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Class
I
phosphoinositide
3-­-kinases
in
immunity…

6.
PI3K
INHIBITORS
OF
BROAD
AND
RESTRICTED
SPECIFICITY.
IMPORTANCE
TO

CANCER.

Hence,
PI3K
inhibitors,
or
inhibitors
of
PI3K
targets
like
Akt
or
mTOR,
have

been
actively
looked
for
as
anti-­-cancer
drugs
(see
(51),
for
a
recent
review).
In

these
assays
p110a-­-,
p110ß-­-,
p110d-­-,
p110?-­-,
dual
p110?/d-­-specific
or
pan-­-PI3K

inhibitors,
as
well
as
dual
PI3K-­-mTOR
inhibitors
are
under
investigation
in

experimental
tests
and
clinical
trials.

7.
ROLE
OF
CLASS
IA
AND
CLASS
IB
PI3KINASES
IN
THE
CONTROL
OF
IMMUNE

RESPONSES.
GENETIC
MODELS
AND
PI3K
INHIBITORS

The
relevance
of
class
IA
PI3K-­-mediated
signals
to
all
steps
of
innate
and

adaptive
immune
responses
immediately
point
to
the
potential
relevance
of

inhibitors
of
PI3K
or
of
PI3K
effectors
as
immunomodulators
and
therapeutic
tools

in
many
socially
relevant
immune-­-mediated
diseases
(17,18,22,52-­-56).
The
role
of

PI3K
in
immunity
has
been
analyzed
in
vivo
by
the
generation
of
mice
lacking

specific
regulatory
and
catalytic
subunits,
or
expressing
kinase-­-dead
mutants
of

specific
subunits,
or
by
means
of
specific
inhibitors
of
PI3K
or
its
downstream

signaling
targets.
In
vitro
the
analysis
has
involved
cell
lines
derived
from
the

above
models,
specific
inhibitors,
and
knock-­-down
approaches
using
siRNA.
We

shall
now
review
the
genetic
and
pharmacological
data
that
supports
this

immunomodulatory
potential
in
the
adaptive
immune
response
mediated
by
B
and

T
lymphocytes.

8.
CLASS
IA
AND
IB
PI3K
IN
IMMUNITY:
LESSONS
FROM
GENETIC
STUDIES
IN
B

LYMPHOCYTES.

B
lymphocytes
are
an
essential
arm
of
the
adaptive
immune
responses
as

the
cells
responsible
of
antibody
responses
against
pathogens;
antibodies
are

produced
in
great
quantities
by
the
B-­-cell
derived
plasma
cells.
The
quality
of
the

antibodies
both
in
terms
of
their
affinity
for
the
antigen
and
the
class
of
the

constant
regions
is
essential
to
efficient
removal
of
parasites,
and
is
largely

determined
by
the
cytokines
in
the
milieu,
particularly
those
secreted
by
antigen-­-
specific
T
helper
cells.
Mature
B
lymphocytes
exist
in
two
major
subsets,
namely

the
B-­-1
cells
found
in
body
cavities
like
the
peritoneum
that
have
innate

properties,
and
the
B-­-2
cells
that
comprise
non-­-recirculating
MZ
(marginal
zone)
B

cells
and
the
FO
(follicular)
B
cells
that
recirculate
through
the
blood
and

secondary
lymphoid
organs.

The
role
of
regulatory
subunits
has
been
analyzed
in
pan-­-p85a-­-/-­-
(p85a-­-/-­-,

p55a-­-/-­-,
p50a-­-/-­-)
defective
mice,
lacking
all
p85a
isoforms.
These
mice
have

perinatal
lethality,
assays
using
RAG2
chimeric
mice
with
hematopoietic
cells

101