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 candida te therapies for Th1-mediated autoimmune disorders. However, depending on t he model and cell types employed, studies of atopic individuals have come t o the opposite conclusion, i.e., that PDE inhibitors may be beneficial in a sthma, Using in vitro immunopharmacologic techniques we analyzed the effect s of PDE4 and PDE3 inhibitors on human immune cells to address these discre pancies and broaden our understanding of their mechanism of action. Our res ults 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 t he developing immune response is explained by the effects of PDE inhibitors on several factors contributing to T cell priming: the cytokine milieu; th e type of costimulatory signal, i.e., up-regulation of CD86 and down-regula tion of CD80; and the Ag avidity. The combination of PDE4 and PDE3 inhibito rs expresses synergistic effects and may broaden the therapeutic window. Fi nally, we observed a differential sensitivity to PDE inhibition in autoreac tive vs foreign Ag-specific T cells and cells derived from multiple scleros is patients vs those derived from healthy donors. This suggests that PDE in hibition,weakens the strength of the T cell stimulus and corrects the under lying disease-associated cytokine skew in T cell-mediated autoimmune disord ers. These new findings broaden the understanding of the immunomodulatory a ctions of PDE inhibitors and underscore their promising drug profile for th e treatment of autoimmune disorders.