Showing papers by "Erwin W. Gelfand published in 2007"

Naturally Occurring Lung CD4+CD25+ T Cell Regulation of Airway Allergic Responses Depends on IL-10 Induction of TGF-β

Abstract: Peripheral tolerance to allergens is mediated in large part by the naturally occurring lung CD4(+)CD25(+) T cells, but their effects on allergen-induced airway responsiveness have not been well defined. Intratracheal, but not i.v., administration of naive lung CD4(+)CD25(+) T cells before allergen challenge of sensitized mice, similar to the administration of the combination of rIL-10 and rTGF-beta, resulted in reduced airway hyperresponsiveness (AHR) and inflammation, lower levels of Th2 cytokines, higher levels of IL-10 and TGF-beta, and less severe lung histopathology. Significantly, CD4(+)CD25(+) T cells isolated from IL-10(-/-) mice had no effect on AHR and inflammation, but when incubated with rIL-10 before transfer, suppressed AHR, and inflammation, and was associated with elevated levels of bronchoalveolar lavage TGF-beta levels. By analogy, anti-TGF-beta treatment reduced regulatory T cell activity. These data identify naturally occurring lung CD4(+)CD25(+) T cells as capable of regulating lung allergic responses in an IL-10- and TGF-beta-dependent manner.

Spontaneous Airway Hyperresponsiveness in Estrogen Receptor-α–deficient Mice

Abstract: Rationale: Airway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans.Objectives: To examine the role of estrogen receptors in modulating lung function and airway responsiveness using estrogen receptor–deficient mice.Methods: Lung function was assessed by a combination of whole-body barometric plethysmography, invasive measurement of airway resistance, and isometric force measurements in isolated bronchial rings. M2 muscarinic receptor expression was assessed by Western blotting, and function was assessed by electrical field stimulation of tracheas in the presence/absence of gallamine. Allergic airway disease was examined after ovalbumin sensitization and exposure.Measurements and Main Results: Estrogen receptor-α knockout mice exhibit a variety of lung function abnormalities and have enhanced airway responsiveness to inhaled methacholine and serotonin under basa...

Intravenous immunoglobulin: properties, mode of action and practical use in dermatology.

Abstract: Since they were first administered to patients with antibody deficiency disorders over 50 years ago, human intravenous immunoglobulin preparations have been used successfully to treat a rapidly increasing number of autoimmune and inflammatory disorders, among which are a series of cutaneous autoimmune and inflammatory diseases. These include dermatomyositis, Kawasaki's disease, a number of autoimmune bullous diseases, severe adverse drug reactions, and other autoimmune and/or allergic conditions, such as atopic dermatitis. Although only a minority of these indications (dermatomyositis, Kawasaki's disease) are officially registered or based on double-blind, placebo-controlled clinical studies, the observed efficacy and safety profile of currently available intravenous immunoglobulin sometimes makes this a treatment of choice for initiation of therapy or for replacement of more toxic alternatives, such as systemic immunosuppressive medications. The increasing use of intravenous immunoglobulin has been associated with further understanding of its mechanism(s) of action, clinical manipulation and associated side-effects, as well as the introduction of improved or new types of intravenous immunoglobulin. This paper reviews the current knowledge of the mode of action of intravenous immunoglobulin, its reported therapeutic effects in cutaneous disease, its mode of administration and safety profile, and compares the currently available intravenous immunoglobulin preparations.

IL-10-treated dendritic cells decrease airway hyperresponsiveness and airway inflammation in mice.

