of transplant could induce long-term graft acceptance in 50% of animals. In both the cardiac and renal transplant models, the thymus and spleen were required.
Comparative Strategies to Induce Long-Term Graft Acceptance in Fully Allogeneic Renal Versus Cardiac Allograft Models by CD28-B7 T Cell Costimulatory Blockade: Role of Thymus and Spleen MEIKE
SCHAUB,*
JOHN
THOMAS
P. VELLA,*
LAURENCE
of Immunogenetics ScIwol,
Boston,
University
Blocking
Abstract. by the
fusion
long-term
graft
models. CTLA4Ig not clear ences
in various
in the
the
with
effect
murine
cardiac
different
models,
d) in 54%
of
the
rat
activated T cell
(2).
receptor
histocompatibility senting
APC
with
an antigen
(APC).
immune
signal
(3-7).
The
of this
second
(8,9).
consisting
of the extracelbular
mobogous
to
murine binding
CD28)
CTLA4Ig,
fused
IgGI, is able to B7-b and
to
an
Fe
±
Portions
August of
American Drs.
study
Society
Schaub
Stadlbauer to Dr.
and
Transplantation.
ton,
MA
Copyright
at
San
Mohamed
equally
H. Sayegh, and
the
Antonio,
contributed
Brigham
signal
and
process
B7
results
a recombinant
of CTLA4
portion
of
induce
Womens
annual November
to
this
of the ©
1998
by the
Society American
phase
of tolerance,
Society
grafts
were
Medical
Wistar-Furth
graft
the
day
induction
of
however,
did
the presence applicability
could
In both
thymus
tolerance. not
plus
transplant
of animals.
the
and
The
require
an
of
Only
splenocytes) of
in 50% models,
time
rejected.
(4 X l0 on
to Lewis
survival
ultimately
acceptance
spleen
maintenance intact
thymus
of a spleen. These data have because human studies with T
blockade
9: 891-898,
Blocking ti-B7
are
being
planned.
(J
Am
Soc
1998)
CD28-B7
in
clinical
in suppressing and
ized
meeting
of
the
1997.
CD28-B7 whether
graft
cardiac
of graft
rejection
here
ments
for
renal
versus
was
the
induction
cardiac MHC
of
I and
There
are
in vascular-
in rodents. reflect
these
two
It is not
the effect
organs.
to determine long-term
allograft
class
re-
of
animal strains or species, differences in the immunobi-
between designed
been
the major
(19.20).
differences
blockade in different they actually represent
mod-
( 13-18).
has
of CTLA4Ig
( I 3, 14) models these
very
trans-
instances
rejection,
survival
efficacy
some
also
of chronic
in the whether
tolerance
CTLA4Ig
long-term
( 1 8) and
however,
albogeneic Street.
to
in
true
models,
be
In transplant
and
and
development
differences
renal
rejection
or an-
to
in various
(I 1,12).
acceptance
albogeneic
barrier
reported
response
models acute
graft
by CTLA4Ig
been
the immune
prevents
to prevent
clear,
has
autoimmune
long-term
reported
costimulation
antibodies
CTLAIg
ported
or
T cell
monoelonal
effective
graft
model. class
The
different the
II incompatible
study
require-
acceptance
using
or
in the
same
fully
strain
corn-
bination. Bos-
The thymus plays the major work from several investigators an
of Nephrology
for
require clinical
acute
in a mean
transplant
costimulatory
on
of Immunogenetics
of Nephrology
*Han,(,r(I
Gene Therapy,
ofdonorcells
graft
required
In non-fully
(ho-
a human
75 Francis
1 $03.0()/0
American
all
renal
were
cell
the
resulted
of CTLA4Ig
and
is
work.
Laboratory Hospital.
into
long-term
induces
1. I 997. TX.
protocol
d, and
cardiac
presented
30th
this
injection
of
fusion
domain
02115.
1046-6673/0905-089 Journal
December
presented
of Nephrology.
and
Correspondence
were
of
injection
plantation
to block this costimulatory signal by B7-2, the two ligands of CD28 (10).
