1: Infect Immun. 2003 May;71(5):2607-14. Changes in pulmonary function and parasite burden in rats infected with Strongyloides venezuelensis concomitant with induction of allergic airway inflammation. Negrao-Correa D, Silveira MR, Borges CM, Souza DG, Teixeira MM. Departamento de Parasitologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. denegra@icb.ufmg.br The prevalence of allergic diseases such as asthma has increased markedly over the past few decades. To evaluate the possible mutual influence of helminth infection and allergy, the combined effects of experimental allergic airway inflammation and infection with Strongyloides venezuelensis on various parasitological and inflammatory indices were evaluated in the rat. A challenge of immunized rats with aerosolized ovalbumin (OVA) resulted in eosinophilic inflammation that peaked 48 h after the challenge and was accompanied by airway hyperresponsiveness (AHR) to an intravenous acetylcholine challenge. S. venezuelensis infection concomitant with an OVA challenge of immunized rats resulted in prolonged pulmonary inflammation with increased eosinophil infiltration in bronchoalveolar lavage fluid but not in the lung tissue. These rats also showed a significant parasite burden reduction, especially during parasite migration through the lungs. However, the fecundity rates of worms that reached the intestine were similar in allergic and nonallergic animals. Despite airway inflammation, the increased responsiveness of the airways in the experimental asthma model was suppressed during parasite migration through the lungs (2 days). In contrast, parasite-induced AHR was unchanged 5 days after infection in immunized and challenged rats. In conclusion, infection with S. venezuelensis interfered with the onset of AHR following an antigen challenge of immunized rats. The ability of parasites to switch off functional airway responses is therapeutically relevant because we may learn from parasites how to modulate lung function and, hence, the AHR characteristic of asthmatic patients. PMID: 12704135 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 2: Nat Med. 2002 Sep;8(9):1024-32. Epub 2002 Jul 29. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, Berry G, DeKruyff RH, Umetsu DT. Division of Immunology and Allergy, Department of Pediatrics, School of Medicine, Stanford University, Stanford, California, USA. Asthma is caused by T-helper cell 2 (Th2)-driven immune responses, but the immunological mechanisms that protect against asthma development are poorly understood. T-cell tolerance, induced by respiratory exposure to allergen, can inhibit the development of airway hyperreactivity (AHR), a cardinal feature of asthma, and we show here that regulatory T (T(R)) cells can mediate this protective effect. Mature pulmonary dendritic cells in the bronchial lymph nodes of mice exposed to respiratory allergen induced the development of T(R) cells, in a process that required T-cell costimulation via the inducible costimulator (ICOS-ICOS-ligand pathway. The T(R) cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mice, T(R) cells blocked the development of AHR. Both the development and the inhibitory function of regulatory cells were dependent on the presence of IL-10 and on ICOS-ICOS-ligand interactions. These studies demonstrate that T(R) cells and the ICOS-ICOS-ligand signaling pathway are critically involved in respiratory tolerance and in downregulating pulmonary inflammation in asthma. PMID: 12145647 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 3: Am J Respir Crit Care Med. 2002 Mar 15;165(6):824-31. The failure of interleukin-10-deficient mice to develop airway hyperresponsiveness is overcome by respiratory syncytial virus infection in allergen-sensitized/challenged mice. Makela MJ, Kanehiro A, Dakhama A, Borish L, Joetham A, Tripp R, Anderson L, Gelfand EW. Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado, USA. Interleukin-10-deficient mice develop a robust pulmonary inflammatory response but no airway hyperresponsiveness (AHR) to inhaled methacholine (MCh) following allergen sensitization and challenge. In the present study, we investigated the effect of respiratory syncytial virus (RSV) infection on AHR and pulmonary inflammation in allergic IL-10-/- mice. Unlike littermate control mice, RSV-infected or ovalbumin (OVA)-sensitized/challenged IL-10-/- mice failed to develop significant AHR. In contrast, sensitized/challenged IL-10-/- mice infected with RSV did develop AHR accompanied by increased eosinophil numbers, both in bronchoalveolar lavage (BAL) and pulmonary tissue, and mucin production in airway epithelium. The cytokine profile in OVA-sensitized/challenged IL-10-/- mice was skewed toward a Th1 response but after RSV infection, this response was more of a Th2 type, with increased IL-5 levels in the BAL. Studies with an RSV mutant that lacks the G and SH genes showed equal enhancement of the AHR response as the parental wild-type strain, indicating that G protein is not essential to this response. These data suggest that RSV infection can overcome the failure of development of AHR in allergic IL-10-/- mice. PMID: 11897651 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 4: Mol Pharmacol. 