Abstract: Background IL-10 affects dendritic cell (DC) function, but the effects on airway hyperresponsiveness (AHR) and inflammation are not defined. Objective We sought to determine the importance of IL-10 in regulating DC function in allergen-induced AHR and airway inflammation. Methods DCs were generated from bone marrow in the presence or absence of IL-10. In vivo IL-10–treated DCs from IL-10 +/+ and IL-10 −/− donors pulsed with ovalbumin (OVA) were transferred to naive or sensitized mice before challenge. In recipient mice AHR, cytokine levels, cell composition of bronchoalveolar lavage (BAL) fluid, and lung histology were monitored. Results In vitro , IL-10–treated DCs expressed lower levels of CD11c, CD80, and CD86; expressed lower levels of IL-12; and suppressed T H 2 cytokine production. In vivo , after transfer of OVA-pulsed IL-10–treated DCs, naive mice did not have AHR, airway eosinophilia, T H 2 cytokine increase in BAL fluid, or goblet cell metaplasia when challenged, and in sensitized and challenged mice IL-10–treated DCs suppressed these responses. Levels of IL-10 in BAL fluid and numbers of lung CD4 + IL-10 + T cells were increased in mice that received OVA-pulsed IL-10–treated DCs. Transfer of IL-10–treated DCs from IL-10–deficient mice were ineffective in suppressing the responses in sensitized and challenged mice. Conclusions These data demonstrate that IL-10–treated DCs are potent suppressors of the development of AHR, inflammation, and T H 2 cytokine production; these regulatory functions are at least in part through the induction of endogenous (DC) production of IL-10. Clinical implications Modification of DC function by IL-10 can attenuate lung allergic responses, including the development of AHR.

CD8+ T Cell-Mediated Airway Hyperresponsiveness and Inflammation Is Dependent on CD4+IL-4+ T Cells

Abstract: CD4+ T cells, particularly Th2 cells, play a pivotal role in allergic airway inflammation. However, the requirements for interactions between CD4+ and CD8+ T cells in airway allergic inflammation have not been delineated. Sensitized and challenged OT-1 mice in which CD8+ T cells expressing the transgene for the OVA(257-264) peptide (SIINFEKL) failed to develop airway hyperresponsiveness (AHR), airway eosinophilia, Th2 cytokine elevation, or goblet cell metaplasia. OT-1 mice that received naive CD4+IL-4+ T cells but not CD4+IL-4- T cells before sensitization developed all of these responses to the same degree as wild-type mice. Moreover, recipients of CD4+IL-4+ T cells developed significant increases in the number of CD8+IL-13+ T cells in the lung, whereas sensitized OT-1 mice that received primed CD4+ T cells just before challenge failed to develop these responses. Sensitized CD8-deficient mice that received CD8+ T cells from OT-1 mice that received naive CD4+ T cells before sensitization increased AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged with allergen. In contrast, sensitized CD8-deficient mice receiving CD8+ T cells from OT-1 mice without CD4+ T cells developed reduced AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged. These data suggest that interactions between CD4+ and CD8+ T cells, in part through IL-4 during the sensitization phase, are essential to the development of CD8+IL-13+ T cell-dependent AHR and airway allergic inflammation.

Airway Hyperresponsiveness through Synergy of γδ T Cells and NKT Cells

Abstract: Mice sensitized and challenged with OVA were used to investigate the role of innate T cells in the development of allergic airway hyperresponsiveness (AHR). AHR, but not eosinophilic airway inflammation, was induced in T cell-deficient mice by small numbers of cotransferred γδ T cells and invariant NKT cells, whereas either cell type alone was not effective. Only Vγ1+Vδ5+ γδ T cells enhanced AHR. Surprisingly, OVA-specific αβ T cells were not required, revealing a pathway of AHR development mediated entirely by innate T cells. The data suggest that lymphocytic synergism, which is key to the Ag-specific adaptive immune response, is also intrinsic to T cell-dependent innate responses.

IL-2 and IL-18 Attenuation of Airway Hyperresponsiveness Requires STAT4, IFN-γ, and Natural Killer Cells

Abstract: IL-18 is known to induce IFN-γ production, which is enhanced when combined with IL-2. In the present study, we investigated whether the combination of exogenous IL-2 and IL-18 alters airway hyperresponsiveness (AHR) and airway inflammation. Sensitized mice exposed to ovalbumin (OVA) challenge developed AHR, inflammatory cells in the bronchoalveolar lavage (BAL) fluid, and increases in levels of Th2 cytokines and goblet cell numbers. The combination of IL-2 and IL-18, but neither alone, prevented these changes while increasing levels of IL-12 and IFN-γ. The combination of IL-2 and IL-18 was ineffective in IFN-γ–deficient and signal transducer and activator of transcription (STAT)4-deficient mice. Flow cytometry analysis showed significant increases in numbers of IFN-γ–positive natural killer (NK) cells in the lung after treatment with the combination therapy, and transfer of lung NK cells isolated from sensitized and challenged mice treated with the combination significantly suppressed AHR and BAL eosinoph...

