Therapeutic potential of phosphodiesterase-4 and -3 inhibitors in Th1-mediated autoimmune diseases.
Phosphodiesterase-4 (PDE4) inhibitors have the potential to modulate immune responses from the Th1 toward the Th2 phenotype and are considered candidate therapies for Th1-mediated autoimmune disorders. However, depending on the model and cell types employed, studies of atopic individuals have come to the opposite conclusion, i.e., that PDE inhibitors may be beneficial in asthma. Using in vitro immunopharmacologic techniques we analyzed the effects of PDE4 and PDE3 inhibitors on human immune cells to address these discrepancies and broaden our understanding of their mechanism of action. Our results indicate that PDE inhibitors have complex inhibitory effects within in vivo achievable concentration ranges on Th1-mediated immunity, whereas Th2-mediated responses are mostly unaffected or enhanced. The Th2 skewing of the developing immune response is explained by the effects of PDE inhibitors on several factors contributing to T cell priming: the cytokine milieu; the type of costimulatory signal, i.e., up-regulation of CD86 and down-regulation of CD80; and the Ag avidity. The combination of PDE4 and PDE3 inhibitors expresses synergistic effects and may broaden the therapeutic window. Finally, we observed a differential sensitivity to PDE inhibition in autoreactive vs foreign Ag-specific T cells and cells derived from multiple sclerosis patients vs those derived from healthy donors. This suggests that PDE inhibition weakens the strength of the T cell stimulus and corrects the underlying disease-associated cytokine skew in T cell-mediated autoimmune disorders. These new findings broaden the understanding of the immunomodulatory actions of PDE inhibitors and underscore their promising drug profile for the treatment of autoimmune disorders.
Bielekova
B
B
Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Lincoln
A
A
McFarland
H
H
Martin
R
R
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use; D000595:Amino Acid Sequence; D001324:Autoantigens / Q000276:immunology; D018122:B7-1 Antigen / Q000096:biosynthesis; D002460:Cell Line; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016207:Cytokines / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000276:immunology / Q000628:therapy*; D004676:Myelin Basic Protein / Q000276:immunology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D020889:Rolipram / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*
D000276:Adjuvants, Immunologic; D001324:Autoantigens; D018122:B7-1 Antigen; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D004676:Myelin Basic Protein; D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram