Inhalant allergen‐specific T‐cell reactivity is detectable in close to 100% of atopic and normal individuals: covert responses are unmasked by serum‐free medium

Upham, John W.; Holt, Barbara J.; Baron‐Hay, M. J.; Yabuhara, Akihiko; Hales, Belinda J.; Thomas, Wayne R.; Loh, Richard; O’Keeffe, Paul; Lj, Palmer; Souëf, P. Le; Sly, Peter D.; Burton, Paul R.; Robinson, B. W.; Holt, Patrick G.

doi:10.1111/j.1365-2222.1995.tb01111.x

Cited by 123 publications

(113 citation statements)

References 23 publications

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“…Although this is the first report based on the use of human cells and clinically relevant allergens in vivo, it confirms the suggestions of some recent murine asthma models (3)(4)(5). Moreover, our findings are consistent with the observations showing the presence of allergen-reactive T cells in the blood of nonallergic persons (12)(13)(14)(15) and demonstrate in vivo that T lymphocytes with a Th1 cytokine pattern can be driven to a Th2 pattern after exposure to the combination of allergen and adjuvant. Although IFN-␥ production became suppressed in the intrapulmonary human lymphocytes, the Th2 cytokines IL-4 and IL-5 were markedly up-regulated.…”

Section: Discussionsupporting

confidence: 81%

The Allergen-Induced Airway Hyperresponsiveness in a Human-Mouse Chimera Model of Asthma Is T Cell and IL-4 and IL-5 Dependent

Tournoy

Kips

Pauwels

2001

The Journal of Immunology

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The cellular and molecular mechanisms involved in the airway hyperresponsiveness (AHR) of patients with allergic asthma remain unclear. A role for Th2 inflammatory cells was suggested based on murine asthma models. No direct evidence exists on the role of these cells in human asthma. The development of a mouse-human chimera might be useful, allowing the in vivo study of the components of the human immune system relevant to asthma. We investigated the role of allergen-reactive T lymphocytes in a human-mouse SCID model. SCID mice were reconstituted intratracheally with human PBMC from healthy, nonallergic, nonasthmatic donors and exposed to an aerosol of house dust mite allergen after i.p. injection with Dermatophagoides pteronyssinus I Ag and alum. The donor T lymphocytes had a Th1 cytokine phenotype. The reconstituted and allergen-challenged mice developed AHR to carbachol. The mouse airways and lungs were infiltrated with human T lymphocytes. No eosinophils or increases in human IgE were observed. The intrapulmonary human T lymphocytes demonstrated an increase in intracytoplasmic IL-4 and IL-5 and a decrease in IFN-γ after exposure to allergen adjuvant. Antagonizing human IL-4/IL-13 or IL-5 resulted in a normalization of the airway responsiveness, despite a sustained intracellular Th2 cytokine production. These results provide evidence that the activated human allergen-reactive Th2 cells producing IL-4 or IL-5 are pivotal in the induction of AHR, whereas no critical role for eosinophils or IgE could be demonstrated. They also demonstrate that human allergen-specific Th1 lymphocytes can be driven to a Th2 phenotype.

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Section: Discussionsupporting

confidence: 81%

The Allergen-Induced Airway Hyperresponsiveness in a Human-Mouse Chimera Model of Asthma Is T Cell and IL-4 and IL-5 Dependent

Tournoy

Kips

Pauwels

2001

The Journal of Immunology

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“…Lymphocytes from cord blood are capable of recognizing and proliferating in response to certain allergens such as milk protein and aeroallergens (17)(18)(19)(20)24). Proliferative responses to house dust mite allergen, birch pollen, and rye grass (5,21,22) have been observed in mononuclear cells collected at birth and found already to be present at 22 weeks gestation (25). The finding in our study of T cell reactivity in response to several indoor allergens and to mitogen evokes several hypotheses.…”

Section: Discussionmentioning

confidence: 56%

“…Evidence that some aspects of allergic disposition are present at birth has arisen from several studies (5,19,(21)(22)(23). Lymphocytes from cord blood are capable of recognizing and proliferating in response to certain allergens such as milk protein and aeroallergens (17)(18)(19)(20)24).…”