12. I997. Accepted
this
and
Hunan
Institute
16.9
a single
obogy Received
‘s Hospital
and
model
concomitant
els,
specificity
on T cells
signaling
unresponsiveness
to a major
costimulatory
of CD28
of
on antigen-pre-
antigen
H. SAYEGH*
Women
kidneys.
as peptide
defines
24.7
Nephrol
by interaction
molecule
second,
interaction
Failure
bound
signal
en-
(>100
process ( 1 ). It is now two signals to become
is provided
(MHC)
This
response.
through
T cell protein
first
complex
cells
provided
The
acceptance
allograft
but did important
combi-
of Wistar-Furth
Allograft rejection is a T cell-dependent well accepted that T cells require at least
and
2 d after
heart
the
complete
strain
graft
recipients
renal
same
CTLA4Ig
study
costimula-
of acute
using
complex-incompatible
Lewis
This
T cell
in rat models
rejection
histocompatibility
the
Transferring
induces
transplant
reported.
CD28-B7
nation. A single injection of murine graftment was able to induce long-term
the
and
experimental
studies
of blocking
CTLA4Ig
allograft
fully
activation
rejection
and
Pennsylvania.
costimulatory
prevents
CHANDRAKER,*
MOHAMED
Brigham of Medicine
Departinent
There are reported differences in the efficacy of in renal and cardiac rodent allograft models, but it is whether these are due to the strain or species differ-
investigates
major
and
ANIL
and
Transplantation,
Philadelphia,
T cell
CTLA4Ig
acceptance
investigated
tion
Massachusetts;
CD28-B7
A. TURKA,t
and
of Pennsylvania,
protein
H. W. STADLBAUER,*
important
splenie
regulatory
role
role in self tolerance. and recent indicates that it also may play
in acquired cells
have
tolerance been
reported
(2 1.22). to play
In addition, an important
892
Journal
of the American
role in maintenance are
no
of tolerance
reports
animals
on
rendered
this study, spleen for
the
of Nephrobogy
in some
role
tolerant
we report induction
CTLA4Ig
Society
of
by
the
models
thymus
T cell
(23,24). and/or
costimulatory
in
Reagents The murine
In
ehimerie
There
spleen blockade.
on the requirement of the thymus and maintenance of graft acceptance
and by
in vito.
Materials
Linsley
fusion
protein
and a corresponding
protein
L6
(Bristol-Myers
Squibb
Pharmaceutical
attle, WA). CTLA4Ig or control venously into the dorsal penile Research
Institute,
East
ously at a dose of2S maintenance therapy
and Methods
CTLA4Ig
recombinant
were
kindly
control
provided
by
Research
Dr.
Institute,
Ig (0.5 mg) was administered vein. Cyclosporine (CsA:
Hanover,
NJ)
was
administered
mg/kg as induction therapy of a dose of 5 mg/kg.
P. Se-
intraSandoz
subeutane-
for 14 d, followed
by
Animals Inbred
male
Lewis
(LEW)
(RTI
brown Norway (RT1”) strain gue Dawbey (Indianapolis, formed
when
LEW
animals
rats served
reached
as recipients
isografts,
or third-party
National
Institutes
tory
(WF)
(RTbt’),
were purchased from Transplant procedures
a body
weight
of renal
or cardiac
BN grafts.
of Health
Wistar-Furth
‘),
rats IN).
of approximately
Animals
Guide
WF
were
and
of Labora-
LEW cally graft
bilateral previously
reject their for survival,
nephreetomy (17).
graft within 2 wk. rejection is defined
within
assuming
surgical
CTLA4Ig
2 h at 37#{176}C, washed
twice
were injected
48
received
model,
WF
were
renal
animals
typi-
Because animals depend as death of the animals.
h posttranspbant
technical
and
In this
APC
and were
cell
in RPM!,
intravenously
and
40
by
plastic
b06/ml)
X
were
of 20 .tg/ml
b0
X
into LEW
suspensions
isolated
(27). APC (10 at a concentration
excluded
on the Deaths
from
analysis,
failure.
Beating grafts of different protocols were buffered saline, harvested, serially sectioned 3-mm slices, and fixed in paraffin and stained
in 10% formalin. with elastic van
slides
by
were
Allograft were
cells
recipients
for
in 1 ml of
on the day of
using
a scale
(28).
vessels
that
Only
to the infrarenal
techniques.
renal
model, does
previously
heterotopic
cardiac
in this
not rely
great
as described on graft
function
was monitored by daily palpation is defined as the day of complete
and confirmed
elastic
degree
Specimens were embedded Gieson. By bight microscopy, arteriosclerosis/arterial
0 to S as described
were
lamina
of
from
perfused with phosphateinto approximately 2- to
cut
staining
orthogonally
were
intimal
et al.
by Adams
and
displayed
a clear
scored.
