The histamine H4 receptor mediates allergic airway inflammation by regulating the activation of CD4+ T cells.
Histamine is an important inflammatory mediator that is released in airways during an asthmatic response. However, current antihistamine drugs are not effective in controlling the disease. The discovery of the histamine H4 receptor (H4R) prompted us to reinvestigate the role of histamine in pulmonary allergic responses. H4R-deficient mice and mice treated with H4R antagonists exhibited decreased allergic lung inflammation, with decreases in infiltrating lung eosinophils and lymphocytes and decreases in Th2 responses. Ex vivo restimulation of T cells showed decreases in IL-4, IL-5, IL-13, IL-6, and IL-17 levels, suggesting that T cell functions were disrupted. In vitro studies indicated that blockade of the H4R on dendritic cells leads to decreases in cytokine and chemokine production and limits their ability to induce Th2 responses in T cells. This work suggests that the H4R can modulate allergic responses via its influence on T cell activation. The study expands the known influences of histamine on the immune system and highlights the therapeutic potential of H4R antagonists in allergic conditions.
Dunford
Paul J
PJ
Johnson & Johnson Pharmaceutical Research and Development, San Diego, CA 92121, USA.
O'Donnell
Niall
N
Riley
Jason P
JP
Williams
Kacy N
KN
Karlsson
Lars
L
Thurmond
Robin L
RL
D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D007211:Indoles / Q000008:administration & dosage; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011968:Receptors, Histamine / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000074040:Receptors, Histamine H4; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
D000485:Allergens; D001562:Benzimidazoles; D016207:Cytokines; C498829:Hrh4 protein, mouse; D007211:Indoles; C506811:JNJ 10191584; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D010047:Ovalbumin