Histamine regulates autoreactive T cell activation and adhesiveness in inflamed brain microcirculation.
Histamine may contribute to the pathology of MS and its animal model EAE. We explored the effects of histamine and specific HR agonists on activation and migratory capacity of myelin-autoreactive T cells. We show that histamine in vitro inhibits proliferation and IFN-γ production of mouse T cells activated against PLP(139-151). These effects were mimicked by the H1R agonist HTMT and the H2R agonist dimaprit and were associated with reduced activation of ERK&frac12; kinase and with increased levels of cell cycle inhibitor p27Kip-1, both involved in T cell proliferation and anergy. H1R and H2R agonists reduced spontaneous and chemokine-induced adhesion of autoreactive T cells to ICAM-1 in vitro and blocked firm adhesion of these cells in inflamed brain microcirculation in vivo. Thus histamine, through H1R and H2R, inhibits activation of myelin-autoreactive T cells and their ability to traffic through the inflamed BBB. Strategies aimed at interfering with the histamine axis might have relevance in the therapy of autoimmune disease of the CNS.
Neurological Institute Foundation, IRCCS Carlo Besta, 20133 Milan, Italy.
Marilena
M
Lapilla
Barbara
B
Gallo
Marianna
M
Martinello
Claudio
C
Procaccini
Massimo
M
Costanza
Silvia
S
Musio
Barbara
B
Rossi
Stefano
S
Angiari
Cinthia
C
Farina
Lawrence
L
Steinman
Giuseppe
G
Matarese
Gabriela
G
Constantin
Rosetta
R
Pedotti
D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology; D001921:Brain / Q000098:blood supply*; D002448:Cell Adhesion / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D005260:Female; D006632:Histamine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D017442:Histamine Agonists / Q000494:pharmacology; D018836:Inflammation Mediators / Q000494:pharmacology* / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008833:Microcirculation / Q000276:immunology*; D009103:Multiple Sclerosis / Q000276:immunology; D011968:Receptors, Histamine / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology
D017442:Histamine Agonists; D018836:Inflammation Mediators; D011968:Receptors, Histamine; C087869:histamine trifluoromethyl-toluidide; D006632:Histamine