Recent evidence from mouse models indicates that neonatal exposure to lipopolysaccharide (LPS) can prevent experimentally induced allergic disease. Furthermore, we noted that human cord blood mononuclear cells (CBMC) have an increased proliferative response to LPS relative to their respective maternal peripheral blood mononuclear cells (PBMC). We sought, therefore, to examine the cytokine expression profile induced by LPS in CBMC and its relationship to the LPS-mediated proliferative response. CBMC and maternal PBMC were evaluated for IL-10, IL-4, IL-13, IL-12 alpha, and IFN-gamma expression after LPS stimulation by real-time PCR. IFN-gamma secretion was detected by enzyme-linked immunosorbent assay. LPS increased IFN-gamma and IL-13, but decreased IL-4 expression in CBMC (P < 0.024, P < 0.014, and P < 0.027, respectively). In PBMC, however, no significant changes in expression were noted after LPS stimulation. Stimulation by LPS significantly increased the secretion of IFN-gamma in CBMC compared with PBMC at the two concentrations analyzed (1 ng/ml, P < 0.048; 10,000 ng/ml, P < 0.003). The magnitude of the LPS-mediated proliferative effect in CBMC directly correlated to the level of induction of IFN-gamma (P < 0.01), but inversely correlated to the induced levels of IL-4 and IL-13 (P < 0.01 and P = 0.01, respectively). No association of the CBMC proliferative response to IL-12 alpha or IL-10 was noted. Thus, a high proliferative response to LPS in CBMC correlates with a change from a Th2- to Th1-induced cytokine expression profile. Since early exposure to LPS may protect against allergic disease, one may speculate that an aberrant response to LPS may increase the likelihood of developing overt disease in susceptible individuals.
Despite an attenuated proliferative response in human cord blood mononuclear cells (CBMCs) to activation of its TCR in vitro, the neonate is capable of mounting a mature T(h)1-type response to BCG vaccination. We hypothesized that in the context of other innate triggers, activation of the TCR can be restored. In order to test this hypothesis, we analyzed CBMC response to LPS, with LPS serving as a surrogate activator of the innate system. We performed proliferative assays on 34 maternal-neonatal pairs of PBMCs and CBMCs, respectively. In all, 30/34 (88%) of CBMCs proliferated in response to LPS (10 microg ml(-1), P < 2.7 x 10(-7)), in contrast to only 10/32 (31%) of their respective maternally derived PBMCs, despite having a comparatively greater response to PHA than did their CBMC counterparts (P < 0.0002). LPS synergized with immobilized anti-human CD3epsilon mAb (1.25-10 microg ml(-1)) to augment the proliferative response in CBMCs but failed to do so in maternally derived PBMCs. LPS responsiveness and its synergy with activation of the TCR in CBMCs were independent of accessory cells. These results are the first evidence that LPS and anti-CD3 mAb are synergistic, demonstrating a critical link between the innate and adaptive immune systems.
Background:We previously demonstrated that the proliferative response to lipopolysaccharide (LPS) in cord blood mononuclear cells (CBMCs) is negatively correlated with the induced expression of interleukin (IL)-4. Our aim, therefore, was to examine whether an impaired cellular response to LPS in infancy is associated with the risk for asthma. Methods: In a prospective cohort study, the relationship between the CBMC response to LPS and the risk of atopy and wheezing after the age of 4 y was evaluated. results: LPS-induced CBMC proliferative responses varied markedly among the 102 infants studied (range, one-to fivefold increase over cells with diluent alone). Ninety-five infants (93%) were followed longitudinally. A higher CBMC proliferative response to LPS was noted in offspring born to nonatopic parents compared with those with at least one atopic parent (P = 0.008). Using a proliferative index cutoff of 2 separated patients into high and low induced IL-4 mRNA responders (P = 0.001). Significantly more children who never wheezed had a greater than twofold LPS-induced CBMC proliferative response compared to those with persistent atopic wheezing (P = 0.046). conclusion: These results demonstrate that CBMC proliferative responses to LPS is impaired in infants born to atopic parents and may be a risk factor for asthma later in life.
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