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Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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In parallel studies, animal models of autoimmune disease and
inflammatory bowel disease have provided compelling evidence of
CD4+ regulatory cells that prevent
immunopathology (12, 13, 14, 15). The phenotype of these
regulatory T cells has been further refined, so that
CD4+CD25+CD45RBlow
T cells are now considered the principle exponents
(16, 17, 18). These cells have been shown capable of
regulating CD4+CD25- or
CD4+CD45RBhigh nontolerant
cells both in vitro and in vivo, preventing the onset of autoimmunity
and gut immunopathology (19, 20, 21, 22). They have also been
shown capable of suppressing in vitro proliferation and IFN-
secretion by CD8+ T cells (23).
To establish the relationship, if any, between the T cells that regulate transplant rejection and those that regulate self-immunopathology, we compared the suppressive ability of CD4+CD25+ and CD4+CD25- T cells from mice rendered tolerant to skin transplants, as well as from naive mice with no previous experience of those particular transplantation alloantigens. We found that both CD4+CD25+ and CD4+CD25- cells from tolerant mice could mediate suppression, although the CD4+CD25- cells were required in larger numbers. However, as mice have 10 times more CD4+CD25- than CD4+CD25+ T cells, we are led to conclude that regulatory cells within both populations are involved in suppression, perhaps acting in concert. In contrast, it was only the CD4+CD25+, but not the CD4+CD25-, cells from naive mice that could prevent naive splenocyte cells from rejecting a skin graft, although at least 5-fold more cells were required than from tolerant donors. This could mean that tolerance-inducing protocols either drive an expansion of regulatory T cells (both CD4+CD25+ and CD4+CD25-), or that they bring about selective deletion of nontolerant cells; or indeed both—the outcome being a tolerance-permissive regulator to immune-effector ratio. These results appear to differ from previously published work (24, 25) where only the CD4+CD25+ cells from tolerant animals have been shown to be regulatory. These differences may be apparent rather than real, simply reflecting insufficient cell doses in the previous studies.
Transcriptional profiling by serial analysis of gene expression (SAGE)3 (26) of CD4+CD25+ and CD4+CD25- T cells from naive mice was used to establish that the two populations have very distinct gene profiles. These may reflect the differing functions of such populations, and with further characterization, may provide diagnostics to allow monitoring of the contributions of each CD4+ subpopulation in circumstances where therapeutic tolerance is desirable.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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CBA/Ca (H-2k), human-CD52 transgenic CP1-CBA/Ca (H-2k) (27), and B10.BR (H-2k) mice were bred and maintained in the specific pathogen-free facilities of the Sir William Dunn School of Pathology (Oxford, U.K.). All groups were age- and sex-matched. All procedures were conducted in accordance with the Home Office Animals (Scientific Procedures) Act of 1986.
Thymectomy and skin grafting
Mice were anesthetized with a mixture of 10 mg/ml Hypnodil and 2 µg/ml Sublimaze (Janssen Pharmaceutica, Tilburg, The Netherlands). A total of 0.12 ml/20 g of body weight was injected i.p. Thymectomy was conducted as described by Monaco et al. (28). In short, a longitudinal incision was made on the anterior surface of the neck, and the thymus was removed as two intact lobes by the application of negative pressure through a glass tip inserted in the anterior mediastinum. Skin grafting was conducted according to a modified technique of Billingham et al. (1). Briefly, full thickness tail skin (1 x 1 cm) was grafted on the lateral flank. Grafts were observed on alternate days after the removal of the bandage at day 8 and considered rejected when no viable donor skin was present. Statistical analysis of graft survival was made by the log rank method (29).
Cell separation and adoptive cell transfer
Cells were obtained from spleens of adult CBA/Ca mice. A single-cell suspension was obtained by passing the splenocytes through a 70-µm cell strainer (BD Biosciences, Oxford, U.K) and the erythrocytes were depleted by water lysis. Cells were counted, diluted in PBS, and injected i.v. into the tail vein. Cell separation was performed by negative selection of CD8+ cells, MHC class II+ cells, and B cells by incubation with the mAbs M5/114, 187.1, and YTS156.7, and subsequent incubation with goat-anti-rat IgG Dynabeads (Dynal Biotech, Oslo, Norway) and magnetic removal. For CD4+ separation, cells were incubated with anti-CD4 microbeads (Miltenyi-Biotech, Bergisch Gladbach, Germany) according to manufacturer’s instructions, and positively selected over two magnetic columns using the "posseld" program of AutoMACS (Miltenyi-Biotech). For separation of CD4+CD25+ T cells, the CD8, class II, and B cell-depleted single-cell suspension was incubated 45 min at 4°C with 7D4-biotin (BD PharMingen, San Diego, CA) 1:100 in PBS, 1% w/v BSA, 5% v/v heat-inactivated normal rabbit serum, and 0.1% w/v sodium azide. Following washing, the cells were incubated 15 min at 4°C with 2 µl/107 cells streptavidin-microbeads (Miltenyi Biotech), and positively selected over two columns using AutoMACS posseld program. CD4+CD25- cells were sorted from the negative fraction obtained following CD4+CD25+ separation, by incubation with 100 µl/107 cells with streptavidin-microbeads, and subsequent negative selection of any remaining CD25+ cells using AutoMACS "possels", and finally, a positive selection step with anti-CD4 microbeads as described above. All sorted fractions were labeled with CD8(YTS156.7)-FITC, CD25(PC61)-PE (BD PharMingen), and CD4(H129.19)-CyCr (BD PharMingen); and assessed in a flow cytometer. Typical purity of CD4+ cells and CD4+CD25- cells was >98%, and purity of CD4+CD25+ >90%. Cells were counted, diluted in PBS, and injected i.v. into the tail vein.
Cell depletion, tolerance induction, and mAbs
For depletion of CP1-CBA T cells, 0.2 mg of CAMPATH-1H (30) was injected i.p. Tolerance was induced in CBA/Ca mice by treatment with 1 mg YTS177.9 (2) and 1 mg YTS105.18 (2) at days 0, 2, and 4 after B10.BR skin transplantation. These mAbs, as well as M5/114 (31), 187.1 (32), YTS156.7 (33), PC61 (34), 4F10 (35), JES5 (36), 11B11 (37), and YCATE55.9 (3) were produced in our laboratory by culture in hollow fiber bioreactors, purified from culture supernatants by 50% ammonium sulfate precipitation, dialysed against PBS, and purity checked by native and SDS gel electrophoresis (PhastGel; Pharmacia, St. Albans, U.K.).
