Environment and T regulatory cells in allergy.

The central role of T regulatory cells in the responses against harmless environmental antigens has been confirmed by many studies. Impaired T regulatory cell function is implicated in many pathological conditions, particularly allergic diseases. The "hygiene hypothesis" suggests that infections and infestations may play a protective role for allergy, whereas environmental pollutants favor the development of allergic diseases. Developing countries suffer from a variety of infections and are also facing an increasing diffusion of environmental pollutants. In these countries allergies increase in relation to the spreading use of xenobiotics (pesticides, herbicides, pollution, etc.) with a rate similar to those of developed countries, overcoming the protective effects of infections. We review here the main mechanisms of non-self tolerance, with particular regard to relations between T regulatory cell activity, infections and infestations such as helminthiasis, and exposure to environmental xenobiotics with relevant diffusion in developing countries.

Immunotoxicity of nanoparticles.

The interaction between NPs and immune system has been demonstrated, however, the data available are limited. Among all traits, i.s. hydrophilicity, lipophilicity, catalytic activity, composition, electronic structure, capacity to bind or coat surface species and solubility, the dimension, and consequently the surface area, seems to be the main factor that contribute to the interactions of NPs with biological tissues and immune system in particular. Certain NPs accumulate to regional lymph nodes, where they can be taken up and processed by dendritic cells, interact with self-proteins and, hence, modify their antigenicity and elicit altered immune responses and even autoimmunity. Other NPs may induce allergic sensitization, i.e. allergic contact dermatitis to Pd. In vitro studies demonstrated that NPs can modulate cytokine production toward Th1 (Pl, Pd, Ni, Co) or Th2 (Ti, mw and sw Carbon) production patterns. Some NPs have been linked to allergic sensitization, however, It is unlikely that NPs can act as a hapten inducing a specific IgE production, likely they can act as adjuvant and induce a specific pattern of cytokines, antibody and cells that favor allergic sensitization to environmental allergens. Furthermore, NPs demonstrated pro-inflammatory effects in the lung in experimental animal with increased expression on IL-1beta, MIP-1alpha, MCP-1, MIP-2, keratinocyte chemoattractant, TARC, GM-CSF, MIP-1alpha and activation of the stress-activated MAPKs p38 and JNKs. All considered, the available data suggest that through the elicitation of an oxidative stress mechanism, engineered NPs may contribute to pro-inflammatory disease processes in the lung, particularly allergy.

Lactobacillus paracasei Lp6 favors immune modulation induced by allergoid treatment in ragweed sensitized mice.

It has been hypothesized that lactic acid bacteria (LAB) could be used as adjuvant for specific immunotherapy (SIT), as various studies conducted on humans and animals converge to define LAB as anti-Th2 modulators and Treg inducers. In the present study we evaluated the effects of LAB, in particular Lactobacillus paracasei Lp6 (Lp6), in a mouse model of ragweed (RW) allergy. Groups of Balb/c mice, experimentally sensitized towards ragweed, were treated by viable Lp6 or by RWallergoid with or without co-administration of Lp6. A control group was sham-sensitized with PBS and sham-treated with water and a group was sensitized with RW and treated with water. Serum IgE, RW-induced release of IFN-gamma, IL-4 and IL-10 from splenocytes and the frequency of CD4CD25 regulatory T cells (Tregs) expressing Foxp3 or IL-10 were evaluated in various groups. RW-allergoid treatment induced a reduction of serum IgE, with a decrease in RW-induced release of IL-4, and an increase in IL-10 and IFN-gamma, along with a significant change in the frequency of Tregs, both CD25+ and -. The joint RWallergoid+ Lp6 treatment induced the highest degree of suppression of allergen-driven IL-4, the greatest reduction of IL-4/IFN-gamma and IL-4/IL-10 ratios and the most significant increase of Foxp3 and IL-10 expressing Tregs. The study shows that Lp6 strengthens the immune modulation induced by allergoid-SIT in RW-sensitized mice, essentially characterized by a differential induction of Tregs associated to a reduction of IL-4; data converge to define a role of SIT adjuvant for Lp6.

Monomeric allergoid intragastric administration induces local and systemic tolerogenic response involving IL-10-producing CD4(+)CD25(+) T regulatory cells in mice.

The efficacy of sublingual immunotherapy, at present one of the treatments of choice for respiratory allergy, relies on the tolerance induced by oral mucosa-associated immune system; however, the gut-associated lymphoid tissue (GALT: Peyers patches and isolated lymphoid follicles) and mesenteric lymph nodes could also be involved, being stimulated by the ingested part of the allergen extract. The aim of the present study is to assess whether the exposure of the allergen exclusively to the GALT induces a tolerogenic response. For this purpose, mice were sensitized with ovalbumin or Par j 1 allergens. The corresponding gastric-resistant monomeric allergoids were then administered via orogastric gavage. After treatment, all mice were tested for: serum IgE, in vitro Th1 and Th2 cytokine release by allergen-stimulated peripheral blood lymphocytes, CD4(+)CD25(+) and CD4(+)CD25(+)IL-10(+) T cells in Peyers patches, mesenteric lymph nodes and spleen. Compared to the control, sensitized groups showed higher levels of serum IgE, lower frequency of CD4+CD25+IL-10+ T cells, at all sites, and higher amounts of in vitroreleased IL-4, IL-6 and TNF-alpha. Compared to the sensitized groups, higher frequency of CD4(+)CD25(+)IL-10(+) T cells was observed in the spleen of both Par-j 1 and OVA sensitized/treated groups and, only for ovalbumin-treated mice, in the Peyers patches and mesenteric lymph nodes, IgE and in vitro cytokines were significantly lower and equivalent to the control group. The results give the first evidence that the intragastric-restricted administration of gastric-resistant allergens restores local and peripheral tolerance in allergen-sensitized mice.

A comparison of nimesulide beta cyclodextrin and nimesulide in postoperative dental pain.

The aim of this study was to assess the efficacy and tolerability of single doses of nimesulide beta cyclodextrin compared with nimesulide in patients with dental pain following surgical procedures. This was a randomised, double-blind, between-patient, multicentre study involving 148 outpatients suffering from moderate to severe pain, who received single doses of either 400 mg nimesulide beta cyclodextrin or 100 mg nimesulide. The principal criterion for efficacy was pain intensity assessed on a visual analogue scale (VAS) 15 minutes after drug intake. Pain intensity was further evaluated 30, 45, 90, 120, 180, 240 and 360 minutes after dosing. Pain relief was evaluated at the same time points by means of a categorical scale. The time point of first pain relief, the use of rescue medication and the global evaluation of efficacy were also recorded. The reduction in pain intensity was significantly more pronounced in the nimesulide beta cyclodextrin group at 15, 30, 45 and 60 minutes (p < 0.01). Pain relief was significantly greater (p < 0.05) and more rapid with nimesulide beta cyclodextrin. In the patient overall assessment of efficacy, nimesulide beta cyclodextrin and nimesulide were rated excellent or good by 95% and 92% respectively; only one patient in the nimesulide beta cyclodextrin group needed rescue medication. Both study drugs were effective and well tolerated in the treatment of acute dental pain, with nimesulide beta cyclodextrin showing a faster onset of analgesic action.