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induced proinflammatory signaling, monovalent or divalent
targeting with either IgA, IgG, IVIg or with Fab/F(ab’) 2 of anti-FcR
antibodies can trigger inhibitory signals towards a whole array
of cellular functions such as phagocytosis, exocytosis and TLR-
or cytokine-mediated responses. At the molecular level, ITAMi is
defined by weak phosphorylation of distal ITAM tyrosines, transient
recruitmentofSykfollowedbystablerecruitmentofthephosphatase
SHP-1. This inhibitory effect renders anergic myeloid cells despite
of heterologous receptor engagement. In vivo ITAMi induction by
antibodies or Ig prevents and treats several inflammatory disorders
in mice such as nephritis or arthritis. Moreover, ex-vivo monovalent
or divalent targeting of FcR on synovial cells from untreated
rheumatoid arthritis patients reversed the spontaneous ITAMa to
an ITAMi anti- inflammatory configuration. Shifting the constitutive
ITAMa signals observed in patients to an ITAMi signaling could
thus reverse cell activation by inducing a myeloid tolerance state,
providing ground for novel treatment options in inflammatory
diseases.
Recurrent herpes virus infection: treatment with dendritic
cells vaccines
Leplina,O.,Tyrinova,T.,Starostina,N.,Ostanin,A.,Chernykh,E.
InstituteofFundamentalandClinicalImmunology,Novosibirsk,Russian
Federation
Chronic recurrent infections caused by herpes simplex virus (HSV)
types 1 and 2 are a serious medical and social challenge. Induction
of an antigen-specific immune response using dendritic cell (DCs)
vaccines, seems to be promising approach for the treatment of
HSV infections. 29 patients (14-with labial and 15 - with genital
herpes) have been enrolled in this study. DCs were generated in
the presence of GM-CSF and IFN-α, loaded with recombinant viral
proteins (HSV1gD or HSV2gD) and were utilized as 2 courses of
vaccinations conducted during 9months. Immunotherapy with DCs
didnot induce serious sideeffects andwas accompaniedby two-fold
decrease in the relapses rate and increase in the length of remission
during the 9 months of treatment. There was a further reduction in
the frequency of relapses and a threefold increase in the duration of
remissions during the subsequent 6-month follow up. The clinical
effect during the treatment and subsequent 6 months follow up
was noted in both labial and genital herpes and was associated with
the induction of antigen specific proliferative response. Analysis
of long-term results based on a survey of patients with followed
up more than 24 months has shown that the beneficial effect of
immunotherapy manifested as reduction in the relapse rate was
maintained in77.8%of the respondents. At this time, antigenspecific
proliferative response was maintained in 66.7%of patients. The data
obtained suggests that dendritic cell vaccines may be a promising
new approach to the treatment of recurrent herpes.
Elucidating the oncogene-driven regulatory T cell responses
during melanoma tumorigenesis
Shabaneh,T.B.,Steinberg,S.M.,Zhang,P.,Turk,M.J.
GeiselSchoolofMedicineatDartmouth,Lebanon,NH,UnitedStates
Regulatory T cells (Tregs) are critical mediators of tumor immune
suppression. While Tregs are found in established tumors, little is
known about the kinetics and dynamics of Treg accumulation and
the factors promoting it during oncogene-driven tumorigenesis.
The present studies characterize Treg response kinetics and
conversion dynamics during early tumor development in a model
of autochthonous, tamoxifen-inducible Braf
V600E
Pten
-/-
melanoma.
While microscopic skin dysplasia appeared 16 days following
tumor induction, FoxP3
+
Treg frequency and absolute numbers
accumulated by day 26, coinciding with locally- invasive neoplasm
development. Braf
V600E
inhibition with PLX4720 prevented Treg
accumulation, suggesting that oncogenic Braf controls this process.
Following adoptive transfer of CD4
+
T cells specific toTRP-1, antigen-
specific FoxP3
+
Tregs preferentially accumulated in tumor-induced
skin and draining lymph nodes (dLNs), as compared to tumor-free
counterparts. In contrast, depletingTregsprior to transfer abrogated
the TRP-1-specific Treg response, suggesting a predominant role for
naturalTregs.
Furthermore, we observed an increase in chemokine (C-C motif)
ligand 17 (Ccl17) and Ccl2 prior to the Treg influx to tumor- induced
skin. Oncogenic Braf regulated expression of Ccl17 and Ccl2,
both of which mediated Treg migration
in vitro
. We are currently
investigating the putative role of Ccl17/2-Ccr4 chemotactic axis in
Treg recruitment to sites of Braf-driven tumorigenesis
invivo.
Raf kinase inhibitor protein mediates intestinal epithelial cell
apoptosis and promotes IBDs in humans and mice
Lin,W.,FashengSu,ChunmeiMa,XiaojianWang
ZhejiangUniversity,InstituteofImmunology,Hangzhou,China
Objective:
Raf kinase inhibitor protein (RKIP) appears to control
cancer cell metastasis and its expression in colonic tissue is related
to colonic cancer development. We sought to identify the roles of
RKIP in maintaining homeostasis of gastrointestinal tract.
Design:
The expression of RKIP was determined by immunohistochemistry
and western-blot analysis. RKIP knock-out (KO) and wild-type
(WT) mice were administered dextran sulfate sodium (DSS) or 2,
4, 6-trinitrobenzenesulfonic acid (TNBS) to induce experimental
colitis, and the mice were assessed based on colitis symptoms
and biochemical approaches. The mechanism was analyzed using
immunoprecipitationandpull-downexperiments.
Results:
TheRKIPexpression ispositively correlatedwith the severity
of inflammatory bowel disease (IBD). RKIP deficiency protects mice
fromdextran sulfate sodium(DSS) - or 2, 4, 6-trinitrobenzenesulfonic
acid (TNBS)-induced colitis and accelerated recovery from colitis.
RKIP deficiency inhibits DSS-induced infiltration of acute-phase
immune cells and reduces productionof proinflammatory cytokines
and chemokines in colon. RKIP deficiency inhibits DSS- or TNBS-
induced colonic epithelial barrier damage and intestinal epithelial
cell (IEC) apoptosis. RKIP deficiency also inhibits TNF-α induced IEC
apoptosis and colitis.
Mechanistically, RKIP enhances the induction of P53-upregulated
modulator of apoptosis (PUMA) by interactingwithTGF-β- activated
kinase 1(TAK1) and promotingTAK1-mediatedNF-κB activation.This
is supported by the observation that TAK1 activation is positively
correlated with the expression of RKIP in human clinical samples
and the development of IBD.
Conclusions:
RKIP contributes to
colitis development by promoting inflammation and mediating IEC
apoptosis andmight represent a therapeutic target of IBD.