Flow cytometry analysis
Peripheral blood samples were depleted of erythrocytes by water
lysis, washed, and resuspended in PBS, 1% w/v BSA, 5% v/v
heat-inactivated normal rabbit serum, and 0.1% w/v sodium azide. Cells
were incubated for 45 min at 4°C with directly conjugated
CAMPATH-1H-FITC, CD8
(53-6.7)-PE (BD PharMingen), and CD4-CyCr. The
cells were washed, resuspended in PBS, 1% w/v BSA, 0.1% w/v sodium
azide, and fixed in 2% v/v formaldehyde solution. Three-color
FACSCaliber analysis (BD Biosciences) was performed using CellQuest (BD
Biosciences) software.
SAGE libraries and differential analysis of gene expression
CD4+CD25+ and
CD4+CD25- cells were
sorted from naive CBA/Ca mice and activated with overnight incubation
with solid-phase anti-CD3 mAb (KT3) at 37°C. T cell populations
were pelleted and resuspended in Promega SV total RNA isolation system
(Promega Z3100; Promega, Madison, WI) lysis buffer (175
µl/2 x 106 cells), and total RNA was
isolated according to the manufacturer’s instructions. First strand
cDNAs were prepared from 1 µg of total RNA from each cell fraction
using Superscript II (Life Technologies, Gaithersburg, MD). Reverse
transcription was initiated using the anchoring primer
5'-GACTCGAGTTGACATCGAGG(T)20V-3' with
incorporation of the SMARTII oligonucleotide (Clontech Laboratories,
Palo Alto, CA) 5'-AAGCAGTGGTAACAACGCAGAGTACGCGGG-3'at the 5' end.
The cDNAs were preamplified with the forward
5'-AGTGGTAACAACGCAGAGTAC-3' and reverse 5'-GACTCGAGTTGACATCGAG-3'
primers using the Advantage-GC cDNA PCR kit (Clontech Laboratories)
with 1 M of the GC-Melt, following the manufacturer’s protocol. cDNAs
were subjected to 16 cycles of preamplification, 94°C for 30 s,
68°C for 7 min. The preamplification steps were monitored by
PCR using various housekeeping and cytokine primers as tests. SAGE was
performed using NlaIII as the anchoring enzyme, BsmF1 as the
tagging enzyme, and SphI as the cloning enzyme, as described
(26). DNA sequencing was performed using the Megabase 1000
(Molecular Dynamics, Sunnyvale, CA). Sequence analysis software SAGE
3.04 
was provided by K. W. Kinzler (Johns Hopkins Oncology
Center, Baltimore, MD). A conservative estimate of the differential
up-regulation of each gene within the given library, compared with a
pool of other libraries, was calculated using a Bayesian statistics
model (38).
Identification of mAbs in the serum
Serum concentrations of JES5 and 11B11 were determined by ELISA. 96-well plates were coated with 10 µg/ml JES5 or 11B11 in 0.1 M NaHCO3, and blocked with 50 µl PBS, 1% BSA. Serum samples from the mice were diluted 1/20 in PBS, 1% BSA containing either rIL-10 (10 ng/ml) or rIL-4 (2 ng/ml), and preincubated for 60 min at room temperature before being transferred into the JES5- or 11B11-coated plates, where the samples were incubated for a further 60 min. After washing with PBS, 0.05% Tween, the plates were incubated 60 min with anti-IL10 (SXC-1) biotin or anti-IL-4 (BVD6-24G2) biotin (both from BD Biosciences). The plates were then incubated with extravidin-peroxidase (Sigma-Aldrich, Poole, U.K.) for 30 min, and developed with substrate buffer and absorbance at 492 nm analyzed with a microplate reader (Labsystems, Helsinki, Finland). Serum 4F10 was determined by incubating serum samples in anti-hamster IgG (HIG-29) (BD Biosciences) coated plates, and detecting any bound hamster Ab with biotin-conjugated HIG-29. Serum PC61 was determined by flow cytometry by incubating CD25+ Con A blasts with the experimental serum diluted 1/5 in PBS, 1% BSA for 30 min at 4°C, followed by addition of anti-CD25 (PC61) PE-conjugated (BD Biosciences), as well as anti-CD4 CyChrome. Three-color FACSCaliber analysis was performed using CellQuest software. In all cases, the experimental serum samples were compared with serum from untreated animals, and serum spiked with mAb to known concentrations.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Regulatory cells that suppress graft rejection by naive spleen cells can be found in the spleens of mice made tolerant to an allograft with therapeutic mAbs (3). We confirmed that 107 spleen cells from naive CBA/Ca mice were, upon adoptive transfer, sufficient to reject B10.BR skin grafts in T cell-depleted hosts (39). An equal number of spleen cells from mice tolerant to B10.BR skin grafts could prevent graft rejection when coadministered with the naive cells.
Tolerance was induced in CBA/Ca mice by treatment with 3 mg of the
combination of nondepleting CD4 and CD8 mAbs administered over 1 wk
following the transplantation of B10.BR skin grafts. We used CP1-CBA
mice as T cell-depleted hosts for cell transfusion (27).
This transgenic strain is histocompatible with CBA/Ca and allows
selective T cell depletion with the human-CD52 mAb CAMPATH-1H
(7), as human CD52 is expressed under the control of the
CD2 promoter in all T cells. CP1-CBA mice were thymectomized at 4 wk of
age, and depleted of T cells with CAMPATH-1H 1 wk before cell transfer
(designated as "empty" mice). The empty mice were transfused with
107 spleen cells from tolerant mice,
107 spleen cells from naive CBA/Ca, or an equal
number (107) of spleen cells from both tolerant
and naive mice. All animals were grafted with B10.BR skin the following
day. Rejection was only observed in the mice transfused with cells from
naive CBA/Ca (Fig. 1
). Spleen cells from
tolerant mice not only failed to reject the skin grafts, but also
abrogated rejection by naive T cells, so demonstrating dominant
tolerance. Similar results were obtained in experiments where 2 x
107 and 4 x 107
spleen cells from both tolerant and naive mice were transfused. We
decided to use 107 spleen cells from naive CBA/Ca
as the target population to assess the number and phenotype of
regulatory cells able to prevent rejection.
