title: Suppression of CD4+ T lymphocyte activation in vitro and experimental encephalomyelitis in vivo by the phosphatidyl inositol 3-kinase inhibitor PIK-75.
abstract: 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 (&#8805;0.1 &#956;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 (&#8804;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.
authors.affiliation: Department of Molecular and Cellular Medicine, Centre of Biological Investigation, CSIC, Madrid, Spain.
authors.forename: Y Y
authors.initials: YY
authors.lastname: Acosta
authors.affiliation: Unit of Cellular Immunology, National Centre of Microbiology, Institute of Health Carlos III, Majadahonda, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Montes-Casado
authors.affiliation: Unit of Cellular Immunology, National Centre of Microbiology, Institute of Health Carlos III, Majadahonda, Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Aragoneses-Fenoll
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, A. Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: U
authors.initials: U
authors.lastname: Dianzani
authors.affiliation: Unit of Cellular Immunology, National Centre of Microbiology, Institute of Health Carlos III, Majadahonda, Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Portoles
authors.affiliation: Department of Molecular and Cellular Medicine, Centre of Biological Investigation, CSIC, Madrid, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Rojo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D005260:Female; D006835:Hydrazones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; D006835:Hydrazones; C549211:PIK 75; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides