Class I phosphoinositide3-‐kinases in immunity…
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6. PI3K INHIBITORSOFBROADANDRESTRICTEDSPECIFICITY. IMPORTANCE TO
CANCER.
Hence, PI3K inhibitors, or inhibitors of PI3K targets likeAkt ormTOR, have
been actively looked for as anti-‐cancer drugs (see (51), for a recent review). In
these assays p110
α
-‐, p110
β
-‐, p110
δ
-‐, p110
γ
-‐, dual p110
γ/δ
-‐specific or pan-‐PI3K
inhibitors, as well as dual PI3K-‐mTOR inhibitors are under investigation in
experimental testsandclinical trials.
7. ROLEOF CLASS IAANDCLASS IB PI3KINASES IN THE CONTROL OF IMMUNE
RESPONSES. GENETICMODELSANDPI3K 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 PI3Kor of PI3Keffectors as immunomodulators and therapeutic tools
inmany socially relevant immune-‐mediateddiseases (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
immunomodulatorypotential in theadaptive immune responsemediatedbyBand
T lymphocytes.
8. CLASS IAAND IBPI3K IN IMMUNITY: LESSONS FROMGENETIC STUDIES INB
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 themilieu, particularly those secreted by antigen-‐
specific T helper cells. Mature B lymphocytes exist in twomajor subsets, namely
the B-‐1 cells found in body cavities like the peritoneum that have innate
properties, and theB-‐2cells that comprisenon-‐recirculatingMZ (marginal zone)B
cells and the FO (follicular) B cells that recirculate through the blood and
secondary lymphoidorgans.
The role of regulatory subunits has been analyzed in pan-‐p85
α
-‐/-‐
(p85
α
-‐/-‐
,
p55
α
-‐/-‐
, p50
α
-‐/-‐
) defective mice, lacking all p85
α
isoforms. These mice have
perinatal lethality, assays using RAG2 chimeric mice with hematopoietic cells
