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Preclinical efficacy of Periostin short interfering RNA in
pulmonary fibrosis
Hinneh,J.
1
,D’Alessandro-Gabazza,C.N.
1
,Toda,M.
1
,Yasuma,T.
2
,
Kentaro,F.
3
,Nishihama,K.
2
,Kobayashi,T.
3
,Etsuko,H.
1
, Gabazza,E.
1
,
Yazunori,Y.
4
1
MieUniversitySchoolofMedicine,DepartmentofImmunology,Tsu,
Japan,
2
MieUniversitySchoolofMedicine,Departmentof Diabetes
andMetabolism,Tsu,Japan,
3
MieUniversitySchoolofMedicine,
DepartmentPulmonaryandCriticalCareMedicine, Tsu,Japan,
4
Aqua
Company,Tsu,Japan
Idiopathic Pulmonary Fibrosis (IPF) is a fatal disease with a mortality
rate of 3 years after diagnosis. While pathogenetic mechanisms
are incompletely understood, the currently accepted paradigm
proposes that injury to the alveolar epithelium is followed by a burst
of pro-inflammatory and fibroproliferative mediators that invoke
responses associated with normal tissue repair. Recent research in
this area has focused on treatment regimenwhich seems to improve
lung function but none has so far been found to increase survival.
Periostin which is a recently characterized matricellular protein
belonging to the fasciclin 1 family has been shown to be elevated in
IPF patients and in bleomycin (BLM) induced lung fibrosis.
In this study we evaluated the effect of periostin siRNA on BLM-
induced lung fibrosis.
The results indicate that periostin is significantly increased on day
3 after BLM treatment and reduced on days 7 and 14 but elevated
on day 21. There was increased infiltration of inflammatory cells in
the scrambled siRNA treated group as compared to periostin siRNA
treated group. The levels of periostin, TGF-beta 1 and collagen were
significantly reduced in periostin siRNA treated group as compared
to scrambled siRNA treated group. Fibrosis was also significantly
reduced as measured by the Ashcroft score. The overall survival was
also improved in the periostin siRNA treated group as compared to
thecontrolgroups. Theseresultsshowthatblockadeofperiostinwith
siRNA may be an effective treatment option for the management of
pulmonary fibrosis.
The involvement of IL-17A and IL-17F in chronic pulmonary
mycobacterial infection
Umemura,M.
1
,Fukui,M.
1
,Tamura,T.
2
,Nakae,S.
3
,Iwakura,Y.
4
,
Matsuzaki,G.
1
1
TropicalBiosphereResearchCenter,UniversityoftheRyukyus,
Okinawa,Japan,
2
LeprosyResearchCenter,NationalInstitute of
InfectiousDiseases, Tokyo, Japan,
3
InstituteofMedical Science,
Universityof Tokyo, Tokyo, Japan,
4
Research Institute for Biomedical
Science,TokyoUniversityofScience,Chiba,Japan
I The interleukin (IL)-17 cytokine family is comprised of six members,
namely IL-17Ato IL-17F. Recent studiesusingcytokine- and receptor-
deficient mice showed that IL-17A and IL-17F were required for
responses to extracellular bacterium
K. pneumoniae
in the lungs and
C. rodentium
in the colon, respectively. However, the involvement
of IL-17A and IL-17F in protective immunity was well not clearly
demonstrated in mycobacterial infected lung. In this study, we
analyzed role of IL-17Aand IL-17F inhost defense against chronically
infected
M. tuberculosis
. using IL-17A and IL-17F KOmice. The IL-17A
KO mice showed significantly decreased survival rates compared
with the wild-type (WT) mice during 250-day observation period. In
contrast, survival rate of the IL-17F KOmicewere similar to that of the
WT mice. Bacterial burdens of various organs of the IL-17F KO mice
on the day 250 were nearly the same as that in the WT mice. In the
infected lungs, the IL-17A KOmice produced less IFN-γ, TNF and IL-6
in comparison to those fromtheWTmice, while cytokine production
of the IL-17F KO mice were similar to that of theWT mice. This result
indicated that the generation of Th1 cells was impaired in the IL-17A
KO mice but not in the IL-17F KO mice infected with
M. tuberculosis
.
These data strongly support the notion that the lack of IL-17F
neither suppress nor enhances protective immunity in the lungafter
mycobacterial infection.
Expression of catalytically inactive Lyn tyrosine kinase limits
inflammation and autoimmune disease
Maxwell,M.
1
,Kong,A.
1
,Tsantikos,E.
1
,Tarlinton,D.
1,2
,Hibbs,M.
1
1
MonashUniversity,Dept.ofImmunologyandPathology,Melbourne,
Australia,
2
Walter&ElizaHallInstitute,Melbourne,Australia
Systemic lupus erythematosus (SLE) is characterized by circulating
IgG antibodies reactive with nuclear antigens, immune complex
deposition in tissues including skin, brain and kidneys with
commensurate activation of the complement cascade and
myeloid cell activation. Activation of the innate arm of the immune
system results in the production of pro-inflammatory cytokines,
exacerbating inflammation and the adaptive immune response. The
combination of inflammation and antibody causes significant and
widespread tissue damage. Lyn-deficient mice with their hyper-
responsive B lymphocytes andmyeloid cells develop autoimmunity
with parallels to SLE, and require both inflammatory factors and B
cells to switch the disease to a pathogenic state. To dissect whether
the kinase activity of Lyn is critical for maintenance of self-tolerance,
we have generated mice carrying a kinase-dead mutation of Lyn.
We show that Lyn
KD/KD
mice share many of the B cell characteristics
of Lyn-deficient mice including B cell developmental defects, hyper-
responsiveness and enhanced signaling, and they are autoreactive.
UnlikeolderLyn-deficient animals,agedLyn
KD/KD
micedonotdevelop
splenomegaly or an expanded myeloid compartment, yet Lyn
KD/
KD
myeloid cells are intrinsically hyper-responsive to growth factor.
Dampened inflammation is not sufficient to drive T cell activation in
Lyn
KD/KD
mice, and while the mice have circulating self-reactive IgG,
the levels do not escalate with age and consequently, they have
mild renal disease and markedly enhanced survival. These data
demonstrate that expression of an inactive form of Lyn is sufficient
to restrain development of autoimmune disease through effects on
the inflammatory component of thedisease.
In vitro
generation of tolerogenic DCs using an inhibitor for
glycogen synthase kinase 3 beta
Ha, S.-J., Yoo,S.B.
YonseiUniversity,DepartmentofBiochemistry,Seoul,Korea,Republicof
Although tolerogenic dendritic cells (tolDCs) has come into the
spotlight as a promising treatment for autoimmune disease and in
transplantation, theoptimal protocol for generating tolDCs and their
clear identity have not been absolutely defined. Here, using bone
marrow-derived DCs (BMDCs), we investigated the effect of various
reagents such as cytokines, organic molecules, small chemicals,