SUPPRESSION OF CD4+ T LYMPHOCYTE ACTIVATION IN VITRO AND EXPERIMENTAL ENCEPHALOMYELITIS IN VIVO BY THE PHOSPHATIDYL INOSITOL 3-KINASE INHIBITOR PIK-75

Class IA phosphatidyl inositol-3 kinases (PI3-K) are important targets in cancer therapy and are essential to immune responses, particularly through costimulation by CD28 and ICOS. Thus, small PI3-K inhibitors are likely candidates to immune intervention. PIK-75 is an efficient inhibitor of the PI3-K p110 alpha catalytic subunits that suppresses tumor growth, and its effects on immune and autoimmune responses should be studied. Here, we describe the effect of PIK-75 on different immune parameters in vitro and in vivo. PIK-75 at concentrations commonly used in vitro (>= 0.1 mu M) inhibited T and B cell activation by Concanavalin A and LPS, respectively, and survival of non-stimulated spleen cells. In naive CD4(+) T lymphocytes, PIK-75 induced apoptosis of resting or activated cells that was prevented by caspase inhibitors. At low nanomolar concentrations (<= 10 nM), PIK-75 inhibited naive CD4(+) T cell proliferation, and IL-2 and IFN-gamma production induced by anti-CD3 plus anti-CD28. In activated CD4(+) T blasts costimulated by ICOS, PIK-75 (<= 10 nM) inhibited IFN-gamma, IL-17A, or IL-21 secretion. Furthermore, PIK-75 (20 mg/kg p.o.) suppressed clinical symptoms in ongoing experimental autoimmune encephalomyelitis (EAE) and inhibited MOG-specific responses in vitro. Thus, PIK-75 is an efficient suppressor of EAE, modulating lymphocyte function and survival.