Suppression of CD4⁺T Lymphocyte Activationin Vitroand Experimental Encephalomyelitisin Vivoby 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 p110α 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-γ production induced by anti-CD3 plus anti-CD28. In activated CD4+ T blasts costimulated by ICOS, PIK-75 (≤10 nM) inhibited IFN-γ, 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.

T-Cell-Specific Loss of the PI-3-Kinase p110α Catalytic Subunit Results in Enhanced Cytokine Production and Antitumor Response

“…In T and B lymphocytes, the p110δ isoform has a major role in ontogeny and adaptive immunity. Intriguingly, the p110α isoform is abundant in lymphocytes and can bind to and participate in the signals of costimulatory molecules like CD28 or ICOS ( 20 , 25 ). Studies with isoform-specific inhibitors suggest that p110α might be relevant in certain T cell functions (i.e., IFN-γ or IL-21 production) but not in others (i.e., IL-2) ( 25 , 26 ).…”

“…Intriguingly, the p110α isoform is abundant in lymphocytes and can bind to and participate in the signals of costimulatory molecules like CD28 or ICOS ( 20 , 25 ). Studies with isoform-specific inhibitors suggest that p110α might be relevant in certain T cell functions (i.e., IFN-γ or IL-21 production) but not in others (i.e., IL-2) ( 25 , 26 ). Consequently, to further determine the importance of PI3K p110α in T cell function, CD4-Cre mice were crossed with mice with a floxed pik3ca gene (p110α flox/flox ) to obtain mice (p110α −/− ΔT) whose T cells lacked the PI3K p110α isoform.…”

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

“…However, the data on the role of p110 in lymphocyte function are scarce, in part because of the embryonic lethality of p110-deficient mice, in part because of the relative non-specificity of some p110 inhibitors [15,16]. Still, specific silencing [14] or the use of highly specific inhibitors of p110 like A66 [17] show a clear, if minor, role of p110 on B cell and T cell activation.…”

Repurposing Kinase Inhibitors as Antiviral Agents to Control Influenza A Virus Replication

“…PIK-75, which inhibits the activity of PI3K and DNA-PK, is still in a late preclinical evaluation stage for the treatment of acute myeloid leukemia, breast cancer, pancreatic cancer, and encephalomyelitis. [52][53][54][55] Nevertheless, extensive bioactivity and safety data on these drugs have been compiled through preclinical studies and/or clinical trials. Thus, it is expected that these drugs can be developed as novel IAV antiviral drugs in a more expedited time frame once their antiviral efficacies are confirmed in the ensuing in vitro and in vivo studies in animal models of influenza virus infection.…”