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We investigated whether the capacity to suppress transplant
rejection pre-existed in naive mice. We isolated
CD4+CD25+ and
CD4+CD25- T cells from the spleens of naive
CBA/Ca mice. Empty CP1-CBA mice were injected with
107 unsorted spleen cells from naive CBA/Ca,
together with 106 of either
CD4+CD25+ or
CD4+CD25- T cells, also
from naive CBA/Ca. All mice were transplanted with B10.BR skin on the
following day. Delayed graft rejection was observed in the group
transferred with the
CD4+CD25+ cells, with 6 of
the 10 mice showing indefinite graft survival (Fig. 2). The animals injected with unsorted
spleen cells alone rejected the skin grafts at a rate similar to
the group receiving
CD4+CD25- T cells. To rule
out an artifact of the sorting procedure, a control experiment was
performed where spleen cells from naive CBA/Ca were sorted and
subsequently remixed to the exact starting proportions. These cells
failed to prevent skin graft rejection upon adoptive transfer (data not
shown). One interpretation for these results is that aggression and
tolerance are the outcome of situations dictated by the numerical
balance between regulatory and effector cells.
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The Ag specificity of the CD4+CD25+ T cells from naive animals that suppress transplant rejection is currently unknown. CD4+CD25+ cells have been shown to inhibit the proliferation of CD4+CD25- cells to different alloantigens in vitro, as long as the CD4+CD25+ cells are themselves preactivated (42). It may be that their repertoire contains receptors directed toward self-Ags (43). If so, then there is the possibility that self-reactive regulators mediate graft acceptance through "linked suppression", where they are brought into the local microenvironment of the alloreactive cell. Alternatively, the receptor repertoire of CD4+CD25+ T cells may show cross-reactivity to alloantigens present in the graft. Given the finding that suppression involves indirect presentation of Ag (44), the "alloantigens" in question are likely to be donor-type peptides presented in conjunction with host-type MHC.
CD4+CD25+ T cells from tolerized mice are more efficient than CD4+CD25- cells as mediators of dominant transplantation tolerance
Having established that
CD4+CD25+ T cells from
naive animals suppress graft rejection, we compared the potency of both
CD4+CD25+ and
CD4+CD25- populations from
tolerized mice in preventing rejection. The
CD4+CD25+ and
CD4+CD25- populations were
purified from the spleens of CBA/Ca mice made tolerant to B10.BR skin
transplants 100–120 days earlier (Fig. 3A). Different numbers of
CD4+CD25+ and
CD4+CD25- T cells were
transferred with the fixed number 107 of naive
spleen cells into empty CP1-CBA recipients. All recipients received
B10.BR skin grafts on the following day. When 105
CD4+CD25+ cells were
transferred together with 107 spleen cells from
naive CBA/Ca, a delay in graft rejection was observed when compared
with the groups transferred with the same number of
CD4+CD25- cells, or with
controls which had received naive spleen cells only (Fig. 3B). However, when the number of
CD4+CD25- T cells was
increased 10-fold to 106, graft rejection was
delayed to an extent comparable to the 105
CD4+CD25+ group. No skin
graft rejection by the naive cells was observed in the groups
transferred with 106
CD4+CD25+ or
107
CD4+CD25- T cells. These
results suggest that both
CD4+CD25+ and
CD4+CD25- cells can
mediate transplantation tolerance, the
CD4+CD25+ T cells being 10
times more potent than
CD4+CD25- cells. However,
as the number of CD4+CD25-
T cells in tolerant mice is 
10 times higher than that of
CD4+CD25+ cells, it is
likely that both populations have a significant role in maintaining
transplantation tolerance.
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The observation that the potency of the CD4+CD25+ population seems to increase following induction of transplantation tolerance is intriguing. It is not clear at this time whether this is due to an expansion of the regulatory cells from pre-existing regulators, whether it results from de novo formation of regulatory cells, or whether this reflects selective inactivation or death of nontolerant cells; so shifting the functional bias of the population toward regulation. It is equally interesting that the CD4+CD25- population is only seen to regulate if derived from tolerant, but not naive, populations. It may be that some "tolerant" CD25+ regulatory cells loose the expression of CD25 and endow the CD4+CD25- population with new regulatory powers, as it has been suggested following homeostatic expansion of CD4+CD25+ T cells (48). Alternatively, activation induced cell death previously reported to occur in the induction of transplantation tolerance (49, 50) may selectively remove effector cells from the CD25- population, unmasking residual regulatory cell activity.
Of interest was the finding that the "potency" of unseparated
tolerized CD4+ cells (containing both
CD4+CD25+ and
CD4+CD25- subpopulations)
seemed greater than the separated populations.
CD4+ cells were sorted from spleens of CBA/Ca
mice tolerant to B10.BR skin grafts using magnetic microbeads, and
different numbers of these cells were injected together with the fixed
number of 107 splenocytes from naive CBA/Ca mice
into empty CP1-CBA recipients (Fig. 4A). All animals received a
B10.BR skin graft on the following day. When 105
or less CD4+ spleen cells were transfused, the
outcome was rejection (Fig. 4B). However, adoptive transfer
of 5 x 105 or more
CD4+ spleen cells from tolerant mice resulted in
graft acceptance. In the CBA/Ca mouse strain, 10% of
CD4+ cells coexpress CD25 in both naive and
tolerant animals. On the basis of these figures, we can calculate that
it takes 5 x 104
CD4+CD25+ cells combined
with 4.5 x 105
CD4+CD25- cells from
tolerant mice to suppress 107 naive spleen cells.
However, we found that neither 105
CD4+CD25+ nor
106
CD4+CD25- cells alone
could provide this degree of suppression (see Fig. 3
). This suggests
that the "unseparated" CD4+ cell population
shows greater potency than the equivalent numbers of sorted
CD4+CD25+ or
CD4+CD25- T cells. Such a
result could possibly reflect impairment of regulatory function from
the cell separation manipulations, or perhaps the enhanced regulation
from CD4+CD25+ and
CD4+CD25- regulatory cells
operating together. Additional experiments are needed to clarify
this.
