One of the BB rat diabetes (diabetes mellitus (DM)) susceptibility genes is an Ian5 mutation resulting in premature apoptosis of naive T cells. Impaired differentiation of regulatory T cells has been suggested as one possible mechanism through which this mutation contributes to antipancreatic autoimmunity. Using Ian5 congenic inbred rats (wild-type (non-lyp BB) and mutated (BB)), we assessed the development of BB regulatory CD8−4+25+T cells and their role in the pathogenesis of DM. BB rats have normal numbers of functional CD8−4+25+Foxp3+ thymocytes. The proportion of CD25+ cells among CD8−4+ recent thymic emigrants is also normal while it is increased among more mature CD8−4+ T cells. However, BB CD8−4+25+Foxp3+ thymocytes fail to undergo homeostatic expansion and survive upon transfer to nude BB rats while Foxp3 expression is reduced in mature CD8−4+25+ T cells suggesting that these cells are mostly activated cells. Consistent with this interpretation, peripheral BB CD8−4+25+ T cells do not suppress anti-TCR-mediated activation of non-lyp BB CD8−4+25− T cells but rather stimulate it. Furthermore, adoptive transfer of unfractionated T cells from diabetic BB donors induces DM in 71% of the recipients while no DM occurred when donor T cells are depleted of CD8−4+25+ cells. Adoptive transfer of 106 regulatory non-lyp BB CD8−4+25+ T cells to young BB rats protects the recipients from DM. Taken together, these results demonstrate that the BB rat Ian5 mutation alters the survival and function of regulatory CD8−4+25+ T cells at the post-thymic level, resulting in clonal expansion of diabetogenic T cells among peripheral CD8−4+25+ cells.
We postulated that the seleno-organic compound ebselen would attenuate neutrophil recruitment and activation after aerosolized challenge with endotoxin (LPS) through its effect as an antioxidant and inhibitor of gene activation. Rats were given ebselen (1–100 mg/kg i.p.) followed by aerosolized LPS exposure (0.3 mg/ml for 30 min). Airway inflammatory indices were measured 4 h postchallenge. Bronchoalveolar lavage (BAL) fluid cellularity and myeloperoxidase activity were used as a measure of neutrophil recruitment and activation. RT-PCR analysis was performed in lung tissue to assess gene expression of TNF-α, cytokine-induced neutrophil chemoattractant-1 (CINC-1), macrophage-inflammatory protein-2 (MIP-2), ICAM-1, IL-10, and inducible NO synthase. Protein levels in lung and BAL were also determined by ELISA. Ebselen pretreatment inhibited neutrophil influx and activation as assessed by BAL fluid cellularity and myeloperoxidase activity in cell-free BAL and BAL cell homogenates. This protective effect was accompanied by a significant reduction in lung and BAL fluid TNF-α and IL-1β protein and/or mRNA levels. Ebselen pretreatment also prevented lung ICAM-1 mRNA up-regulation in response to airway challenge with LPS. This was not a global effect of ebselen on LPS-induced gene expression, because the rise in lung and BAL CINC-1 and MIP-2 protein levels were unaffected as were lung mRNA expressions for CINC-1, MIP-2, IL-10, and inducible NO synthase. These data suggest that the anti-inflammatory properties of ebselen are achieved through an inhibition of lung ICAM-1 expression possibly through an inhibition of TNF-α and IL-1β, which are potent neutrophil recruiting mediators and effective inducers of ICAM-1 expression.
Treatment of patients with invasive fungal infections was associated with a significantly higher inpatient hospital cost compared with controls. However, due to new diagnostic techniques and effective antifungal therapy, the relative cost of these infections appears to be at least stable compared with the previous decade. These findings can help assess the utility of cost-avoidance strategies such as antifungal prophylaxis and application of appropriate treatment.
1 The antigen-induced in¯ammatory response in the Brown Norway rat is a model commonly used to assess the impact of novel compounds on airway eosinophilia. A detailed functional, cellular and molecular characterization of this model has not yet been performed within a single study. This information together with the temporal changes in this phenomenon should be known before this model can be used, with con®dence, to elucidate the mechanisms of action of novel antiin¯ammatory drugs. 2 Antigen challenge caused an accumulation of eosinophils in lung tissue 24 h after challenge. Accumulation of CD2 + T cells was not apparent until after 72 h. 3 Interestingly, mRNA for the Th2 type cytokines interleukin (IL)-4, IL-5 and IL-13 and eotaxin were elevated in lung tissue after challenge and the expression of IL-13 and eotaxin protein increased at around 8 ± 12 h. The temporal changes in both the biomarker production and the functional responses are important factors to consider in protocol design prior to initiating a compound screening program. 4 A neutralising antibody (R73) against ab-TCR caused a signi®cant reduction in T cell numbers accompanied by a signi®cant suppression of eosinophil accumulation. 5 Airway hyperreactivity (AHR) was not apparent in this speci®c Brown Norway model in sensitized animals after a single or multiple challenges although eosinophil in¯ux was seen in the same animals. 6 In conclusion, this is a convenient pre-clinical model (incorporating the measurement of biomarkers and functional responses) for screening novel small molecule inhibitors and/or biotherapeutics targeted against T cell/eosinophil in®ltration/activation.
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