ETP-46321, a dual p110α/δ class IA phosphoinositide 3-kinase inhibitor modulates T lymphocyte activation and collagen-induced arthritis.

摘要: Class IA phosphoinositide 3-kinases (PI3Ks) are essential to function of normal and tumor cells, modulate immune responses. T lymphocytes express high levels p110α p110δ class PI3K. Whereas the functioning PI3K in autoimmune reactions is well established, role less understood. Here, a novel dual p110α/δ inhibitor (ETP-46321) highly specific (A66) or (IC87114) inhibitors have been compared concerning cell activation vitro, as effect on responses protein antigen collagen-induced arthritis vivo. In vitro naive CD4(+) by anti-CD3 anti-CD28 was inhibited more effectively than measured cytokine secretion (IL-2, IL-10, IFN-γ), T-bet expression NFAT activation. activated cells re-stimulated through CD3 ICOS, IC87114 Akt Erk activation, IL-2, IL-4, IL-17A, IFN-γ better A66. The ETP-46321, plus also IL-21 differentiated follicular (Tfh) IL-17-producing (Th17) helper cells. vivo, therapeutic administration ETP-46321 significantly arthritis, antigen-specific antibody responses, IL-17A IFN-γ, clinical symptoms. Hence, PI3Ks important regulation; inhibition both subunits may be an effective approach inflammatory diseases like rheumatoid arthritis.