Page 108 - 80_01

José
María
Rojo,
Pilar
Portolés

What
is
perhaps
more
surprising
of
the
results
using
genetic
models,
is
the

certain
selectivity
of
PI3K
subunits
in
terms
of
the
lymphocyte
population(s)
and

processes
affected.
This
applies
not
only
to
PI3K
subunits,
but
also
to
other
protein

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
p110a
and

p110ß,
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

to
have
undesired
side
effects
including
increased
susceptibility
to
infection
(4).

10.
CLASS
IA
AND
IB
PI3K
IN
IMMUNITY:
LESSONS
FROM
SPECIFIC
INHIBITORS

IN
B
LYMPHOCYTE
FUNCTION

As
mentioned
before,
genetic
defects
in
p110d
affect
particularly
B-­-1
and
B-­-
2
marginal
zone
B
lymphocytes;
the
similarity
of
these
defects
and
those
of
mice

lacking
Akt
or
the
PI3K-­-recruiting
costimulatory
molecule
CD19
might
indicate
a

role
of
a
CD19/p110d
PI3K/
Akt/
Foxo1
downstream
signal
in
B-­-1
and
MZ
B-­-2

differentiation
(reviewed
in
(22)).
Using
the
p110d
inhibitor
IC87114,
Bilancio
et

al.
(80)
found
strong
inhibition
of
anti-­-BCR-­-induced
proliferation
of
B
lymphocytes,

Ca2+
flux,
or
phosphorylation
of
downstream
targets
like
Akt,
or
the
Akt
targets

forkhead
transcription
factor/forkhead
box
O3a
(FOXO3a),
and
p70
S6
kinase
(p70

S6K),
and
partial
inhibition
of
extracellular
signal-­-regulated
kinase
(Erk),
that

mimicked
p110d
defects.
In
contrast,
the
p110?/a
inhibitor
AS-­-604850
had
no

detectable
effect
on
these
parameters
(80).
Despite
the
fact
that
p110d,
rather
than

p110a
catalytic
subunits
of
PI3K,
had
detectable
effects
in
B
lymphocytes
and
B

cell
responses,
and
p110d
binds
to
the
BCR
(15),
So
et
al.
recently
analyzed
highly

specific
p110a
inhibitors
to
assess
a
possible
role
for
the
p110a-­-subunit
in
B
cell

function
(81).
They
observed
a
minor
but
clear
effect
of
p110a-­-specific
inhibitors

A66
and
MLN1117
on
early
Akt
activation
and
Ca2+
flux,
or
B
cell
proliferation

induced
by
BCR
stimuli
in
vitro,
but
not
by
cytokines
IL-­-4
or
BAFF.
This
inhibition

106