A study of health effect estimates using competing methods to model personal exposures to ambient PM2.5.

Abstract: Various methods have been developed recently to estimate personal exposures to ambient particulate matter less than 2.5 microm in diameter (PM2.5) using fixed outdoor monitors as well as personal exposure monitors. One class of estimators involves extrapolating values using ambient-source components of PM2.5, such as sulfate and iron. A key step in extrapolating these values is to correct for differences in infiltration characteristics of the component used in extrapolation (such as sulfate within PM2.5) and PM2.5. When this is not done, resulting health effect estimates will be biased. Another class of approaches involves factor analysis methods such as positive matrix factorization (PMF). Using either an extrapolation or a factor analysis method in conjunction with regression calibration allows one to estimate the direct effects of ambient PM2.5 on health, eliminating bias caused by using fixed outdoor monitors and estimated personal ambient PM2.5 concentrations. Several forms of the extrapolation method are defined, including some new ones. Health effect estimates that result from the use of these methods are compared with those from an expanded PMF analysis using data collected from a health study of asthmatic children conducted in Denver, Colorado. Examining differences in health effect estimates among the various methods using a measure of lung function (forced expiratory volume in 1 s) as the health indicator demonstrated the importance of the correction factor(s) in the extrapolation methods and that PMF yielded results comparable with the extrapolation methods that incorporated correction factors.

Activation of naturally occurring lung CD4(+)CD25(+) regulatory T cells requires CD8 and MHC I interaction.

Abstract: Naturally occurring Foxp3+CD4+CD25+ T cells (nTregs) isolated from lungs of naive mice regulate allergic airway hyperresponsiveness (AHR) and inflammation. Here, we demonstrate the critical requirement for engagement of MHC class I on CD4+CD25+ T cells by CD8 for the functional activation of these nTregs. Suppression of allergen-induced AHR and inflammation by nTregs was abolished in mice treated with anti-CD8. Correspondingly, decreased levels of IL-10 and TGF-β and increased levels of Th2 cytokines in bronchoalveolar lavage were detected in these treated mice. Similarly, nTregs isolated from β2m−/− mice or from mice treated with anti-MHC I antibody in vitro before intratracheal transfer failed to modulate AHR or inflammation. Coculture of nTregs with CD8+ T cells increased IL-10 and TGF-β. Addition of anti-MHC I or anti-CD8 reduced IL-10 and TGF-β. These results demonstrate that functional activation of nTregs requires the interaction between MHC I on CD4+CD25+ T cells and CD8.

Arhgef1 is required by T cells for the development of airway hyperreactivity and inflammation.

Abstract: Rationale: Arhgef1 is an intracellular protein, expressed by hematopoietic cells, that regulates signaling by both G protein–coupled receptors and RhoA, and, consequently, is required for appropriate migration and adhesion of diverse leukocyte populations.Objectives: To evaluate a possible contribution for Arhgef1 in the development of airway inflammation and airway hyperreactivity.Methods: Arhgef1-deficient (Arhgef1−/−) and wild-type (WT) mice were sensitized and airway challenged, followed by measurement of airway responsiveness to inhaled methacholine. Inflammation was assessed by several parameters that included flow cytometric analysis and histology. Arhgef1-deficient recipients were reconstituted with WT T lymphocytes before sensitization and challenge, and again measured for airway responsiveness and inflammation. Cytokine production in response to specific antigen was measured in cultures of isolated leukocytes from lung and spleen and compared with the levels generated in lung and spleen explant ...