Faculty Bibliography

The large inhibitory effect of IL-13 blockers on the asthma phenotype prompted us to ask whether IL-13 would play a role in regulating the allergic immune response in addition to its documented effects on structural pulmonary cells. Because IL-13 does not interact with murine T or B cells, but with monocytes, macrophages, and dendritic cells (DCs), we examined the role of IL-13 in the activation of pulmonary macrophages and DCs and in the priming of an immune response to a harmless, inhaled Ag. We found that a majority of cells called 'alveolar or interstitial macrophages' express CD11c at high levels (CD11c(high)) and are a mixture of at least two cell types as follows: 1) cells of a mixed phenotype expressing DC and macrophage markers (CD11c, CD205, and F4/80) but little MHC class II (MHC II); and 2) DC-like cells expressing CD11c, CD205, MHC II, and costimulatory molecules. Endogenous IL-13 was necessary to induce and sustain the increase in MHC II and CD40 expression by pulmonary CD11c(high) cells, demonstrated by giving an IL-13 inhibitor as a measure of prevention or reversal to allergen-primed and -challenged mice. Conversely, IL-13 given by inhalation to naive mice increased the expression of MHC II and costimulatory molecules by CD11c(high) cells in an IL-4Ralpha-dependent manner. We found that exogenous IL-13 exaggerated the immune and inflammatory responses to an inhaled, harmless Ag, whereas endogenous IL-13 was necessary for the priming of naive mice with an inhaled, harmless Ag. These data indicate that blockade of IL-13 may have therapeutic potential for controlling the immune response to inhaled Ags

This study was designed to determine if aerosolized hyaluronan (HA) could prevent airspace enlargement and elastic fiber injury in a mouse model of cigarette smoke-induced pulmonary emphysema. Compared to untreated/smoked controls, HA-treated animals showed statistically significant reductions in mean linear intercept (54 versus 65 microm; P < .001) and elastic fiber breakdown products (desmosine and isodesmosine) in bronchoalveolar lavage fluid (0.3 versus 7.0 ng/mL; P < .05). As in previous studies, the aerosolized HA showed preferential binding to elastic fibers, suggesting that it may protect them from injury. These findings support further investigation of the potential use of HA as a treatment for pulmonary emphysema

The interactions between dendritic cells (DCs) and T cells determine the fate of an immune response to pathogenic microbes and to harmless allergens alike. The interactions between DCs and T cells is dependent on the maturation and differentiation status of DCs. This status is affected by the cellular lineage of the DCs and by signals that the cells receive from the environment and from T cells. A specific subpopulation of DCs (dendritic cell type 2 [DC2]) induces the development of T helper 2 (Th2) responses. Unregulated Th2 responses induce and cause inflammation in allergy and asthma. If it would be possible to target DC2 cells for prophylactic or therapeutic measures, then it may be possible to change the T cell response to allergens on a long-term basis. In the past few years, there have been major research efforts to elucidate molecular determinants of DC maturation. This review summarizes the new findings and their potential for future clinical application

A mouse model of human immunodeficiency virus type 1 (HIV-1) infection would be extremely valuable for evaluation of therapies and vaccines; however, multiple blocks to productive infection of NIH 3T3 and other mouse cell lines have been reported. The authors investigated the replication of HIV-1 in primary mouse astrocytes, lymphocytes, and macrophages in culture by infection with intact HIV-1 pseudotyped with the vesicular stomatitis virus G envelope glycoprotein (VSV-G) or with the envelope glycoprotein of amphotropic murine leukemia virus. Astrocytes, lymphocytes, and macrophages were susceptible to productive infection as variously assayed by detection of p24 and Tat proteins, viral protease-mediated processing of Gag, appropriately spliced viral RNA, and infectious progeny virus. As expected, NIH 3T3 cells were not susceptible to productive infection by VSV/NL4. Susceptibility mapped neither to the Fv locus nor to a possible polymorphism in cyclin T1. This study indicates that there are no intrinsic intracellular barriers to HIV-1 replication in primary mouse cells when virus entry is efficient

In horses prone to developing recurrent airway obstruction (RAO), we tested the hypotheses that the cytokine profile in the bronchoalveolar lavage (BAL) cells of affected horses would reflect a polarized Th-2 response; that cytokine and chemokine alterations would occur within 24 h of allergen exposure; and that allergen exposure would induce alterations in the expression of the transcription factor t-bet (t-box-expressed in T-cells). The expression levels of interleukin-4 (IL-4), IL-13, Interferon-gamma (IFN-gamma), t-bet, IL-8 and granulocyte-macrophage colony stimulating factor (GM-CSF) were measured in BAL cells obtained from control and RAO-susceptible horses during an asymptomatic phase and at 24 h and 5 weeks post-stabling and hay exposure. At each sampling time, BAL neutrophil percentages in the RAO-group exceeded controls. In the RAO-group, only IL-13 expression was decreased 2-fold during the asymptomatic phase. No differences in cytokine or chemokine expression were detected during the acute exposure phase. During the chronic phase, IFN-gamma and IL-8 expression levels were 2.5- and 3-fold greater, respectively, in the RAO-group. No other differences in gene expression were detected. We conclude that the cytokine profile of the airway cells does not reflect a polarized Th-2 response; that increases in IFN-gamma result from a t-bet independent pathway and that chemokines from epithelial or interstitial cells may contribute to early neutrophil influx

Inflammation and airway remodeling are two responses readily apparent in asthma and other inflammatory disorders of the airway and lungs. Both adenosine and IL-13 play critical roles in contributing pathways. A new study reveals a previously unrecognized interaction between adenosine and IL-13 that indicates a mutual stimulation that may contribute to the nature and severity of airway inflammation and fibrosis

Experimental animal models of Allergic Bronchopulmonary Aspergillosis (ABPA) serve several purposes. Both common and distinct pathological features occurring in natural and experimental diseases are of great interest as they serve to identify the key elements in the pathogenesis. Experimentally induced diseases can be modeled to understand the various parameters such as antigen and route of exposure, genetic background and the role of response modifiers in the disease process. Furthermore, animals with targeted gene-deletion or with insertion of transgenes have been studied to define the roles of specific cells, receptors and mediators in the pathogenesis. The resulting conclusions have been used to formulate hypothesis, which have to be tested for their application to human disease

Airway inflammation and airway hyperresponsiveness (AHR) are hallmarks of asthma. Cytokines produced by T helper type 2 (Th2) lymphocytes have been implicated in both processes. There is strong support for the idea that Th2 cytokines can produce AHR indirectly by promoting the recruitment of inflammatory cells. Less attention has been given to the possibility that Th2 cytokines might induce AHR by acting directly on resident airway cells. To investigate this, we polarized and activated CD4(+) T cells in vitro and analyzed airway function after administration of lymphocyte-conditioned media to the airways of naive mice. Th2-lymphocyte-conditioned medium induced AHR within 6 h. This finding was reproduced in mast-cell-deficient and in T- and B-lymphocyte-deficient mice. AHR did not occur when Th2-lymphocyte-conditioned medium was administered to mice lacking the IL-4 receptor alpha subunit or Stat6, suggesting a critical role for interleukin (IL)-4 and/or IL-13. This was confirmed by the finding that recombinant IL-4 and IL-13 both induced AHR within 6 h. The induction of AHR occurred in the absence of inflammatory cell recruitment or mucus production. These results strongly suggest that products of activated Th2 lymphocytes can rapidly perturb airway function through direct effects on resident airway cells