Model
transplanted
mierovascular
examined
thickening, internal
C’ardiac
recipient
previously
murine
harvested,
above.
Arteriosclerosis
as described
occurring
the
were
described
as described with
RPMI
Model
rats underwent
Hearts
as
CTL44Ig
spleens
transplantation.
Allograft
albograft.
with
or BN)
prepared
incubated
Animals.
Renal
were
(WF
LEW to
ofAPC
Donor
adherence
according Use
Incubation
200 g.
albografts.
housed
for the Care
and
Harlan Sprawere per-
vessels
by standard
(25).
allograft
for survival.
Statistical
In contrast
to
model, Graft
the
function
Analyses
Differences
P value
in survival
of
unmodified of
in vivo
A single
injec-
acute
rejec-
100 d) in 54% animals and
a murine
survival
In
of celland
vitro
prevented
(Table I ),confirming results of our In comparison, in the heterotopic allograft CTLA4Ig
as effective. they accepted
heart
CTLA4Ig.
graft
all
not
inhibition
responses
murine
2 posttransplant
long-term with
(BN)
donor-specific
used
day
whereas
animals
on day 0 was tolerant because
control
time,
original study. WF into LEW
10.8
Ig
d)
cardiac
injection of 0.5 mg of murine graft survival but did not lead to
CD28-B7
Table
Allograft
1.
Blockade
in Vascularized
Transplantation
893
survival” Category
Survival
(days)
Median
Renal CTLA4Ig
day
2
CTLA4Ig
day
0
14, 17, 1 8, 20,
30, 30,
5, 10, 20,
55,
100
>
100
>
(ii
(ii
control
Ig
4, 5, 6, 7, 32
control
unmodified
5, 13, 13,
7)
=
3)
=
54%
> 1 00
days”
43%
> 100
days”
6
14
13
Cardiac CTLA4Ig
alone
day
0
13,
CTLA4Ig
alone
day
2
10. 16, 16, 16, 36, 54
donor
cells
+ CTLA4Ig
day
0
donor
cells
+ CTLA4Ig
day
2
BN
cells
+
irradiated
CTLA4Ig
donor
donor
APC
day
cells
12,
0
with
day
0
CTLA4Ig
day
0
a b
BN,
p
cP
100 dayse
acceptance of
in the of
mg)
prolong
graft
survival;
all
(Table
1). In
addition,
donor
X
later
survival
were
majority
4
1). However,
grafts
survival
in these
when
long-term ofdonor
not
days
specific term
of
survivors
on day
(>
tance
in this
(WF)
the
recipients
single
result
day in
day
were
rejected
within
of
specificity
was
confirmed
9
of
d
by
with
4
10
in an islet that
ex
vivo
prevents recipients
their in the
Similar
autoimmune
could
was
the
long-
rejected
(WF)
improved
heart accep-
to 67% infused
2-wk
2
donor-
two
graft
were by
from day long-
true into
graft
cell
APC
transplant
of
on the
course
rejection absence
when
were model.
CTLA4Ig
of donor
of
also the
islet
et
cells into
administration
reported
in which and
Steurer
transplanted
of systemic
observations with
model,
preineubation
encephabomyelitis of
day
in 30%
Long-term be
we
to the
grafts
donor-spbenoeytes followed
studies
of CTLA4Ig.
other
a donor-strain d).
of sur-
CTLA4Ig.
demonstrate (BN)
1).
1).
showed
CTLA4Ig
I 00
regimen
x
every
A third-party (>
(Table
acceptance.
resulted
whereas
tolerizing
(Table
albogeneic
eubation
d).
transplantation
CTLA4Ig al. (30)
graft acceptance cells alone did not
100
not differ-
of
second
in
of
injection
In contrast
To
l0)
day
allograft
graft
regimen 1 ).
transplanted
accepted
when
In recent
with donor
(Table we
8 postengraftment,
recipi-
prolong
of CTLA4Ig this
acceptance tolerance,
was alone
administration doses.
the
a single
did
of seven
protocol,
graft
model
X
on
CTLA4Ig
permanent
mg
(4
given
recipients
with
repeated
a total
single-injection term
induce 0.5
14 for
splenocytes
transplant
of
received
2 to
permanently
a
not
effect
Recipients
treated
test).
mg)
2 posttransplant
could the
was
both
on
but
(BN)
cardiac
on day
studied
LEW
compared when
in the
CTLA4Ig vivab
third-party
that in animals
Because
day
by
did
by log-rank
allograft
ent from
rather
donor
(assessed
transplant;
2 d later of
l0
administered
of recipients had 1). Administration
the
followed
2 d
of graft (Table
on
model
all
( 14) reported
ci’ al.
