Redirection of Human Autoreactive T-Cells Upon Interaction With Dendritic Cells Modulated by TX527, an Analog of 1,25 Dihydroxyvitamin D3

Redirection of Human Autoreactive T-Cells Upon Interaction With Dendritic Cells Modulated by TX527, an Analog of 1,25 Dihydroxyvitamin D 3 Astrid G.S. van Halteren 1 , Evelyne van Etten 2 , Esther C. de Jong 3 , Roger Bouillon 2 , Bart O. Roep 1 and Chantal Mathieu 2 1 Department of Immunohematology and Blood Transfusion, Leids Universitair Medisch Centrum, Leiden, the Netherlands 2 Laboratory for Experimental Medicine and Endocrinology (LEGENDO), Katholieke Universiteit Leuven, Leuven, Belgium 3 Department of Cell Biology and Histology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Abstract The active form of vitamin D 3 , 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), is a potent immunomodulator known to affect T-cells through targeting antigen-presenting cells such as dendritic cells (DCs). We studied the effects of a novel nonhypercalcemic 1,25(OH) 2 D 3 analog, TX527, on DC differentiation, maturation, and function with respect to stimulation of a committed human GAD65-specific autoreactive T-cell clone. Continuous addition of TX527 impaired interleukin (IL)-4 and granulocyte/macrophage colony-stimulating factor (GM-CSF)-driven DC differentiation as well as lipopolysaccharide (LPS) and interferon-γ (IFN-γ)-induced maturation into Th1-promoting DC (DC1), as characterized by marked changes in DC morphology and abrogation of IL-12p70 release upon CD40 ligation. Addition of TX527 during maturation did not affect DC morphology but significantly changed DC cytokine profiles. The potential of treated DCs to alter the response pattern of committed autoreactive T-cells was found to depend on the timing of TX527 exposure. Continuously TX527-treated DCs significantly inhibited T-cell proliferation and blocked IFN-γ, IL-10, but not IL-13 production, whereas DCs treated during maturation failed to inhibit T-cell proliferation but affected IL-10 and IFN-γ production. Collectively, we provide evidence that nonhypercalcemic TX527 is a potent in vitro DC modulator, yielding DCs with the potential to change cytokine responses of committed autoreactive T-cells. Footnotes Address correspondence and reprint requests to Dr. B.O. Roep, Department of Immunohematology and Blood Transfusion, Leids Universitair Medisch Centrum, E3Q, LUMC, P.O. Box 9600, 2300 RC Leiden, the Netherlands. E-mail: A.G.S.van_Halteren{at}lumc.nl . Received for publication 16 November 2001 and accepted in revised form 21 February 2002. 1,25(OH) 2 D 3 , 1α,25-dihydroxyvita