Section: Discussionmentioning

confidence: 99%

Fetal Cord Blood: Aspects of Heightened Immune Responses

Schaub¹,

Tantisira

Gibbons

et al. 2005

J Clin Immunol

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Neonatal immune responses have been associated with the development of atopy in childhood. We assessed in cord blood mononuclear cells (CBMC) whether increased allergen/mitogen-induced lymphoproliferation (LP) is associated with pro-allergic Th2 cytokine IL-13 or Th1 cytokine IFN-γ secretion. We determined whether LP to one allergen is related to heightened lymphocyte function to other allergens/mitogen. CBMC from 135 neonates were stimulated with house dust mite (Derf1), cockroach, ovalbumin, or mitogen. LP to one allergen was associated with significantly increased LP to other allergens/mitogen. Increased Derf1-LP was associated with increased Derf1-induced IL-13 secretion (r = 0.21, p = 0.01). After adjusting for neonatal gender, race, and maternal smoking, Derf1-LP remained associated with Derf1-IL-13 (OR 3.08, 95% CI 1.56-6.10). Increased mitogeninduced proliferation was associated with increased mitogen-induced IL-13 secretion (r = 0.37, p < 0.001). For some individuals, a predisposition to a heightened immune response is already evident at birth. Whether this phenotype results in atopy in childhood warrants further investigation.

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“…PBMCs were isolated after centrifugation of the blood over a Lymphoprep density gradient (Axis-Shield). Some PBMCs were cryopreserved for later use, and previous studies from our laboratory (30) have shown that cellular immune responses are not distorted by this process. From the remaining PBMCs, CD14 ϩ monocytes were isolated by positive selection using MACS beads (Miltenyi Biotech) according to the manufacturer's instructions.…”

Section: Generation Of Monocyte-derived Dcs (Mddc) In Cultures With 1mentioning

confidence: 99%

Airway Epithelial Cells Regulate the Functional Phenotype of Locally Differentiating Dendritic Cells: Implications for the Pathogenesis of Infectious and Allergic Airway Disease

Rate

Upham

Bosco

et al. 2009

The Journal of Immunology

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Atopic asthma pathogenesis is driven by the combined effects of airway inflammation generated during responses to viral infections and aeroallergens, and both these pathways are regulated by dendritic cells (DC) that differentiate locally from monocytic precursors. These DCs normally exhibit a sentinel phenotype characterized by active Ag sampling but attenuated presentation capability, which limits the intensity of local expression of adaptive immunity. How this tight control of airway DC functions is normally maintained, and why it breaks down in some atopics leading to immunopathological changes in airway tissues, is unknown. We postulated that signals from adjacent airway epithelial cells (AEC) contribute to regulation of local differentiation of DC. We tested this in a coculture model containing both cell types in a GM-CSF-IL-4-enriched cytokine milieu characteristic of the atopic asthmatic airway mucosa. We demonstrate that contact with AEC during DC differentiation up-regulates expression of the function-associated markers MHC class II, CD40, CD80, TLR3, and TLR4 on DCs with concomitant up-regulation of Ag uptake/processing. Moreover, the AEC-conditioned DCs displayed increased LPS responsiveness evidenced by higher production of IL-12, IL-6, IL-10, and TNF-α. The Th2 memory-activating properties of AEC-conditioned DCs were also selectively attenuated. Data from microarray and blocking experiments implicate AEC-derived type 1 IFNs and IL-6 in modulation of DC differentiation. Collectively, these findings suggest that resting AECs modulate local DC differentiation to optimize antimicrobial defenses in the airways and in the process down-modulate capacity for expression of potentially damaging Th2 immunity.

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Inhalant allergen‐specific T‐cell reactivity is detectable in close to 100% of atopic and normal individuals: covert responses are unmasked by serum‐free medium

Cited by 123 publications

References 23 publications

The Allergen-Induced Airway Hyperresponsiveness in a Human-Mouse Chimera Model of Asthma Is T Cell and IL-4 and IL-5 Dependent

The Allergen-Induced Airway Hyperresponsiveness in a Human-Mouse Chimera Model of Asthma Is T Cell and IL-4 and IL-5 Dependent

Fetal Cord Blood: Aspects of Heightened Immune Responses

Airway Epithelial Cells Regulate the Functional Phenotype of Locally Differentiating Dendritic Cells: Implications for the Pathogenesis of Infectious and Allergic Airway Disease

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