0 in the cardiac
(0.5
the
into
of CTLA4Ig
transplant
(0.5
to renal
BN
cells
injection
8.5
CTLA4Ig
passenger
in the Lin
8.5
1 1, 11
of
I).
because
to “tolerize”
of donor
CTLA4Ig
(ii
with
we can
donor-derived
model,
days”
7’
combination
1 1 d (Table
combination,
fact,
administration
prolongation
transplant, 50% (>100 d) (Table
In
by a single
CTLA4Ig
2 CTLA4Ig
be easier
allograft
model,
within
of
administration
long-term In
18,
administration
1 ). Control a similar protocol
hypothesized
(17).
cardiac
>100 175d.e
on
of CTLA4Ig was significompared with the kidney
number
it may
allografts
grafts mg)
effective;
with
allografts
been
day
33 d (Table
donor-recipient
It has
cells
their (0.5
marginally
treated
Ig rejected
donor
+
rejected
within
and animals their
50%
cell. groups.
of CTLA4Ig
allografts
animals
6)
=
13,
70, 9.
CTLA4Ig
animals
of control
ents.
68,
14
rat; APC, antigen-presenting with organ-specific control
with
(ii
14,
6, 6, 7, 10,
transplant
unmodified
kidney
2 to
1). Administration
rejected
>100
6, 8, 9, 10
acceptance;
54 d (Table
animals
65,
unmodified
brown Norway 0.001 compared 0.01.
100
d)
These
grafts
displayed
score,
0.83
±
isograft
controls
separate
group
relevant
protocol
for
d).
100
being
(Figures
was
not
score.
These 0.4, 2)
cells
and
significantly ±
was
(5 mg/d
for
treated
of WF
cardiac
ii
7:
mean
with
a significant
with CTLA4Ig-treated animals were not
harvest
from a
a clinically by
1 mg/d
severe
earlier
vessel
111 ±
(P
difference
100
kidney heart
(ii
7, 9, 15, 8, 14,
Splenectomy kidney
day
3)
=
136
16,
16
+14 18. 21,
26,
29,
>100
(pi
I)
=
a Thymeetomy or splenectomy was performed 7 to 14 d before or 14 d after transplantation. In the renal allograft model, CTLA4Ig was given on day 2, in the cardiac model CTLA4Ig and donor cells were concomitantly administered on the day of engraftment.
Allograft,
CTLA4Ig
Cells
+
the same combination.
MHC class I and class II incompatible As we have shown previously, a single
of CTLA4Ig
2 d after
lograft
rejection
and
>50%
of recipients
cardiac
allograft
combination,
Only
bination
with
resulted
that
long-term
graft
Our
Cyclosporine
strain
infusion
to induce
long-term
diac
allografts
the best was
with
the
strain
CTLA4
Although the costimulatory
(37).
with main
of B7-l patterns
unknown
mechanisms blockade
(14,16),
it
donor alloantigens results rendering the animal more ade. Figure
2.
controls, cells
Representative albografts
on the day
sections
treated
with
of engraftment,
(from top to bottom, XbOO).
respectively,
of coronary a single and
from elastic
dose
arteries
albografts van
from
isograft
of CTLA4Ig+ Gieson;
treated
donor with
magnification,
CsA
Alternatively,
earlier important
donor
progenitors)
that of
B7
costimulatory
the
most
ap-
may
vary
be related
to temporal
molecules
in the target
of the
been in
negative
T cell
donor graft that
shown vitro and regu-
activation
cells synergize acceptance re-
administration
of
in upregulation of B7 molecules, susceptible to costimubatory blockadministration of CTLA4,
of tolerance
express
study,
administration
initial
is possible
of car-
in that
and B7-2 has after activation
of how to promote
antigen
bone
that
to be necessary
blockade
after
of expression
in induction
Premature deficient
donor
upregulation
( 14) in
showed
Therefore,
may
of
recipi-
et al.
they
CTLA4Ig
expression
occurs
induction
albograft
in rat recipients
of costimulatory
In addition,
molecule
of recipients.
of Lin
costimulatory
and
in corn-
for
However.
when
in
of transplantation
seems
2 posttransplant.