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CD4+CD25+ and CD4+CD25- cells differ in gene expression
To validate the separation procedures adopted to isolate
CD4+CD25- and
CD4+CD25+ T cells, we
examined the nature of genes expressed in each population, either
resting or activated with solid-phase CD3 mAbs, using SAGE. A
differential analysis of the four SAGE libraries is displayed in Fig. 5 as scatter plots comparing
CD4+CD25- spleen cells
with CD4+CD25+ spleen cells
before and after stimulation. A number of transcripts that do not
differ between the two populations before activation are highlighted in
Fig. 5A. These include the housekeeping genes EF-1 and
GAPDH, the T cell-specific genes CD3
and Ly116 (a Th1 marker), the
activation marker OX40, together with 2
microglobulin and MHC-I (K, D, and L, although this latter tag is
slightly higher in
CD4+CD25- cells). Very few
tags appear to be specific to either one of the populations; but 28
tags are significantly up-regulated in
CD4+CD25+ cells (most of
which we have as yet been unable to assign to known genes), and 97 tags
significantly up-regulated in
CD4+CD25- cells. The
majority of the latter tags (at least 58) map to transcripts normally
considered housekeeping genes (shown in gray, and defined as being
nondifferential (i.e., SD < mean) across 16 other SAGE libraries,
including ribosomal proteins and essential metabolic enzymes (38, 51). This relative loss of housekeeping transcripts is further
exemplified after CD3 stimulation of the two populations (Fig. 5B), and includes GAPDH, EF-1, and also
2 microglobulin (while CD3, MHC-I, and OX40
change little). This apparent loss of housekeeping gene expression may
be explained by the different capacities of the two populations to
proceed through the cell cycle; it may be that
CD4+CD25+ cells that do not
proliferate in response to TCR ligation do not require many of the
synthetic and metabolic enzymes, but express a set of new functional
proteins without any cell division. It is clear that
CD4+CD25+ cells have indeed
expressed at least 103 new transcripts as a result of their activation
(Fig. 5B); and therefore, are behaving in a manner that is
quite distinct from
CD4+CD25- cells. Most of
these tags are unique among the SAGE libraries we have constructed so
far (38, 51), and have not yet been assigned to known
genes. Although we used SAGE results exclusively to confirm the
distinctiveness of the
CD4+CD25+ and
CD4+CD25- T cells, we have
thus far identified four novel candidate genes from the Celera
Discovery System mouse gene database (marked as transcripts mCT5392,
mCT2519, mCT6469, and mCT4200), whose roles are currently under
investigation.
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There are several conflicting reports in the literature
implicating particular cytokines and cell surface molecules in dominant
tolerance. In some in vivo and in vitro studies, Abs to CTLA-4 (4F10)
and CD25 (PC61) have interfered with suppression (52, 53),
although others did not find a role for CTLA-4 in vitro
(54). We could not implicate CTLA-4 in our readout of
suppression (see below). Other studies have also described a role for
IL-10, IL-4, and TGF in suppression by regulatory T cells, where
high doses of mAbs were used in an attempt to neutralize the effect of
the target cytokines (24, 39, 43, 55, 56). We could not
implicate these same molecules in our own studies.
We transfused 20 x 106 spleen cells from
CBA/Ca mice tolerant to B10.BR skin into empty CP1-CBA mice, together
with the same number of spleen cells from naive CBA/Ca animals (as
described in Fig. 1). Separate groups of these animals were treated
with high doses of anti-IL4 mAb (11B11), anti-IL10 mAb (JES5),
or both in combination; anti-CD25 mAb (PC61), anti-CTLA-4
(4F10), or both in combination. One control group was treated with
anti-canine CD8 (YCATE55), and another control group received naive
spleen cells in the absence of spleen cells from tolerant mice. The
mAbs were administered in doses of 2 mg at days -4, -2, 0, 5, and
then weekly until rejection. The adoptive cell transfer was performed
at day -1, and B10.BR skin transplants at day 0. Blood samples from
all mice were collected at days 20 and 60 to determine the level of the
injected mAbs in the sera. The serum concentration of the injected Abs,
as determined by binding inhibition, was >100 µg/ml in all
PC61-treated mice (two mice injected with PC61 + 4F10 had serum levels
between 1 and 10 µg/ml at day 60); all JES5-treated mice had serum
concentrations of the mAb between 10 and 100 µg/ml; all 11B11-treated
mice had serum concentrations of the mAb >100 µg/ml (except four
mice also injected with JES5 where the mAb concentrations were between
10 and 100 µg/ml at days 20 and 60). The serum concentration of 4F10
was determined through an anti-hamster IgG ELISA. All mice had a
serum concentration of hamster Ab between 1 and 10 µg/ml at day 20,
dropping to <1 µg/ml at day 60.
The group transferred with cells from naive mice readily rejected the
test skin grafts (Fig. 6A).
However, indefinite graft survival was observed in all other groups,
suggesting that those particular targeted molecules do not play a
critical role in dominant transplantation tolerance in this model. A
similar experiment focused on the naive
CD4+CD25+ population. We
transferred 106 sorted
CD4+CD25+ spleen cells from
naive CBA/Ca mice, together with 107 splenocytes
from naive CBA/Ca mice, as described. Some of the mice were treated
with a combination of anti-CTLA-4 and anti-IL-10 mAbs in the
doses mentioned above. Treatment with these mAbs did not result in any
significant difference in tolerance induced by
CD4+CD25+ cells (Fig. 6B). A similar experiment with sorted
CD4+CD25+ spleen cells from
tolerized mice had a comparable result, with none of the mice treated
with the mAbs rejecting their grafts (data not shown). Therefore, we
can exclude a role for the targeted molecules as mediators of
regulation in the experimental system we studied. Previous
demonstrations of roles for these molecules in other experimental
readouts suggest: 1) that regulation may involve diverse molecular
mediators depending on the precise microenvironment where it operates;
or 2) that dominant tolerance exploits multiple redundant suppressive
pathways where blockade of any one would not impact the outcome; or 3)
that some of the effects seen are on the effector population in
rendering them more sensitive to Ag-mediated signals–this may be a
very plausible explanation for the effects of CTLA-4 mAbs, which should
in principle enhance signaling (57, 58); or 4) that
regulation takes place in a compartment which the injected mAb cannot
easily access, such as the transplanted skin graft itself.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Luis Graca, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, U.K. E-mail address: luis.graca{at}pathology.oxford.ac.uk
3 Abbreviations used in this paper: SAGE, serial analysis of gene expression; MST, median survival time.
Received for publication January 11, 2002. Accepted for publication March 29, 2002.
