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 p110alpha 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 μM) 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 (less than 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.Y.Y.A. is recipient of a Predoctoral Fellowship of the "Junta deAmpliacion de Estudios" (JAE) Program (e.S.I.e., Ministerio de Ciencia e Innovacion, Spain). P.P. is a Tenured Sciencist of e.S.I.e. at the Centro Nacional de Microbiologia, Instituto de Salud Carlos III. This work was supported by Grants PI070620, PI070484 (Plan Estatal I+D+i, ISCIIISubdireccion General de Evaluaci6n y Fomento de la Investigacion, Ministerio de Economia y Competitividad, Spain) to J.M.R. and P.P, and by Associazione Italiana Ricerca sui Cancro (AIRC, Milan) to U.D.S