Biomedical subjects

Jonathan R Lamb

Publications and source records attributed to Jonathan R Lamb.

21 records · Page 2Linked to original sources

PubMed2002

Scavenger receptor-specific allergen delivery elicits IFN-gamma-dominated immunity and directs established TH2-dominated responses to a nonallergic phenotype.

BACKGROUND: Immunotherapeutic approaches to allergy consist of reliably changing allergen-specific T(H)2 immunity associated with secretion of IL-4, IL-5, and IL-13, along with IgE antibodies in atopic individuals to T(H)1 immunity. Our earlier data show that targeting of protein antigens to antigen-presenting cells (APCs), such as macrophages, by means of scavenger receptors (SRs) results in a pronounced T(H)1 immunity. Here we demonstrate a novel experimental approach for the conversion of T(H)2 immunity to T(H)1 immunity by using SR delivery of allergens. OBJECTIVES: We sought to show that targeting of allergens by means of SRs to APCs triggers T(H)1 immunity and that an established T(H)2 immunity to the Der p 1-immunodominant peptide 111-139 (p1, 111-139) can be modulated to a nonallergic T(H)1 phenotype. METHODS: Analysis of the T cell-derived cytokines IL-4, IL-5, IL-13, and IFN-gamma in response to p1, 111-139 in C57BL/6 mice 7 to 42 days after immunization, measurement of specific antibody responses, eosinophilic infiltrate, and skin hypersensitivity in response to allergen challenge constitute the parameters of in vivo immunity. RESULTS: We show that p1, 111-139, when delivered to APCs by means of SR, elicits a T(H)1-dominant immunity. If it is delivered to APCs either after chemical coupling to SR ligands or by means of mere coadsorption on alum in the presence of an SR ligand, the established T(H)2 immunity can be modified to T(H)1 immunity. CONCLUSIONS: SR-mediated delivery of allergens has immunotherapeutic potential that may be usable in atopic individuals.

Animals↗

PubMed2002

Vbeta18.1(+) and V(alpha)2.3(+) T-cell subsets are associated with house dust mite allergy in human subjects.

BACKGROUND: The recognition of allergenic peptides by T cells through their T-cell receptor (TCR) represents a crucial step in the initiation of an allergen-specific immune response. In parallel to the superantigen-driven restricted expansion of Vbeta subsets in autoimmune and infectious diseases, reports in animals and human subjects have shown a similar capacity of classical antigens. OBJECTIVE: The study was performed to analyze the V(alpha)/Vbeta expression in house dust mite (HDM) allergy. METHODS: The TCR repertoire of 15 subjects with HDM allergy, 22 atopic subjects without HDM allergy, and 19 nonatopic individuals, members of 2 extended and 4 nuclear families, was determined. By using flow cytometry, the expression of 22 Vbeta and 3 V(alpha) elements was analyzed in vivo and after in vitro allergen stimulation. RESULTS: In comparison with nonatopic and atopic individuals without HDM allergy, freshly isolated PBMCs of individuals with HDM allergy showed a significantly higher frequency of Vbeta18(+) and V(alpha)2.3(+) T cells. Although members of all 3 groups had a similar lymphocyte proliferation response after in vitro stimulation with Der p 1 or Der p 1 peptide(101-131), a significant expansion of Vbeta18(+) and V(alpha)2.3(+) T cells in vitro occurred only in individuals with HDM allergy. Moreover, the degree of expansion correlated with the levels of allergen-specific IgE antibodies. No expansion of Vbeta18(+) and V(alpha)2.3(+) was observed after mitogen stimulation with PHA, indicating allergen specificity of the response. CONCLUSION: Our results strongly suggest restricted TCR V(alpha)/Vbeta gene use in HDM allergy and might be a step toward TCR-based immunotherapy.

Adolescent↗

PubMed2002

Kinetics and mode of peptide delivery via the respiratory mucosa determine the outcome of activation versus TH2 immunity in allergic inflammation of the airways.

BACKGROUND: Specific immunotherapy involving systemic injection of allergen, though highly effective, can cause severe side effects due to IgE-mediated activation of effector cells. Allergen-derived peptides might provide a safer alternative. We have investigated the use of mucosally delivered peptide to induce CD4(+) T(H)2 cell tolerance and thus protect against allergen-induced airway inflammation. OBJECTIVE: The purpose of this study was to investigate whether intranasal administration of an allergen-derived peptide, either alone or adsorbed to chitosan, can prevent the induction of T(H)2-mediated pulmonary inflammation after sensitization and challenge of the airways with allergen. METHODS: Mice were given (intranasally) a peptide containing an immunodominant epitope of the Dermatophagoides pteronyssinus (Der p) 1 allergen, either as soluble antigen or adsorbed to chitosan, before sensitization and allergen challenge. Pulmonary inflammation, antigen-specific CD4(+) T-cell responses, and antibody levels in sera were then determined. RESULTS: Mice given peptide adsorbed to chitosan had significant reductions in airway eosinophilia, which correlated with reduced levels of IL-4 and IL-5 in the bronchoalveolar lavage fluid. There was decreased recruitment of activated CD4(+) T cells into the airways after allergen challenge, which correlated with a loss of Der p 1-specific T-cell cytokine responses in the periphery and the localized production of IL-10 by antigen-specific T cells in bronchial lymph nodes. Induction of peripheral T-cell tolerance was preceded by transient T-cell activation and IFN-gamma production. CONCLUSION: Our data demonstrate that suppression of airway inflammation by intranasal administration of peptide antigen adsorbed to chitosan is initiated by transient T-cell activation and maintained by the production of IL-10 by antigen-specific T cells in the draining lymph nodes.

Administration, Intranasal↗