JoséMaríaRojo, Pilar Portolés
112
Theeffect of PI3Kinhibitorson lupushasbeenanalyzed indifferentmodels.
In theMRL-‐
lpr
model of lupus, Barber et al. describedapreventiveand therapeutic
effect of the p110
γ
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 p65
PI3K
transgene mouse
model of lupus when p110
γ
was deleted (114). Resistance to activation-‐induced
cell death inT lymphocytes isan important factor toSLEdevelopment, as shown in
the enhancedPI3Kactivity in lymphocytes fromSLEpatients due to higher p110
δ
(115); this enhanced resistance to activation induced cell death was abolished,
upon inhibitionof p110
δ
with IC87114, particularly in thememoryTcells 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 p110
δ
signals in haploinsuficient Lyn
−/−
110δ
+/ D910A
mice ameliorates the disease, with
lower autoantibody levels andnephritisbyamechanismthat involved lowerTcell
activationrather thanattenuationofBlymphocyteresponses (116).
12.c. Multiple sclerosis (MS) andExperimental AutoimmuneEncephalomyelitis
(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 antigenpresentingcells.
T lymphocytes specific formyelin antigens that secrete IFN-‐
γ
, 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-‐deadmutant
110δ
D910A
had a milder form of EAE induced by the rat Myelin Oligodendrocyte
Glycoprotein (MOG) peptide
35-‐55
, and lower number of lesions and T cell
inflammatory infiltration, plus enhancedapoptosis (86). Asdiscussed inaprevious
section, in this study the p110
δ
inhibitor IC87114 inhibited the differentiation of
IFN-‐
γ
producing Th1 cells and IL-‐17 producing Th17 cells, yet Th17 more
effectively than Th1, indicating a potential for PI3K as a target inMS therapy. We
have recentlyusedanoral therapeutic treatmentwith thedual p110
α
andDNA-‐PK
inhibitor PIK-‐75 to significantly inhibit MOG-‐induced EAE symptoms (117). This
was accompaniedby 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-‐
γ
, IL-‐17A, or IL-‐21) secretion in the nanomolar range.
