte macrophage‐colony stimulating factor (GM‐CSF) recruits immune cells to the pancreas and delays STZ‐induced diabetes

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