JoséMaríaRojo, Pilar Portolés
110
(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 p110
δ
inhibitor IC87114 on antigen-‐induced
proliferation or IL-‐2 production in CD8
+
T lymphocytes; inhibition was complete
when IFN-‐
γ
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 phosphorylationbut not CD8
+
proliferation, thatwas dependent on
PDK1 (103). Still, blocking p110
δ
or Akt enhanced the expression of molecules
involved in lymph node homing and homing itself,
showing their
immunomodulatorypotential inthesecells.
12. PI3K INPATHOLOGICAL IMMUNERESPONSES
Given the relevant roleof PI3K in immune responses, particularly thep110
γ
and p110
δ
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.
Althoughweshall focuson theroleof adaptive immuneresponse in thesediseases,
it is important to remember that PI3Khaveanessential role in the functionof cells
of the innate arm of immunity like macrophages and dendritic cells,
polymorphonuclear leukocytes,mast cells, ornatural 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
activationof effector function in innateandadaptive immunityelements.
12.a. Rheumatoidarthritis.
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 frommice lackingp110
γ
catalytic subunits indicate that thesemiceare
resistant to the development of clinical symptoms of arthritis. Oral administration
of the p110
γ
inhibitor AS-‐605240 ameliorated the symptoms in two experimental