T cell combination,
splenocytes
studies
survival
of
(34-36).
latory
strain graft
cardiac
CTLA4Ig.
organ. Indeed, expression to follow distinct temporal in vivo
WF to LEW permanent
in which
obtained
of expression
acute
day
splenocytes
with
was
to the
in >50%
and
with
albograft
to day timing
patterns
in renal
al-
protocol
requirements
combination,
treated
delayed
the
survival
different
of donor
outcome
propriate
are
are consistent
additional
on
renal
acceptance
of donor
given
survival
rat
acute
graft
model in the same not able to induce
allograft
there
data
this
administration
in long-term
a different
Applying
CTLA4Ig
indicating
ents.
Allograft,
rejection were
prevents
in long-term
(1 7).
we
acceptance.
engraftment results
rat strain injection
result
in
may
be
(38).
marrow-derived MHC
may which
class molecules
cells
(dendritic
II molecules induced
cell but
alloantigen-
are
896
Journal
specific
of the American
hyporesponsiveness
ported
studies
approach
APC
in our
vaseularized
with
planation
ciently
provided
direct
MHC
on donor
recognizing
to
may
solid
islet
organ
(30),
that
entity.
experimental (41).
intragraft
expression that
dependent
rejection
shown prevents in both
albogeneic
that cardiac
and
study,
long-term
strated
minimal
intimal
thickening
and
isograft
controls.
In the
relevant
protocol
of chronic
opment
of chronic
costimulatory
cell long-term
degree
of transplant
strategies
vent
role
and
chronic
It has
role
portant
mic
injections
been
shown
but
in initiating
than
immunosuppression
that
to induce
induction Yamada
ci’ a!. indicate
cells
permanent that
acquired
the
responsible
for maintaining
and
thymus
maintenance In summary,
to
under-
to
allograft thymus
has
spleen
play
(21-24). survival a central
of Th2
Our
the
that
presumably these
cells
The
phenotype
of tolerance.
these cells
observations
spleen,
and
cells
are
function
currently
remain
are
under
as regulatory
tolerance
data
as the sole
cells
in
controversial
results
suggest
of T cell
activation
regimen
to induce
long-term
specific
tolerance
in vascularized
MHC
compare
class
different our
graft
I and
importance spleen
also
of organ
blockade
induce
phases
of
of
be confirmed
tolerance
long-term
requires and
distinct
address
the
transplantation.
of
the
thymus
and
to ablografts.
are being thymus
in large in adult
T cell
versus
mechanisms may be of imclinical trials with costimuthe
to involute
targeting
of
tolerance
recipients
requirement
is known
of
the
to
kidney
in cardiac robe
donor-
Using
combination
models
pivotal
in transplant
efficacy
allografts.
pathway
of these because
even
induction
cell transfusion
A greater understanding portant clinical relevance.
the
that organ
different
is a potent
and
strain
costimulatory
the
of costimu-
engraftment
indicate
highlight
in mediating
the thymus
organ
in different
of donor
data
acceptance
II incompatible
observations in blocking
blockade
by CTLA4Ig
graft
models
acceptance
that
animal life,
planned.
for
studies, and
costimulation
In
induction this as
of
because may
limit
a means
to
in humans.
of chronic
a means
donor
in
a state
is depen-
Our
or deletion
thymus,
allograft our
pathway
latory
latory
the
as
responses
of
should
tolerance
or soluble
the
function
tolerance
of developing
and
in
Whether
do-
only
our data
regulatory
investigation.
pre-
Acknowledgments This
immune
of donor
initially
the
to minimize
the process
originating
exist
procedure,
thymus.
in our model.
cells
however,
the
acceptance
not
of anergy
acceptance
phase,
after
graft
but
highly
had been splenectorejected their grafts
2 wk
spleen
a state
regulatory
particular,
with not
that
that
(45).
in regulating
indicating
to
devel-
indicate
In addition,
the importance
affect
way also
mild
similar
not
against
of graft
suggest
Our
a clinically
in combination
vaseulopathy.
