title: Histamine H(4) receptor antagonism inhibits allergen-specific T-cell responses mediated by human dendritic cells.
abstract: Dendritic cells are potential targets in allergy therapy as they, under the influence of their microenvironment, regulate T-cell responses. Histamine has been shown to promote Th2 polarization by dendritic cells. However, neither the mechanism nor the functionality of the different histamine receptors in this process has been fully elucidated. The aim of the present study was to identify factors involved in histamine-mediated dendritic cell activation as well as to study dendritic cell expression of histamine H(1) and H(4) receptors and their influence on allergen-specific T-cell responses in grass pollen allergy. Assessment of dendritic cell gene regulation by histamine using mRNA microarrays demonstrated that histamine alters many immunoregulatory genes of which the majority are novel in this context. Additionally, immunocytochemical stainings showed protein expression of histamine H(1) and H(4) receptors on dendritic cells from healthy and allergic donors. Furthermore, histamine H(1) and H(4) receptor antagonists (pyrilamine/N-(4-methoxybenzyl)-N',N'-dimethyl-N-pyridin-2-ylethane-1,2-diamine and JNJ7777120/1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine, respectively) were shown to influence histamine-induced dendritic cell maturation. Interestingly, JNJ7777120 inhibited dendritic cells' capacity to induce allergen-specific T-cell proliferation. In conclusion, H(4) receptor antagonism suppressed DC-induced, allergen-specific T-cell responses in humans and might thus inhibit allergic responses. This finding indicates that the H(4) receptor is a potential treatment target in human allergic conditions.
authors.affiliation: Department of Immunotechnology, BMC D13, Lund University, SE-221 84 Lund, Sweden. kristina.lundberg@immun.lth.se
authors.forename: Kristina
authors.initials: K
authors.lastname: Lundberg
authors.forename: Sissela
authors.initials: S
authors.lastname: Broos
authors.forename: Lennart
authors.initials: L
authors.lastname: Greiff
authors.forename: Carl A K
authors.initials: CA
authors.lastname: Borrebaeck
authors.forename: Malin
authors.initials: M
authors.lastname: Lindstedt
mesh_terms: D000328:Adult; D000485:Allergens / Q000276:immunology*; D016022:Case-Control Studies; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011968:Receptors, Histamine / Q000235:genetics / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D055815:Young Adult
chemical_list: D000485:Allergens; C418607:HRH4 protein, human; D007211:Indoles; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D011969:Receptors, Histamine H1; D000074040:Receptors, Histamine H4; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D006632:Histamine; D011738:Pyrilamine