Differential regulation of dendritic cell function by the immunomodulatory drug thalidomide.
Thalidomide (Thal) was shown to be a potent immunomodulating agent. Because of their central role in controlling immunity, we investigated the effects of Thal on monocyte-derived dendritic cells (Mo-DC). The addition of 10 micro g/ml or 20 micro g/ml Thal from the beginning of monocyte culture with granulocyte macrophage-colony stimulating factor and interleukin (IL)-4 did not block Mo-DC differentiation. Moreover, Thal alone could not induce Mo-DC maturation. However, Thal exerted a modulation of Mo-DC functional properties. At 10 micro g/ml, Thal modified the allostimulatory capacity of DC little, whereas a dose of 20 micro g/ml up-regulated this capacity (P=.05) and increased IL-12p70 production in a dose-dependent manner between 10 and 20 micro g/ml (P=.001). Mo-DC generated with 10 micro g/ml Thal were poor stimulators of T helper cell type 1 (Th1) responses (P=.01), but 20 micro g/ml was able to strengthen Th1 responses (P=.03). Also, Thal induced a significant reduction of IL-10 production in response to the maturation-inducing stimulus CD40L. Similarly, tumor necrosis factor alpha production was significantly decreased when Mo-DC were exposed to 10 micro g/ml Thal, and a dose of 20 micro g/ml did not induce any significant changes. The effects of Thal in vitro on the secretion of IL-12p70 and strengthening of Th1 responses might contribute to the antitumor effects of Thal. Thus, DC appear to be potential targets for the immunomodulatory capacity of Thal, defining a new mechanism of action of this drug.
Mohty
Mohamad
M
Laboratoire d'Immunologie des Tumeurs, Institut Paoli-Calmettes, Université de la Méditerranée, Marseille, France. mohtym@marseille.fnclcc.fr
Stoppa
Anne-Marie
AM
Blaise
Didier
D
Isnardon
Daniel
D
Gastaut
Jean-Albert
JA
Olive
Daniel
D
Gaugler
Béatrice
B
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D013792:Thalidomide / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D016207:Cytokines; D013792:Thalidomide