Page 112 - 80_01

José
María
Rojo,
Pilar
Portolés

(101).
In
contrast,
Phu
et
al.
observed
clear
inhibition
of
anti-­-CD3-­-induced

proliferation
and
cytotoxic
function
in
CD8+
T
lymphocytes
cultured
in
the

presence
of
Wortmannin
or
LY294002
(102).
More
recently,
Soond
et
al.
found
a

clear
inhibition
by
LY294002
or
the
p110d
inhibitor
IC87114
on
antigen-­-induced

proliferation
or
IL-­-2
production
in
CD8+
T
lymphocytes;
inhibition
was
complete

when
IFN-­-?
was
analyzed.
D.
Cantrell’s
group
has
recently
analyzed
the
role
of

PI3K
in
IL-­-2-­-induced
expansion
of
previously
activated
CD8+
T
lymphocytes.

Interestingly,
although
IL-­-2
activated
PI3K-­-dependent
activation
of
Akt

phosphorylation
in
these
cells,
inhibitors
of
PI3K
like
IC87114
blocked
IL-­-2-­-
dependent
Akt
phosphorylation
but
not
CD8+
proliferation,
that
was
dependent
on

PDK1
(103).
Still,
blocking
p110d
or
Akt
enhanced
the
expression
of
molecules

involved
in
lymph
node
homing
and
homing
itself,
showing
their

immunomodulatory
potential
in
these
cells.

12.
PI3K
IN
PATHOLOGICAL
IMMUNE
RESPONSES

Given
the
relevant
role
of
PI3K
in
immune
responses,
particularly
the
p110?

and
p110d
of
high
expression
in
leukocytes,
there
has
been
an
obvious
interest
in

analyzing
the
possible
use
of
PI3K
inhibitors
in
both
organ-­-specific
and
systemic

autoimmune
diseases
of
social
impact
including
rheumatoid
arthritis,
systemic

lupus
erythematosus,
multiple
sclerosis,
or
its
animal
experimental
models.

Although
we
shall
focus
on
the
role
of
adaptive
immune
response
in
these
diseases,

it
is
important
to
remember
that
PI3K
have
an
essential
role
in
the
function
of
cells

of
the
innate
arm
of
immunity
like
macrophages
and
dendritic
cells,

polymorphonuclear
leukocytes,
mast
cells,
or
natural
killer
(NK)
lymphocytes
(52).

So,
the
ultimate
effect
of
PI3K
inhibitors
in
immune
responses
in
vivo
will
largely

depend
on
their
joint
effects
on
the
development,
expansion,
mobility,
and

activation
of
effector
function
in
innate
and
adaptive
immunity
elements.

12.a.
Rheumatoid
arthritis.

Rheumatoid
arthritis
(RA)
affects
a
significant
fraction
of
the
population.
It

is
an
immune-­-mediated,
chronic
inflammatory
disease
of
the
joints
that
are

infiltrated
by
leukocytes.
This
eventually
leads
to
the
formation
of
pannus,
the

damage
of
cartilage
and
bone
erosion.
From
many
data,
including
those
from

animal
experimental
models
it
is
assumed
that
in
the
development
of
arthritis

participate
immune
response
cellular
elements
from
both
the
innate

(macrophages,
neutrophils,
mast
cells)
and
adaptive
(T
and
B
lympocytes)

immunity.

Data
from
mice
lacking
p110?
catalytic
subunits
indicate
that
these
mice
are

resistant
to
the
development
of
clinical
symptoms
of
arthritis.
Oral
administration

of
the
p110?
inhibitor
AS-­-605240
ameliorated
the
symptoms
in
two
experimental

110