Multiple Sclerosis
J Immunol. 2006 Jun 15;176(12):7325-34. Lab Invest.
2006 May 15; [Epub ahead of print] J
Bone Miner Res. 2006 Jun;21(6):946-55.
Chronic Immune Therapy Induces a Progressive
Increase in Intratumoral T Suppressor Activity
and a Concurrent Loss of Tumor-Specific CD8+ T Effectors in her-2/neu
Transgenic Mice Bearing Advanced Spontaneous Tumors.
Nair
RE, Kilinc MO, Jones
SA, Egilmez NK.
A single intratumoral injection of IL-12 and
GM-CSF-encapsulated microspheres induces the
complete regression of advanced spontaneous tumors in her-2/neu transgenic
mice. However, tumor regression in this model is transient and long-term
cure is not achieved due to recurrence. Posttherapy
molecular analysis of immune activation/suppression markers within the
tumor microenvironment demonstrated a dramatic up-regulation of IFN-gamma
and a concomitant down-regulation of Forkhead/winged-helix
protein 3 (Foxp3), TGFbeta, and IL-10 expression.
Therapy-induced reversion of immune suppression was transient since all
three markers of suppression recovered rapidly and surpassed pretherapy levels by day 7 after treatment, resulting in
tumor resurgence. Repeated treatment enhanced short-term tumor regression,
but did not augment long-term survival. Serial long-term analysis
demonstrated that although chronic stimulation enhanced the IFN-gamma
response, this was countered by a parallel increase in Foxp3, TGFbeta, and IL-10 expression. Analysis of
tumor-infiltrating T lymphocyte populations showed that the expression of
Foxp3 and IL-10 was associated with CD4(+)CD25(+)
T cells. Repeated treatment resulted in a progressive increase in tumor-infiltrating
CD4(+)CD25(+)Foxp3(+) T suppressor cells
establishing their role in long-term neutralization of antitumor
activity. Analysis of tumor-infiltrating CD8(+) T
cells demonstrated that although treatment enhanced IFN-gamma production, antitumor cytotoxicity was
diminished. Monitoring of CD8(+) T cells that
specifically recognized a dominant MHC class I her-2/neu peptide showed a
dramatic increase in tetramer-specific CD8(+) T cells after the first
treatment; however, continuous therapy resulted in the loss of this
population. These results demonstrate that both enhanced suppressor
activity and deletion of tumor-specific T cells are responsible for the
progressive loss of efficacy that is associated with chronic immune
therapy.
PMID: 16751376 [PubMed - in process]
UBD, a downstream element of FOXP3, allows the
identification of LGALS3, a new marker of human regulatory T cells.
Ocklenburg F, Moharregh-Khiabani D, Geffers R, Janke V, Pfoertner S, Garritsen H, Groebe L, Klempnauer J, Dittmar KE, Weiss
S, Buer J, Probst-Kepper M.
1Junior Research Group for Xenotransplantation,
Department of Visceral and Transplant Surgery,
Here, we report the identification of the ubiquitin-like
gene UBD as a downstream element of FOXP3 in human activated regulatory CD4(+)CD25(hi) T cells (T(reg)).
Retroviral transduction of UBD in human allo-reactive
effector CD4(+) T helper
(T(h)) cells upregulates CD25 and mediates downregulation of IL4 and IL5 expression similar to overexpression of FOXP3. Moreover, UBD impairs T(h) cell proliferation without upregulation
of FOXP3 and impairs calcium mobilization. In the presence of ionomycin, overexpression of
UBD in T(h) cells leads to the induction of IL1R2
that resemble FOXP3-transduced T(h) cells and naturally derived T(reg) cells. A comparison of the transcriptome
of FOXP3- and UBD-transduced T(h)
cells with T(reg) cells allowed the
identification of the gene LGALS3. However, high levels of LGALS3 protein
expression were observed only in human CD4(+)CD25(hi)
derived T(reg) cells and FOXP3-transduced T(h)
cells, whereas little was induced in UBD-transduced
T(h) cells. Thus, UBD contributes to the anergic
phenotype of human regulatory T cells and acts downstream in FOXP3 induced
regulatory signaling pathways, including regulation of LGALS3 expression.
High levels of LGALS3 expression represent a FOXP3-signature of human
antigen-stimulated CD4(+)CD25(hi) derived regulatory T cells.Laboratory
Investigation advance online publication, 15 May 2006;
doi:10.1038/labinvest.3700432.
PMID: 16702978 [PubMed - as supplied by
publisher]
Fibroblast growth factor-2 is an
immediate-early gene induced by mechanical stress in osteogenic
cells.
Li CF, Hughes-Fulford M.
Laboratory of Cell Growth, Northern California Institute for Research and
Education, San Francisco, California, USA.
Fifteen minutes of physiological MS induces FGF-2 in osteogenic
cells. Here, we show that MS induced proliferation in both MC3T3-E1 and BMOp cells isolated from Fgf2(+/+)
mice; Fgf2(-/-) BMOp cells required exogenous
FGF-2 for a normal proliferation response. The induction of fgf-2 is
mediated by PKA and ERK pathways. INTRODUCTION: Mechanical stress (MS)
induces gene expression and proliferation of osteogenic
MC3T3-E1 cells. We have previously shown that physiological levels of MS in
MC3T3-E1 cells causes extracellular
signal-regulated kinase (ERK)1/2
phosphorylation. Here we evaluate the induction
and importance of fibroblast growth factor-2 (FGF-2) for MS-induced
proliferation. MATERIALS AND METHODS: We characterized the MS induction of
fgf-2 using a 15-minute pulse of 120 mustrain and
studied the stability of fgf-2 message using actinomycin
D. Bone marrow stromal cells (BMOp)
isolated from Fgf2(-/-) and Fgf2(+/+) mice were used to study the
importance of FGF-2 in MS-induced proliferation. RESULTS: We found that the
induction of fgf-2 by MS is dependent on both protein kinase
A (PKA) and ERK pathways. MS transiently induces fgf-2 within 30 minutes.
FGF-2 receptor (FGFR2) was also significantly increased within 1 h. All
three isoforms of FGF-2 (24, 22, and 18 kDa) were significantly increased by MS. The
MS-mediated increase of fgf-2 mRNA was caused by new synthesis and not
stabilization. Pretreatment of MC3T3-E1 cells with cycloheximide
showed that the induction of fgf-2 did not require new protein synthesis. Pretreating MC3T3-E1 cells with the mitogen-activated
protein kinase (MAPK)/ERK kinase
1/2 (MEK1/2) inhibitor, U0126, or H-89, a PKA inhibitor, significantly
inhibited the induction of fgf-2, showing that mechanical induction of
fgf-2 is dependent on ERK and PKA signaling pathways. The downstream
consequence of a single 15-minute stress pulse was a 3.5-fold increase in
cell number in MC3T3-E1 compared with growth in nonstressed
control cells. In studies using bone marrow osteoprogenitor
cells (BMOp) isolated from Fgf2(+/+)and Fgf2(-/-)
mice, we found that FGF-2 was necessary for a full proliferative
response to MS. CONCLUSIONS: These studies show that FGF-2 is an
immediate-early gene induced by MS, and its expression is mediated by both
the PKA and MAPK signal transduction pathways. FGF-2 was required for a
full proliferative response.
PMID: 16753025 [PubMed - in process]