2001 Apr;59(4):716-24. Cell-specific regulation of human aryl hydrocarbon receptor expression by transforming growth factor-beta(1). Wolff S, Harper PA, Wong JM, Mostert V, Wang Y, Abel J. Department of Experimental Toxicology, Medical Institute of Environmental Hygiene at the Heinrich-Heine-University, Dusseldorf, Germany. Previous studies showed that TGF-beta down-regulates aryl hydrocarbon (AhR) expression in human lung carcinoma cells A549. Here we analyzed the molecular mechanisms by which TGF-beta modulates AhR expression. A 5799-nucleotide 5'-flanking region of human AhR gene was isolated. Transient transfection studies of full-length (hAhRP) and deletion promoter constructs indicate the requirement of a cis-regulatory element encompassing -1980 to -1892 for full constitutive activity. Basal hAhRP activity occurs in a cell-specific manner; human hepatoma HepG2 cells possess a 10-fold higher activity compared with A549 cells. TGF-beta exerts cell-specific effects on hAhRP activity. Treatment of cells with 100 pM TGF-beta leads to a 50% inhibition in A549 and a 3-fold induction in HepG2 cells. Deletion mutagenesis identified a TGF-beta-responsive sequence containing a functional conserved Smad-binding element. Transient overexpression of Smad 2, 3, and 4 indicates that these signal transducers modulate hAhRP activity. The down-regulation of AhR by TGF-beta is modulated by 5'-TG-3'-interacting factor (TGIF). Transient overexpression of TGIF in MDA-MB231 and HepG2 cells led to inhibition of hAhRP activity and a similar decrease of AhR mRNA expression. Our findings indicate that Smad proteins are involved in the cell-specific regulation of AhR expression by TGF-beta. PMID: 11259615 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 5: Am J Physiol Lung Cell Mol Physiol. 2001 Feb;280(2):L363-8. IL-10 gene knockout attenuates allergen-induced airway hyperresponsiveness in C57BL/6 mice. Justice JP, Shibata Y, Sur S, Mustafa J, Fan M, Van Scott MR. Departments of Physiology and Pharmacology, Brody School of Medicine at East Carolina University, Greenville, North Carolina 27858, USA. Intratracheal administration of interleukin-10 (IL-10) has been reported to inhibit allergic inflammation but augment airway hyperresponsiveness (AHR). In the present study, airway and smooth muscle responsiveness to methacholine (MCh) were compared in wild-type (WT) and IL-10-deficient (IL-10-KO) mice to investigate the role of endogenous IL-10 in AHR development. Naive WT and IL-10-KO mice exhibited similar dose-dependent increases in airway resistance (Raw) to intravenous MCh. Sensitization and challenge with ragweed (RW) induced a twofold increase in responsiveness to intravenous MCh in WT mice, but hyperresponsiveness was not observed in similarly treated IL-10-KO mice. Likewise, tracheal rings from RW-sensitized and -challenged WT mice exhibited a fourfold greater responsiveness to MCh than IL-10-KO tracheal preparations. Measurements of airway constriction by whole body plethysmography further supported the Raw and tracheal ring data (i.e., AHR was not observed in the absence of IL-10). Interestingly, factors previously implicated in the development of AHR, including IL-4, IL-5, IL-13, IgA, IgG1, IgE, eosinophilia, and lymphocyte recruitment to the airways, were upregulated in the IL-10-KO mice. Treatment with recombinant murine IL-10 at the time of allergen challenge reduced the magnitude of inflammation but reinstated AHR development in IL-10-KO mice. Adoptive transfer of mononuclear splenocytes to IL-10-sufficient severe combined immunodeficient mice indicated that lymphocytes were an important source of the IL-10 impacting AHR development. These results provide evidence that IL-10 expression promotes the development of allergen-induced smooth muscle hyperresponsiveness. PMID: 11159016 [PubMed - indexed for MEDLINE] ---------------------------------------------------------------