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155:1151.[Abstract]
,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J. Immunol. 167:1945. and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4+CD45RC- cells and CD4+CD8- thymocytes. J. Exp. Med. 189:279. but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RBlow CD4+ T cells. J. Exp. Med. 183:2669.This article has been cited by other articles:
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  K. Nagahama, Z. Fehervari, T. Oida, T. Yamaguchi, O. Ogawa, and S. Sakaguchi Differential control of allo-antigen-specific regulatory T cells and effector T cells by anti-CD4 and other agents in establishing transplantation tolerance Int. Immunol., April 1, 2009; 21(4): 379 - 391. [Abstract] [Full Text] [PDF]
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 N. D. Verma, K. M. Plain, M. Nomura, G. T. Tran, C. Robinson, R. Boyd, S. J. Hodgkinson, and B. M. Hall CD4+CD25+ T cells alloactivated ex vivo by IL-2 or IL-4 become potent alloantigen-specific inhibitors of rejection with different phenotypes, suggesting separate pathways of activation by Th1 and Th2 responses Blood, January 8, 2009; 113(2): 479 - 487. [Abstract] [Full Text] [PDF]
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A. D. Griesemer, J. C. LaMattina, M. Okumi, J. D. Etter, A. Shimizu, D. H. Sachs, and K. Yamada Linked Suppression across an MHC-Mismatched Barrier in a Miniature Swine Kidney Transplantation Model J. Immunol., September 15, 2008; 181(6): 4027 - 4036. [Abstract] [Full Text] [PDF]
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A. L. Tang, J. R. Teijaro, M. N. Njau, S. S. Chandran, A. Azimzadeh, S. G. Nadler, D. M. Rothstein, and D. L. Farber CTLA4 Expression Is an Indicator and Regulator of Steady-State CD4+FoxP3+ T Cell Homeostasis J. Immunol., August 1, 2008; 181(3): 1806 - 1813. [Abstract] [Full Text] [PDF]
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G. T. Schnickel, S. Bastani, G. R. Hsieh, A. Shefizadeh, R. Bhatia, M. C. Fishbein, J. Belperio, and A. Ardehali Combined CXCR3/CCR5 Blockade Attenuates Acute and Chronic Rejection J. Immunol., April 1, 2008; 180(7): 4714 - 4721. [Abstract] [Full Text] [PDF]
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C. H. Cook, A. A. Bickerstaff, J.-J. Wang, T. Nadasdy, P. Della Pelle, R. B. Colvin, and C. G. Orosz Spontaneous Renal Allograft Acceptance Associated with "Regulatory" Dendritic Cells and IDO J. Immunol., March 1, 2008; 180(5): 3103 - 3112. [Abstract] [Full Text] [PDF]
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 S. S. Lee, W. Gao, S. Mazzola, M. N. Thomas, E. Csizmadia, L. E Otterbein, F. H. Bach, and H. Wang Heme oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells FASEB J, November 1, 2007; 21(13): 3450 - 3457. [Abstract] [Full Text] [PDF]
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S. F. Yates, A. M. Paterson, K. F. Nolan, S. P. Cobbold, N. J. Saunders, H. Waldmann, and P. J. Fairchild Induction of Regulatory T Cells and Dominant Tolerance by Dendritic Cells Incapable of Full Activation J. Immunol., July 15, 2007; 179(2): 967 - 976. [Abstract] [Full Text] [PDF]
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D. Golshayan, S. Jiang, J. Tsang, M. I. Garin, C. Mottet, and R. I. Lechler In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance Blood, January 15, 2007; 109(2): 827 - 835. [Abstract] [Full Text] [PDF]
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T. Iwai, Y. Tomita, S. Okano, I. Shimizu, Y. Yasunami, T. Kajiwara, Y. Yoshikai, M. Taniguchi, K. Nomoto, and H. Yasui Regulatory Roles of NKT Cells in the Induction and Maintenance of Cyclophosphamide-Induced Tolerance J. Immunol., December 15, 2006; 177(12): 8400 - 8409. [Abstract] [Full Text] [PDF]
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Y. Zhai, L. Meng, F. Gao, Y. Wang, R. W. Busuttil, and J. W. Kupiec-Weglinski CD4+ T Regulatory Cell Induction and Function in Transplant Recipients after CD154 Blockade Is TLR4 Independent J. Immunol., May 15, 2006; 176(10): 5988 - 5994. [Abstract] [Full Text] [PDF]
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B. P.-L. Lee, W. Chen, H. Shi, S. D. Der, R. Forster, and L. Zhang CXCR5/CXCL13 Interaction Is Important for Double-Negative Regulatory T Cell Homing to Cardiac Allografts J. Immunol., May 1, 2006; 176(9): 5276 - 5283. [Abstract] [Full Text] [PDF]
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D. C. Neujahr, C. Chen, X. Huang, J. F. Markmann, S. Cobbold, H. Waldmann, M. H. Sayegh, W. W. Hancock, and L. A. Turka Accelerated Memory Cell Homeostasis during T Cell Depletion and Approaches to Overcome It. J. Immunol., April 15, 2006; 176(8): 4632 - 4639. [Abstract] [Full Text] [PDF]
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 H. Keino, M. Takeuchi, T. Kezuka, T. Hattori, M. Usui, O. Taguchi, J. W. Streilein, and J. Stein-Streilein Induction of Eye-Derived Tolerance Does Not Depend on Naturally Occurring CD4+CD25+ T Regulatory Cells. Invest. Ophthalmol. Vis. Sci., March 1, 2006; 47(3): 1047 - 1055. [Abstract] [Full Text] [PDF]
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K. Rieger, C. Loddenkemper, J. Maul, T. Fietz, D. Wolff, H. Terpe, B. Steiner, E. Berg, S. Miehlke, M. Bornhauser, et al. Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD Blood, February 15, 2006; 107(4): 1717 - 1723. [Abstract] [Full Text] [PDF]