(21,22),
did
is a powerful
of T cells
very
observations
acceptance,
suggested
of
regimen
These
mechanism
of
The
is also
maintenance
of permanent
presence
argue
the
within
14 d
survival.
acceptance
recipients that almost entirely
loss
the time Seventy-
thymectomy
long-term
graft
during
a state
the
undergone
on to have
to be
its presence
i.e. , after
phase,
had
(46).
seems
of tolerance,
not to be mandatory.
permanent
allograft that
on
regimens
demon-
with
combination,
by CTLA4Ig
rejection
been
CsA
highlight
rather
in
heart, re-
In the
allografts
compromise,
strain
have
of non-fully
( 19.20).
that
Splenectomy
same
costimulatory
models
cardiac
luminal
same
rejection.
graft
alloantigen-
chronic
arteriosclerosis
transfusion
induce
the key
of little
blockade
T cell
sug-
We
of
the thyrnus
phase
appears
model
(17,47,48).
of
been
Although
went
phase
transplant
hearts or kidneys that had engraftment rejected their
maintenance
of animals
transplantation
induction
T lym-
cytokines,
(44).
combinations
surviving
in
upregulation
by both
allograft
of
intersti-
and
of experimental
renal
degrees
graft
It has
CD28-B7
strain
current
that
factors
blocking
in-
Studies
inflammatory
is mediated
of
determinant
(19,42,43).
development
(LEW-F344)
nor-specific
and
ar-
understood
(3 1,32).
shown
alloantigen-independent
activation
percent
strongly
to conven-
major
is significant
of activation
chronic
degrees
poorly
during
rejection,
indicating
graft
by macrophages
there
growth-factors
previously
score
allorecognition
responsive
the
have
infiltrated
and and
This
recipient
resulted
1 yr posttransplant
outcome
rejection
In addition,
chemokines,
five
manner.
animal
the induction
of acute
acutely.
of vaseularized
variable
is not
long-term
are
phocytes
than
fibrosis.
which
and
vessels
in the
in a large
dependent on the spleen; mized before engraftment
in contra-
by progressive
becomes
chronic
and
rejection
more and
and
function
jection
direct
manifested
immunosuppression,
gested
albo(recipipeptides
rejection
during
after
would
recognizing
Therefore,
blocking
survive
inflammation
clinicopathobogic
tium
(40).
gbomeruloselerosis,
albograft
this
alborecognition
to prevent
rejection
terioselerosis,
tional
antigen,
in an acute
important
point
effi-
tolerance
allografts
dent
grafts
chronic
terstitiab
will APC.
allografts.
Clinically, develop
cells
CTLA4Ig
albo-MHC-derived
molecule)
not be sufficient
ex-
is most
T cell
indirect
processed
on self-MHC
distinction
not
In our study, rat recipients of WF undergone thymectomy 7 d before
rejection
possible
costimulation
(recipient but
acute
with
the
the of
but not on recipient
presenting
alborecognition
T cell
presented alone
cell
of peripheral
incubation
One
APC
cells,
re-
to
(30),
by
model.
CD28-mediated
cells),
contrast
not abrogate
of donor
the
In
transplantation
abbograft
on donor by
block
cell
could
treatment
that
(39).
of B7 molecules
cardiac
B7 molecules
To the extent
of islet
blockade
CTLA4Ig
is that
block
of Nephrology
i,1 vitro
in a model
of cx s’i’o
donor
ent
Society
an
im-
Intrathy-
antigen
have
or tolerance role
in the
tolerance. More recently, data by that the thymus is required for induction
work
was
Research
Grants
recipient
of
Award.
ship grant supported
in part
34965-03
National
and Kidney
is an established
and Dr. Chandraker from the Juvenile by a fellowship
(Sta 461/b-I). tance.
the
Dr. Turka
Association,
supported Al
We thank
by National Al
Institutes
40629-01.
Foundation
Dr.
of Health
Sayegh
Clinician
investigator
of the American
is the recipient
of a research
is the Scientist Heart fellow-
Diabetes Foundation. Dr. Stadlbauer from Deutsche Forsehungsgemeinsehaft
Cheng
Kwok
for excellent
technical
is
assis-
CD28-B7
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