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Introduction
Central tolerance
Peripheral
tolerance
Foxp3+ Tregs
Clonal anergy or clonal deletion
I
P
E
X
one mechanism
regulating
recessive
tolerance
is
costimulation.
mmunosuppressive therapy
Foxp3
mutant
scurfy
mice
OX40
OX40 activates
PI3k/PKB, NFB1, and NFAT
pathways.
Suppressive events
CD30/TNF
RSF8
Wild type
C57BL/6
Wild type
Scurfy
Scurfy
B6.Cg-Foxp3sf/J (sf)
Anti-CD4
antibody
[YTS177.9].
Reported to block
MHC class II T cell
responses in vivo
and in vitro and
induces tolerance.
Express a
simian
diphtheria
toxin. DT
administration
results in
ablation of
Foxp3+CD4+T
reg cells.
strain
mutation produce no
mature T cells or B cells
have no CD3+or T cell
receptor (TCR)
T lymphocyte
specific Thy1a
costimulatory
signaling
through
CD28 in mouse T cells
(as a substitute
activating signal for
CD30
Foxp3
CD44
OX40
CD4
CD62L Antibodies
CD69
Fc receptors were
blocked using
CD16/32
2.5. qPCR
On
negatively
isolated
Tnfrsf4
5-gcttggagttgactgtgttcc-3
5- gggtctgctttccagataagg-3
Tnfrsf8
5-tggagaggaggttgtcaagtc-3
5-gaggaaggcagctcacagat-3
The severity of
autoimmunity:
Inflammatory
cell
Infiltration
Necrosis
Analysed
using the
program
AutMess
Liver
Lung
Pancraetic
Skin
Sirius Red staining
collagen
fibres in
liver
sections
2.7. ELISA
antimouse IgG
OptEIA TMB
AMA titers
antimitochondrial
antibodies
Optical density
450 nm vs 570
nm.
Autoantibodie
90%
of patients
s
with
autoimmune
primary
cirrhosis
biliary
develop
Developed
typical
autoimmune
disease
(exfoliative dermatitis of
the tail, ears, growth
retardation and lethargy)
2- 3 w
Rescue at 21 days
of age
Lacked
signs
autoimmune desease.
Inflammation scores
of liver, lung and
pancreas were all
clearly reduced in
YTS177.9-treated
For explored if
anti-CD4induced
tolerance on a
cellular level.
polyclonal
CD4 T cell
activation
(62L/69)
Analyzed AMA as an
indirect activity of
autoantigen-specifc CD4
T cells.
Sf
Tx
CD44+CD62Llow T cells
Foxp3DTR
DT 0 day
Isotype 0,28 d
Peripheral blood
anti-CD4 antibody
28
d
anti-CD4
antibody on
day 0.
Efficient depletion of
Foxp3 Tregs in all DTtreated
augmented the
Survival
no inhibition of T cell
activation
adoptive
transfer of sf
CD4 T cells into
Rag1-/- mice is
sufficient
to
transfer
fulminant
autoimmunity
investigated the
characteristics
of
anti-CD4induced Foxp3independent
tolerance
in
detail.
RAG -/sf(YTS177.9)
To distinguish
between recessive
T
cell-intrinsic
tolerization
and
classical dominant /
infectious tolerance
sf(Iso)
develope
d disease
Isotype / sf CD4 T
YTS177.9 / CD4 T
cells
cells
+
+
untx
sf
Th1.1 CD4
untx sf Th1.1 CD4
Mixtures of sf
CD4 T cells were
analyzed prior to
injection
Thy1.1 vs.
CD4
expression
of
CD4+CD3+ T
cells
55 days after
mixed
T cell transfer
the frequencies
of sf CD4 T cells
among
the
mixture had not
changed
sf(YTS177.9)
have no survivalor
proliferation
defect compared
to sf(Iso)
Cx.
YTS177.9induced tolerance is
transient, T cellintrinsic and non
infectious
in
the
absence
of
Foxp3
autoimmune
every 4 days
liver
pathology
was clearly
reduced
following
anti-CD4
therapy
serum
(AMA)
associated
with
autoimmune liver diseases
were reduced.
Chronic liver
inflammation
resulting
in
fibrosis
and
eventually
liver
cirrhosis
Evaluated
collagen
deposition in liver
sections from sf
mice
CX.
anti-CD4
therapy not only
reduced
inflammation but
also
secondary fibrosis
and
tissue
fbrosis
reduced Sirius
Red staining
Tx
OX40was
strongly
expressed
3-4
weeks
old
CD4 T cells
Hypothesized:
1
anti-CD4
could
attenuate
signals
from one or both
receptors.
anti-CD4
treatment reduces
OX40 and CD30
expression in vivo
expression