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S. G. Zheng, L. Meng, J. H. Wang, M. Watanabe, M. L. Barr, D. V. Cramer, J. D. Gray, and D. A. Horwitz Transfer of regulatory T cells generated ex vivo modifies graft rejection through induction of tolerogenic CD4+CD25+ cells in the recipient Int. Immunol., February 1, 2006; 18(2): 279 - 289. [Abstract] [Full Text] [PDF]
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A. Sanchez-Fueyo, S. Sandner, A. Habicht, C. Mariat, J. Kenny, N. Degauque, X. X. Zheng, T. B. Strom, L. A. Turka, and M. H. Sayegh Specificity of CD4+CD25+ Regulatory T Cell Function in Alloimmunity J. Immunol., January 1, 2006; 176(1): 329 - 334. [Abstract] [Full Text] [PDF]
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A. S. Krupnick, A. E. Gelman, W. Barchet, S. Richardson, F. H. Kreisel, L. A. Turka, M. Colonna, G. A. Patterson, and D. Kreisel Cutting Edge: Murine Vascular Endothelium Activates and Induces the Generation of Allogeneic CD4+25+Foxp3+ Regulatory T Cells J. Immunol., November 15, 2005; 175(10): 6265 - 6270. [Abstract] [Full Text] [PDF]
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H. Kitade, M. Kawai, O. Rutgeerts, W. Landuyt, M. Waer, C. Mathieu, and J. Pirenne Early Presence of Regulatory Cells in Transplanted Rats Rendered Tolerant by Donor-Specific Blood Transfusion J. Immunol., October 15, 2005; 175(8): 4963 - 4970. [Abstract] [Full Text] [PDF]
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S. P Hickman and L. A Turka Homeostatic T cell proliferation as a barrier to T cell tolerance Phil Trans R Soc B, September 29, 2005; 360(1461): 1713 - 1721. [Abstract] [Full Text] [PDF]
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 M. Sho, K. Kishimoto, H. Harada, M. Livak, A. Sanchez-Fueyo, A. Yamada, X. X. Zheng, T. B. Strom, G. P. Basadonna, M. H. Sayegh, et al. Requirements for induction and maintenance of peripheral tolerance in stringent allograft models PNAS, September 13, 2005; 102(37): 13230 - 13235. [Abstract] [Full Text] [PDF]
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W. Chen, D. Zhou, J. R. Torrealba, T. K. Waddell, D. Grant, and L. Zhang Donor Lymphocyte Infusion Induces Long-Term Donor-Specific Cardiac Xenograft Survival through Activation of Recipient Double-Negative Regulatory T Cells J. Immunol., September 1, 2005; 175(5): 3409 - 3416. [Abstract] [Full Text] [PDF]
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H. J. P. M. Koenen, E. Fasse, and I. Joosten CD27/CFSE-Based Ex Vivo Selection of Highly Suppressive Alloantigen-Specific Human Regulatory T Cells J. Immunol., June 15, 2005; 174(12): 7573 - 7583. [Abstract] [Full Text] [PDF]
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B. P.-L. Lee, E. Mansfield, S.-C. Hsieh, T. Hernandez-Boussard, W. Chen, C. W. Thomson, M. S. Ford, S. E. Bosinger, S. Der, Z.-x. Zhang, et al. Expression Profiling of Murine Double-Negative Regulatory T Cells Suggest Mechanisms for Prolonged Cardiac Allograft Survival J. Immunol., April 15, 2005; 174(8): 4535 - 4544. [Abstract] [Full Text] [PDF]
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J. Shimizu, R. Iida, Y. Sato, E. Moriizumi, A. Nishikawa, and Y. Ishida Cross-Linking of CD45 on Suppressive/Regulatory T Cells Leads to the Abrogation of Their Suppressive Activity In Vitro J. Immunol., April 1, 2005; 174(7): 4090 - 4097. [Abstract] [Full Text] [PDF]
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A. Bushell, E. Jones, A. Gallimore, and K. Wood The Generation of CD25+CD4+ Regulatory T Cells That Prevent Allograft Rejection Does Not Compromise Immunity to a Viral Pathogen J. Immunol., March 15, 2005; 174(6): 3290 - 3297. [Abstract] [Full Text] [PDF]
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S. Schenk, D. D. Kish, C. He, T. El-Sawy, E. Chiffoleau, C. Chen, Z. Wu, S. Sandner, A. V. Gorbachev, K. Fukamachi, et al. Alloreactive T Cell Responses and Acute Rejection of Single Class II MHC-Disparate Heart Allografts Are under Strict Regulation by CD4+CD25+ T Cells J. Immunol., March 15, 2005; 174(6): 3741 - 3748. [Abstract] [Full Text] [PDF]
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C. Y. Liu, M. Battaglia, S. H. Lee, Q.-H. Sun, R. H. Aster, and G. P. Visentin Platelet Factor 4 Differentially Modulates CD4+CD25+ (Regulatory) versus CD4+CD25- (Nonregulatory) T Cells J. Immunol., March 1, 2005; 174(5): 2680 - 2686. [Abstract] [Full Text] [PDF]
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 M. Cascalho and J. L. Platt New Technologies for Organ Replacement and Augmentation Mayo Clin. Proc., March 1, 2005; 80(3): 370 - 378. [Abstract] [PDF]
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P. E. Rao, A. L. Petrone, and P. D. Ponath Differentiation and Expansion of T Cells with Regulatory Function from Human Peripheral Lymphocytes by Stimulation in the Presence of TGF-{beta} J. Immunol., February 1, 2005; 174(3): 1446 - 1455. [Abstract] [Full Text] [PDF]
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 X.-Y. Zhu, Y.-H. Zhou, M.-Y. Wang, L.-P. Jin, M.-M. Yuan, and D.-J. Li Blockade of CD86 Signaling Facilitates a Th2 Bias at the Maternal-Fetal Interface and Expands Peripheral CD4+CD25+ Regulatory T Cells to Rescue Abortion-Prone Fetuses Biol Reprod, February 1, 2005; 72(2): 338 - 345. [Abstract] [Full Text] [PDF]
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A. E. Foster, M. Marangolo, M. M. Sartor, S. I. Alexander, M. Hu, K. F. Bradstock, and D. J. Gottlieb Human CD62L- memory T cells are less responsive to alloantigen stimulation than CD62L+ naive T cells: potential for adoptive immunotherapy and allodepletion Blood, October 15, 2004; 104(8): 2403 - 2409. [Abstract] [Full Text] [PDF]
