Dihydropyridine receptors are selective markers of Th2 cells and can be targeted to prevent Th2-dependent immunopathological disorders.
Th1 cells that produce IFN-gamma are essential in the elimination of intracellular pathogens, and Th2 cells that synthetize IL-4 control the eradication of helminths. However, highly polarized Th1 or Th2 responses may be harmful and even lethal. Thus, the development of strategies to selectively down-modulate Th1 or Th2 responses is of therapeutic importance. Herein, we demonstrate that dihydropyridine receptors (DHPR) are expressed on Th2 and not on Th1 murine cells. By using selective agonists and antagonists of DHPR, we show that DHPR are involved in TCR-dependent calcium response in Th2 cells as well as in IL-4, IL-5, and IL-10 synthesis. Nicardipine, an inhibitor of DHPR, is beneficial in experimental models of Th2-dependent pathologies in rats. It strongly inhibits the Th2-mediated autoimmune glomerulonephritis induced by injecting Brown Norway (BN) rats with heavy metals. This drug also prevents the chronic graft vs host reaction induced by injecting CD4(+) T cells from BN rats into (LEW x BN)F(1) hybrids. By contrast, treatment with nicardipine has no effect on the Th1-dependent experimental autoimmune encephalomyelitis triggered in LEW rats immunized with myelin. These data indicate that 1) DHPR are a selective marker of Th2 cells, 2) these calcium channels contribute to calcium signaling in Th2 cells, and 3) blockers of these channels are beneficial in the treatment of Th2-mediated pathologies.
Savignac
Magali
M
Institut National de la Santé et de la Recherche Médicale Unité 563, Institut Federatif de Recherche 30, Hôpital Purpan, Toulouse, France.
Gomes
Bruno
B
Gallard
Alexandra
A
Narbonnet
Stéphane
S
Moreau
Marc
M
Leclerc
Catherine
C
Paulet
Pierre
P
Mariamé
Bernard
B
Druet
Philippe
P
Saoudi
Abdelhadi
A
Fournié
Gilbert J
GJ
Guéry
Jean-Charles
JC
Pelletier
Lucette
L
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D015415:Biomarkers; D002121:Calcium Channel Blockers / Q000008:administration & dosage; D020746:Calcium Channels, L-Type / Q000096:biosynthesis / Q000502:physiology*; D002454:Cell Differentiation / Q000276:immunology; D002908:Chronic Disease; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D006086:Graft vs Host Disease / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D015847:Interleukin-4 / Q000096:biosynthesis; D008297:Male; D019216:Metals, Heavy / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009529:Nicardipine / Q000008:administration & dosage; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
D015415:Biomarkers; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D019216:Metals, Heavy; D015847:Interleukin-4; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009529:Nicardipine