JoséMaríaRojo, Pilar Portolés
106
What is perhapsmore surprising of the results using geneticmodels, is the
certain selectivity of PI3K subunits in terms of the lymphocyte population(s) and
processes affected. This appliesnot only toPI3Ksubunits, but also tootherprotein
targets of PI3K, giving clues as to the possibility of selective immune intervention
using PI3K inhibitors or its downstream effector molecules in autoimmune
diseases or other immune-‐based illnesses. The importance of PI3K in different
types of cancer has boosted a very active search for small pharmacological
inhibitors directed at one or several PI3K subunits and/or PI3K downstream
targets like Akt or mTOR. These inhibitors have the potential of being used to
modulate immune responses. The use of inhibitors, though, has to take into
account the harming potential to the host, particularly in long-‐term treatment of
chronic diseases. These adverse effects can be due to off-‐target effects of a
particular drug, but also to on-‐target effects of inhibitors of widely distributed
enzymes fulfilling essential functions, as are PI3Ks. However, pre-‐clinical models
and clinical trials in cancer indicate that treatments with PI3K inhibitors can be
well tolerated, even when using inhibitors of the widely expressed p110
α
and
p110
β
, or even pan-‐class I PI3K inhibitors (51). Another aspect to be taken into
account is that, like any other immunosuppressive drug, PI3K inhibitors are likely
tohaveundesiredsideeffects including increasedsusceptibility to infection(4).
10. CLASS IAAND IB PI3K IN IMMUNITY: LESSONS FROMSPECIFIC INHIBITORS
INBLYMPHOCYTEFUNCTION
Asmentionedbefore, geneticdefects inp110
δ
affect particularlyB-‐1andB-‐
2marginal zone B lymphocytes; the similarity of these defects and those of mice
lacking Akt or the PI3K-‐recruiting costimulatory molecule CD19might indicate a
role of a CD19/p110
δ
PI3K/ Akt/ Foxo1 downstream signal in B-‐1 and MZ B-‐2
differentiation (reviewed in (22)). Using the p110
δ
inhibitor IC87114, Bilancio et
al. (80) foundstrong inhibitionof anti-‐BCR-‐inducedproliferationofB lymphocytes,
Ca
2+
flux, or phosphorylation of downstream targets like Akt, or the Akt targets
forkhead transcription factor/forkheadboxO3a (FOXO3a), andp70S6kinase (p70
S6K), and partial inhibition of extracellular signal-‐regulated kinase (Erk), that
mimicked p110
δ
defects. In contrast, the p110
γ
/
α
inhibitor AS-‐604850 had no
detectableeffect on theseparameters (80). Despite the fact that p110
δ
, rather than
p110
α
catalytic subunits of PI3K, had detectable effects in B lymphocytes and B
cell responses, andp110
δ
binds to the BCR (15), So et al. recently analyzedhighly
specific p110
α
inhibitors to assess a possible role for the p110
α
-‐subunit in B cell
function (81). They observed aminor but clear effect of p110
α
-‐specific inhibitors
A66 and MLN1117 on early Akt activation and Ca
2+
flux, or B cell proliferation
induced by BCR stimuli
in vitro
, but not by cytokines IL-‐4 or BAFF. This inhibition