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S. Makita, T. Kanai, S. Oshima, K. Uraushihara, T. Totsuka, T. Sawada, T. Nakamura, K. Koganei, T. Fukushima, and M. Watanabe CD4+CD25bright T Cells in Human Intestinal Lamina Propria as Regulatory Cells J. Immunol., September 1, 2004; 173(5): 3119 - 3130. [Abstract] [Full Text] [PDF]
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E. Nishimura, T. Sakihama, R. Setoguchi, K. Tanaka, and S. Sakaguchi Induction of antigen-specific immunologic tolerance by in vivo and in vitro antigen-specific expansion of naturally arising Foxp3+CD25+CD4+ regulatory T cells Int. Immunol., August 1, 2004; 16(8): 1189 - 1201. [Abstract] [Full Text] [PDF]
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P. Hoffmann, R. Eder, L. A. Kunz-Schughart, R. Andreesen, and M. Edinger Large-scale in vitro expansion of polyclonal human CD4+CD25high regulatory T cells Blood, August 1, 2004; 104(3): 895 - 903. [Abstract] [Full Text] [PDF]
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L. Graca, A. Le Moine, C.-Y. Lin, P. J. Fairchild, S. P. Cobbold, and H. Waldmann Donor-specific transplantation tolerance: The paradoxical behavior of CD4+CD25+ T cells PNAS, July 6, 2004; 101(27): 10122 - 10126. [Abstract] [Full Text] [PDF]
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S. Vigouroux, E. Yvon, E. Biagi, and M. K. Brenner Antigen-induced regulatory T cells Blood, July 1, 2004; 104(1): 26 - 33. [Abstract] [Full Text] [PDF]
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 T. L. Sumpter and D. S. Wilkes Role of autoimmunity in organ allograft rejection: a focus on immunity to type V collagen in the pathogenesis of lung transplant rejection Am J Physiol Lung Cell Mol Physiol, June 1, 2004; 286(6): L1129 - L1139. [Abstract] [Full Text] [PDF]
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M. K. Lee IV, D. J. Moore, B. P. Jarrett, M. M. Lian, S. Deng, X. Huang, J. W. Markmann, M. Chiaccio, C. F. Barker, A. J. Caton, et al. Promotion of Allograft Survival by CD4+CD25+ Regulatory T Cells: Evidence for In Vivo Inhibition of Effector Cell Proliferation J. Immunol., June 1, 2004; 172(11): 6539 - 6544. [Abstract] [Full Text] [PDF]
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O. Joffre, N. Gorsse, P. Romagnoli, D. Hudrisier, and J. P. M. van Meerwijk Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes Blood, June 1, 2004; 103(11): 4216 - 4221. [Abstract] [Full Text] [PDF]
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J. Kurtz, J. Shaffer, A. Lie, N. Anosova, G. Benichou, and M. Sykes Mechanisms of early peripheral CD4 T-cell tolerance induction by anti-CD154 monoclonal antibody and allogeneic bone marrow transplantation: evidence for anergy and deletion but not regulatory cells Blood, June 1, 2004; 103(11): 4336 - 4343. [Abstract] [Full Text] [PDF]
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T.-C. Chen, S. P. Cobbold, P. J. Fairchild, and H. Waldmann Generation of Anergic and Regulatory T Cells following Prolonged Exposure to a Harmless Antigen J. Immunol., May 15, 2004; 172(10): 5900 - 5907. [Abstract] [Full Text] [PDF]
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S. P. Cobbold, R. Castejon, E. Adams, D. Zelenika, L. Graca, S. Humm, and H. Waldmann Induction of foxP3+ Regulatory T Cells in the Periphery of T Cell Receptor Transgenic Mice Tolerized to Transplants J. Immunol., May 15, 2004; 172(10): 6003 - 6010. [Abstract] [Full Text] [PDF]
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J.-G. Chai, E. James, H. Dewchand, E. Simpson, and D. Scott Transplantation tolerance induced by intranasal administration of HY peptides Blood, May 15, 2004; 103(10): 3951 - 3959. [Abstract] [Full Text] [PDF]
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Y. Chen, P. S. Heeger, and A. Valujskikh In Vivo Helper Functions of Alloreactive Memory CD4+ T Cells Remain Intact Despite Donor-Specific Transfusion and Anti-CD40 Ligand Therapy J. Immunol., May 1, 2004; 172(9): 5456 - 5466. [Abstract] [Full Text] [PDF]
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R. Y. Chandawarkar, M. S. Wagh, J. T. Kovalchin, and P. Srivastava Immune modulation with high-dose heat-shock protein gp96: therapy of murine autoimmune diabetes and encephalomyelitis Int. Immunol., April 1, 2004; 16(4): 615 - 624. [Abstract] [Full Text] [PDF]
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B. H. Nelson IL-2, Regulatory T Cells, and Tolerance J. Immunol., April 1, 2004; 172(7): 3983 - 3988. [Abstract] [Full Text] [PDF]
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X. Zhang, D. N. Koldzic, L. Izikson, J. Reddy, R. F. Nazareno, S. Sakaguchi, V. K. Kuchroo, and H. L. Weiner IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells Int. Immunol., February 1, 2004; 16(2): 249 - 256. [Abstract] [Full Text] [PDF]
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L. A. Stephens, A. N. Barclay, and D. Mason Phenotypic characterization of regulatory CD4+CD25+ T cells in rats Int. Immunol., February 1, 2004; 16(2): 365 - 375. [Abstract] [Full Text] [PDF]
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S. G. Zheng, J. H. Wang, M. N. Koss, F. Quismorio Jr., J. D. Gray, and D. A. Horwitz CD4+ and CD8+ Regulatory T Cells Generated Ex Vivo with IL-2 and TGF-{beta} Suppress a Stimulatory Graft-versus-Host Disease with a Lupus-Like Syndrome J. Immunol., February 1, 2004; 172(3): 1531 - 1539. [Abstract] [Full Text] [PDF]
