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Dihydropyridine Receptors Are Selective Markers of Th2 Cells and Can Be Targeted to Prevent Th2-Dependent Immunopathological Disorders¹

Magali Savignac^2,*, Bruno Gomes^2,*, Alexandra Gallard^*, Stéphane Narbonnet^*, Marc Moreau, Catherine Leclerc, Pierre Paulet^*, Bernard Mariamé^*, Philippe Druet^*, Abdelhadi Saoudi^*, Gilbert J. Fournié^*, Jean-Charles Guéry^* and Lucette Pelletier^3,*

^* Institut National de la Santé et de la Recherche Médicale Unité 563, Institut Federatif de Recherche 30, Hôpital Purpan, Toulouse, France; and Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5547, Université Paul Sabatier, Toulouse, France

Th1 cells that produce IFN- 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)F₁ 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.

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