Page 114 - 80_01

José
María
Rojo,
Pilar
Portolés

The
effect
of
PI3K
inhibitors
on
lupus
has
been
analyzed
in
different
models.

In
the
MRL-­-lpr
model
of
lupus,
Barber
et
al.
described
a
preventive
and
therapeutic

effect
of
the
p110?
inhibitor
AS605240
on
autoantibodies,
proteinuria,
and

reduced
number
of
pathogenic
CD4+
memory
T
lymphocytes
due
to
enhanced
cell

death
(113),
a
finding
that
was
also
observed
in
the
p65PI3K
transgene
mouse

model
of
lupus
when
p110?
was
deleted
(114).
Resistance
to
activation-­-induced

cell
death
in
T
lymphocytes
is
an
important
factor
to
SLE
development,
as
shown
in

the
enhanced
PI3K
activity
in
lymphocytes
from
SLE
patients
due
to
higher
p110d

(115);
this
enhanced
resistance
to
activation
induced
cell
death
was
abolished,

upon
inhibition
of
p110d
with
IC87114,
particularly
in
the
memory
T
cells
that
are

enhanced
in
these
patients
(115).
Yet
another
model
of
SLE
is
the
Lyn
deficient

mice.
Lyn-­-/-­-
mice
have
enhanced
PI3K
signaling,
and
simple
attenuation
of
p110d

signals
in
haploinsuficient
Lyn-/-110d+/
D910A
mice
ameliorates
the
disease,
with

lower
autoantibody
levels
and
nephritis
by
a
mechanism
that
involved
lower
T
cell

activation
rather
than
attenuation
of
B
lymphocyte
responses
(116).

12.c.
Multiple
sclerosis
(MS)
and
Experimental
Autoimmune
Encephalomyelitis

(EAE).

Multiple
sclerosis
is
an
inflammatory
disease
characterized
by

demyelination
of
the
central
nervous
system
(CNS).
Experimental
autoimmune

encephalomyelitis
is
the
model
of
choice
for
MS
in
mice,
and
is
induced
by

immunization
with
proteins
or
protein
fragments
in
susceptible
strains
of
mice.

Inflammation
and
axonal
damage
is
si
accompanied
by
infiltration
of
T

lymphocytes
and
other
leukocytes,
and
in
certain
cases
by
the
formation
of

structures
resembling
lymphoid
follicles;
these
contain
T
and
B
cells,
plus

professional
antigen
presenting
cells.

T
lymphocytes
specific
for
myelin
antigens
that
secrete
IFN-­-?,
IL-­-17,
or
IL-­-9

are
able
of
inducing
EAE,
hence
it
is
reasonable
to
assume
that
therapeutic

approaches
that
suppress
the
secretion
of
these
cytokines
can
be
useful
in

controlling
the
evolution
of
the
disease.
Mice
expressing
the
kinase-­-dead
mutant

110dD910A
had
a
milder
form
of
EAE
induced
by
the
rat
Myelin
Oligodendrocyte

Glycoprotein
(MOG)
peptide35-­-55,
and
lower
number
of
lesions
and
T
cell

inflammatory
infiltration,
plus
enhanced
apoptosis
(86).
As
discussed
in
a
previous

section,
in
this
study
the
p110d
inhibitor
IC87114
inhibited
the
differentiation
of

IFN-­-?
producing
Th1
cells
and
IL-­-17
producing
Th17
cells,
yet
Th17
more

effectively
than
Th1,
indicating
a
potential
for
PI3K
as
a
target
in
MS
therapy.
We

have
recently
used
an
oral
therapeutic
treatment
with
the
dual
p110a
and
DNA-­-PK

inhibitor
PIK-­-75
to
significantly
inhibit
MOG-­-induced
EAE
symptoms
(117).
This

was
accompanied
by
in
vitro
observations
showing
that
PIK-­-75
induced
cell
death

in
resting
or
activated
T
and
B
lymphocytes,
or
CD4+
T
lymphocyte
proliferation

and
cytokine
(IL-­-2,
IFN-­-?,
IL-­-17A,
or
IL-­-21)
secretion
in
the
nanomolar
range.

112