Immunobiology
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According to the hygiene hypothesis, triggering the immune system with microbial components during childhood balances the inherent Th2 bias. In contrast, specific immunotherapy involves exposure of the patient to the allergen in order to achieve desensitization to subsequent contact. In a human in vitro allergy model the potential of the TLR2/6 agonist BPPcysMPEG to modulate antigen presenting cells and allergen-specific immune responses was evaluated. ⋯ The treatment with BPPcysMPEG induced a Th1-dominated cytokine milieu in mediastinal lymph nodes, while allergen-specific immune responses in splenocytes were diminished. The co-administration of allergen and BPPcysMPEG reduced cytokine secretion upon restimulation in mediastinal lymph nodes and splenocytes. From these data we conclude that BPPcysMPEG was able to influence the immune system with regard to subsequent allergen contact by TLR2/6 agonization.
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The shift between pro-inflammatory (M1) and anti-inflammatory (M2) states of macrophage polarization allows the resolution of inflammatory processes as well as the maintenance of a basal anti-inflammatory environment in tissues continuously exposed to harmless antigens (e.g., lung and gut). To identify markers for the anti-inflammatory state of macrophages, expression profiling was performed on human macrophages polarized by either GM-CSF or M-CSF, which lead to the generation of TNF-alpha and IL-12p40-producing pro-inflammatory macrophages [M1 (GM-CSF)] or IL-10-producing anti-inflammatory macrophages [M2 (M-CSF)] upon exposure to LPS, respectively. A different iron metabolism gene signature was detected in both macrophage types, with the heme regulatory molecules CD163 and Heme Oxygenase-1 (HO-1) being preferentially expressed by M2 (M-CSF) macrophages. ⋯ In contrast to the HO-1 inhibitor tin protoporphyrin (SnPP), the administration of cobalt protoporphyrin (CoPP), a potent inducer of HO-1 resulted in increased LPS-triggered IL-10 release from M2 (M-CSF) macrophages. The data suggests that HO-1 is important for the anti-inflammatory activities of M-CSF-polarized M2 macrophages. Moreover, since M2 (M-CSF) macrophages also express higher levels of the CD163 scavenger receptor, the CD163/HO-1/IL-10 axis appears to contribute to the generation of an immunosuppressive environment within the tumor stroma.
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The soluble form of the haptoglobin-hemoglobin (Hp-Hb) scavenger receptor (sCD163) is a specific plasma/serum marker for macrophage activity. Here, we have characterized molecular forms in serum and investigated a role of sCD163 as a binder of Hp-Hb complexes. ⋯ Serum sCD163 is a homogenous protein covering more than 94% of the CD163 ectodomain including the Hp-Hb-binding region. However, CD163 is a poor competitor of Hp-Hb uptake, probably because of its soluble nature, where Hp-Hb cannot take advantage of receptor cross-linkage.
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The human nasopharynx is an important ecological niche for Streptococcus pneumoniae, and asymptomatic nasopharyngeal carriage is a common precursor to invasive disease. However, knowledge of the immunological events, which occur during carriage, both on a cellular and humoral level, remains limited. Here, we present a long-term stable model of asymptomatic nasopharyngeal carriage using outbred naïve mice, in which we have investigated the effect of previous nasopharyngeal exposure to pneumococci, in the prevention of subsequent carriage and invasive disease. ⋯ In this case systemic anti-PspA and anti-capsular antibody IgM concentrations showed a strong correlation with reduced bacterial numbers in the lungs and nasopharynx, respectively and also with increased levels of IL17A and CD4+ T cells in lungs of pre-colonised mice. Prior nasopharyngeal colonisation with PLN-A also resulted in significant cross-serotype protection with mice protected from invasive disease with serotype 3 strain (A66) after pre-colonisation with a serotype 2 strain (D39). Our results suggest that both mucosal and systemic antibody as well as cellular host factors have a role in long-term protection against both colonisation and invasive pneumococcal challenge.
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Pseudomonas aeruginosa is a common cause of lung infection in immune compromised individuals. Studies in humans and mice have demonstrated that P. aeruginosa lung infection is associated with a predominant Th2 immune response, whereas Th1 responses are accompanied by a better pulmonary outcome. Regulatory T cells (Tregs) are a subpopulation of T cells with unique immunologic characteristics that suppress effector T cell functions. ⋯ Similarly, no differences in lung histology and airway neutrophil infiltration were observed between anti-CD25 and control Ab-treated animals. Furthermore, no difference in survival outcome was found between anti-CD25 and control Ab-treated animals. These data demonstrate that although P. aeruginosa lung infection causes an increase of Tregs, the endogenous natural CD4+CD25+ Treg cells do not contribute significantly to the host response to this bacterium.