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D.-A. Gross, M. Leboeuf, B. Gjata, O. Danos, and J. Davoust CD4+CD25+ regulatory T cells inhibit immune-mediated transgene rejection Blood, December 15, 2003; 102(13): 4326 - 4328. [Abstract] [Full Text] [PDF]
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M. Tone, Y. Tone, E. Adams, S. F. Yates, M. R. Frewin, S. P. Cobbold, and H. Waldmann From The Cover: Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells PNAS, December 9, 2003; 100(25): 15059 - 15064. [Abstract] [Full Text] [PDF]
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 K. J. Young, L. S. Kay, M. J. Phillips, and L. Zhang Antitumor Activity Mediated by Double-Negative T Cells Cancer Res., November 15, 2003; 63(22): 8014 - 8021. [Abstract] [Full Text] [PDF]
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P. Feunou, L. Poulin, C. Habran, A. Le Moine, M. Goldman, and M. Y. Braun CD4+CD25+ and CD4+CD25- T Cells Act Respectively as Inducer and Effector T Suppressor Cells in Superantigen-Induced Tolerance J. Immunol., October 1, 2003; 171(7): 3475 - 3484. [Abstract] [Full Text] [PDF]
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 S. Fisson, G. Darrasse-Jeze, E. Litvinova, F. Septier, D. Klatzmann, R. Liblau, and B. L. Salomon Continuous Activation of Autoreactive CD4+ CD25+ Regulatory T Cells in the Steady State J. Exp. Med., September 2, 2003; 198(5): 737 - 746. [Abstract] [Full Text] [PDF]
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K. Uraushihara, T. Kanai, K. Ko, T. Totsuka, S. Makita, R. Iiyama, T. Nakamura, and M. Watanabe Regulation of Murine Inflammatory Bowel Disease by CD25+ and CD25- CD4+ Glucocorticoid-Induced TNF Receptor Family-Related Gene+ Regulatory T Cells J. Immunol., July 15, 2003; 171(2): 708 - 716. [Abstract] [Full Text] [PDF]
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K. J. Young, B. DuTemple, M. J. Phillips, and L. Zhang Inhibition of Graft-Versus-Host Disease by Double-Negative Regulatory T Cells J. Immunol., July 1, 2003; 171(1): 134 - 141. [Abstract] [Full Text] [PDF]
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T. Pearson, T. G. Markees, D. V. Serreze, M. A. Pierce, M. P. Marron, L. S. Wicker, L. B. Peterson, L. D. Shultz, J. P. Mordes, A. A. Rossini, et al. Genetic Disassociation of Autoimmunity and Resistance to Costimulation Blockade-Induced Transplantation Tolerance in Nonobese Diabetic Mice J. Immunol., July 1, 2003; 171(1): 185 - 195. [Abstract] [Full Text] [PDF]
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 A. D. Salama, N. Najafian, M. R. Clarkson, W. E. Harmon, and M. H. Sayegh Regulatory CD25+ T Cells in Human Kidney Transplant Recipients J. Am. Soc. Nephrol., June 1, 2003; 14(6): 1643 - 1651. [Abstract] [Full Text] [PDF]
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S. Grundstrom, L. Cederbom, A. Sundstedt, P. Scheipers, and F. Ivars Superantigen-Induced Regulatory T Cells Display Different Suppressive Functions in the Presence or Absence of Natural CD4+CD25+ Regulatory T Cells In Vivo J. Immunol., May 15, 2003; 170(10): 5008 - 5017. [Abstract] [Full Text] [PDF]
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N. E. Phillips, T. G. Markees, J. P. Mordes, D. L. Greiner, and A. A. Rossini Blockade of CD40-Mediated Signaling Is Sufficient for Inducing Islet But Not Skin Transplantation Tolerance J. Immunol., March 15, 2003; 170(6): 3015 - 3023. [Abstract] [Full Text] [PDF]
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T. Oida, X. Zhang, M. Goto, S. Hachimura, M. Totsuka, S. Kaminogawa, and H. L. Weiner CD4+CD25- T Cells That Express Latency-Associated Peptide on the Surface Suppress CD4+CD45RBhigh-Induced Colitis by a TGF-{beta}-Dependent Mechanism J. Immunol., March 1, 2003; 170(5): 2516 - 2522. [Abstract] [Full Text] [PDF]
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W. Chen, M. S. Ford, K. J. Young, M. I. Cybulsky, and L. Zhang Role of Double-Negative Regulatory T Cells in Long-Term Cardiac Xenograft Survival J. Immunol., February 15, 2003; 170(4): 1846 - 1853. [Abstract] [Full Text] [PDF]
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 G. Rajagopalan, Y. C. Kudva, R. A. Flavell, and C. S. David Accelerated Diabetes in Rat Insulin Promoter-Tumor Necrosis Factor-{alpha} Transgenic Nonobese Diabetic Mice Lacking Major Histocompatibility Class II Molecules Diabetes, February 1, 2003; 52(2): 342 - 347. [Abstract] [Full Text] [PDF]
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L. Graca, S. P. Cobbold, and H. Waldmann Identification of Regulatory T Cells in Tolerated Allografts J. Exp. Med., June 17, 2002; 195(12): 1641 - 1646. [Abstract] [Full Text] [PDF]
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) or
2 x 107 (
) spleen cells from naive
CBA/Ca;107 (
) or 2 x 107 (
) spleen
cells from CBA/Ca mice tolerant of B10.BR skin grafts; 107
or 2 x 107 spleen cells from the same naive CBA/Ca
donors, together with an equal number of spleen cells tolerant donors
(
and 
); and a final group was not injected (
). All animals
received a B10.BR skin graft on the following day (day 0). Only mice
transfused with cells from naive donors rejected the skin grafts, the
rejection being slightly faster when more cells were transfused. The
spleen cells from tolerant donors not only allowed indefinite graft
survival, but were also able to suppress rejection mediated by the
naive cells injected at the same time.
Mean) and are depicted in
gray. For clarity, most of differentially expressed tags are
represented in black, and the nondifferential in white. The following
gene transcripts were identified by their SAGE tags as follows:
