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Alvin J. Siteman Cancer Center, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-10
but did not secrete IFN-
. When cocultured with activated
CD8+ cells or CD4+25- cells,
Treg potently suppressed their proliferation and secretion
of IFN-. We conclude that the prevalence of Treg is
increased in the peripheral blood as well as in the tumor
microenvironment of patients with invasive breast or pancreas cancers.
These Treg may mitigate the immune response against cancer,
and may partly explain the poor immune response against tumor
Ags. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain
(CD25). Treg have been isolated from human PBMCs
(2) and mouse spleen (3). These cells are
thought to be a functionally unique subset of T lymphocytes that play
an important function in maintaining immune homeostasis and protecting
the host against autoimmune diseases (4, 5). Mice that are
deficient in this subset of T cells develop T cell-mediated autoimmune
diseases such as type I diabetes due to insulitis (6),
hypothyroidism due to thyroiditis (7), infertility due to
oophoritis/orchitis (8), and pernicious anemia due to
gastritis (9). In addition to CD4 and CD25 markers,
Treg also constitutively express CD45RO and CD152
(CTLA-4). Ex vivo studies on these cells reveal a poorly proliferative
cell population that secretes inhibitory cytokines such as TGF- and
IL-10 (2). They also inhibit the proliferation of
CD4+25- and
CD8+ lymphocytes (10). Their
mechanism of action remains an area of active investigation. When Treg are depleted using mAb, transplanted tumors in mice are efficiently rejected by the host immune system (11, 12). This finding suggests that Treg, which function as a protective mechanism against autoimmunity, may also mitigate the immune response against cancers. A previous study demonstrated that large numbers of CD4+25+ lymphocytes infiltrate the tumor microenvironment of non-small cell lung cancers and ovarian cancers (13). This may partly explain the poor clinical response to cancer vaccines even after measurable postvaccination increases in tumor-specific CTLs (14). Prevalence of Treg in the circulation and tumor microenvironment of cancer patients has not been extensively studied previously, and interactions between human tumors and Treg are unknown.
Animal studies indicate that suppressor cells similar to Treg that protect against autoimmunity may also impair immune response against tumor Ags. In mice that carry chemically induced fibrosarcoma, CD4+ Treg down-regulated the activity of effector cells against the tumor (15). Passive transfer of these suppressor T cells from fibrosarcoma-bearing hosts impaired generation of tumor-specific immunity in recipients (16). Similar observations have been made with other murine tumors (17, 18, 19, 20). Administration of a monoclonal anti-CD25 Ab that depletes the immune system of CD4+25+ Treg cells has been shown to promote the rejection of tumors derived from leukemia, myeloma, and sarcoma (21). In the recent report by Sutmuller et al. (12), a synergism between treatment with anti-CTLA-4 Ab and depletion of CD25+ cells with anti-CD25 Ab was observed. This synergism led to more efficient rejection of transplanted tumors than when treated with either Ab alone.
Immune tolerance to tumor may contribute to progression of the tumor by local invasion as well as metastatic spread. In mice, development of a suppressor T cell population that inhibits the antitumor immune response preceded tumor progression (22). In a different experimental system, advanced stage metastatic lymphoma was rejected by the host if suppressor CD4+ T cells were eliminated by a single dose of vinblastine, a chemotherapeutic agent (23).
These studies combined with other indirect evidence lead us to
formulate the hypothesis that invasive cancer in humans is associated
with an expansion of Treg that suppress a
tumor-specific immune response. To test this hypothesis, we collected
samples of peripheral blood, tumor, and regional tumor-infiltrated
lymph nodes from 65 patients undergoing surgery for either breast or
pancreas ductal adenocarcinoma. We compared the prevalence of
CD4+25+
Treg in these samples to that of 35 normal
individuals and patients who underwent surgical procedures for benign
diseases and carcinoma in situ. In addition, we performed functional
analysis on patient-derived Treg, confirming
their suppressor cytokine profiles and their antiproliferative effect
on activated CD4+CD25- and
CD8+ autologous lymphocytes. We show that
the prevalence of Treg in the peripheral
blood of breast and pancreas cancer patients is increased when compared
with normal individuals. Similarly, Treg are
present in tumor-infiltrating lymphocytes (TIL) and regional lymph
nodes infiltrated by tumor. These cells secrete IL-10 and TGF-, and
prevent activated
CD4+CD25- and
CD8+ from proliferating.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Following a research protocol approved by the Washington
University School of Medicine Human Studies Committee (St. Louis, MO),
peripheral blood, tumor, and tumor-infiltrated lymph nodes were
obtained from patients undergoing resections for breast or pancreas
cancers. Blood samples were also obtained from normal healthy
volunteers and patients undergoing surgery for benign diseases as
controls. All the breast cancer patients and 13 of 25 pancreas cancer
patients were female. Of 35 patients with breast cancer, 21 carried
stage II or higher disease. All except one pancreas cancer patient
carried stage II or higher disease with invasive tumors (Table I
). Any patient who had received
chemotherapy before obtaining specimens was excluded from the
study.
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CD4+ cells were isolated from heparinized blood using Rosette Sep CD4+ cell enrichment mixture according to the manufacturer’s guidelines. The resulting 90% pure CD4+ cells (data not shown) were washed, and CD25+ cells were positively selected by labeling with anti-CD25 tetrameric Ab complex and magnetic colloid, followed by separation using magnetic columns. CD25+ and CD25- fractions were separated and saved. The CD4+ cell enrichment mixture, CD25 tetrameric Ab complex, magnetic colloid, and separation columns were obtained from StemCell Technologies (Vancouver, Canada).
Isolation of Treg from tumor-draining lymph nodes
Fresh lymph nodes obtained from patients were minced with a scalpel, pipetted repeatedly in PBS containing 2% FBS, and strained through a 40-µm mesh to obtain a single-cell suspension. RBC were lysed by incubating in ACK lysis buffer for 5 min. Using the CD4+ cell isolation kit (Miltenyi Biotec, Germany), CD4+ lymphocytes were isolated and fractionated into CD25- and CD25+ fractions using anti-CD25 microbeads (Miltenyi Biotec, Auburn, CA).
Isolation of PBMC
Heparinized blood was diluted 1/1 v/v with PBS before Ficoll density centrifugation. The buffy coat containing PBMC was harvested, contaminating RBCs lysed by incubating in ACK lysing buffer (0.15 M NH4Cl, 10 mM KHCO3, 0.1 mM EDTA, pH 7.4), and washed twice in cold PBS.
Isolation of CD8+ cells
CD8+ cells were isolated from heparinized blood using Rosette Sep CD8+ cell enrichment mixture (StemCell Technologies) according to the manufacturer’s guidelines. The enriched cell population contained >85% CD8+ cells as determined by cell surface staining and flow cytometry analysis.
Isolation of TILs and lymph node lymphocytes (LNLs)
Fresh pieces of tumor and draining regional lymph nodes were minced into 1-mm-size pieces and digested in a buffer containing 1 mg/ml collagenase (Sigma-Aldrich, St. Louis, MO), 2.5 U/ml hyaluronidase (Sigma-Aldrich), and 0.1 mg/ml DNase (Sigma-Aldrich) for 2 h to obtain a single-cell suspension. Resulting cells were washed twice in PBS and used for additional experiments.
Cell culture
T cells were cultured in X-VIVO 15 medium (BioWhittaker, Walkersville, MD) containing 2% autologous serum, 10 U/ml rIL-2 (Endogen, Woburn, MA), and 10 µg/ml of anti-CD28 Ab (clone CD28.2; BD PharMingen, San Diego, CA). For cytokine secretion assays, 1.25 x 104 cells were grown in anti-CD3 Ab (OKT3)-coated round bottom 96-well plates, and culture supernatant was harvested after 72 h. In coculture experiments, 1.25 x 104 of CD4+CD25- cells or CD8+ cells were incubated with the specified ratio of the CD4+25+ cells. Again, the culture supernatant was harvested after 72 h for cytokine assays.
Cell proliferation assay
Cell proliferation in coculture experiments was determined by incorporation of radiolabeled thymidine after incubation with medium containing 1 µCi/well (10 µCi/ml) of [3H]thymidine for 16–18 h. Incorporated radioactivity was counted using a scintillation counter.
ELISA
Culture supernatant concentrations of IFN-, TGF-,
and IL-10 were measured by using commercially available ELISA kits
(BioSource International, Camarillo, CA) according to the protocols
provided by the manufacturer.
Immunofluorescence labeling and flow cytometry
PBMC, TIL, and LNL isolated respectively from peripheral blood, fresh tumor samples, and regional lymph nodes were used for two- and three-color cell surface labeling using Abs against CD4, CD25, CTLA4 (CD152), and CD45RO. All the Abs were obtained from BD PharMingen. Labeled cells were analyzed by using FACSCalibur flow cytometer and CellQuest software (BD Biosciences, Mountain View, CA). With each sample, a negative control with isotype-matched control Abs was used to determine the positive and negative cell populations. The p values were determined using the Student t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We analyzed the PBL from 35 patients with breast ductal carcinoma
and 30 patients with pancreas adenocarcinoma by flow cytometry after
cell surface labeling for coexpression of CD4 and CD25 molecules. The
prevalence of CD4+25+ cells
as a percentage of total CD4+ population was
determined by standard determination of quadrant statistics. These
percentages were compared with that of 35 normal donors and patients
who underwent surgical resections of benign breast and pancreatic
lesions. There was no significant difference between the prevalence of
CD4+25+ cells in normal
donors and patients with benign disease (n = 6, data
not shown). Representative dot plots of breast (Fig. 1A) and pancreas (Fig. 1B) cancer patients as well as normal donors (Fig. 1C) are shown. Cumulative data for all the patients and
normal donors are presented in a bar chart and a scatter chart (Fig. 1, D and E). The prevalence of
CD4+25+ cells in breast
cancer patients was 16.6% (SE 1.22) and in pancreas cancer patients
was 13.2% (SE 1.13), as compared with that of normal donors, which was
8.6% (SE 0.71). The prevalence of
CD4+25+ cells in both
breast (p < 0.001) and pancreas
(p < 0.015) cancer patients was significantly
higher than in normal individuals.
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To verify that the more prevalent
CD4+25+ lymphocytes in
cancer patients are indeed similar to well-documented
Treg isolated from normal donors, we compared the
cell surface expression of CTLA-4 and CD45RO molecules by three-color
staining and flow cytometry. PBL freshly isolated from cancer patients
and normal donors were labeled with FITC-conjugated anti-CD4,
PE-conjugated anti-CD25, and CyChrome-conjugated anti-CTLA-4 or
anti-CD45RO. As shown in Fig. 2A,
CD4+25+ cell population was
first identified and the expression of either CTLA-4 (Fig. 2B) or CD45RO (Fig. 2C) was analyzed in this
gated population. The majority of
CD4+25+ cells from cancer
patients coexpress CTLA-4 and CD45RO molecules similar to
Treg of normal donors. We further characterized
these CD4+25+ cells by
analyzing the cytokine expression pattern. CD4+
cells were purified to >90% purity from peripheral blood of normal
donors as well as cancer patients by negative selection as described in
Materials and Methods. CD4+ cells were
separated into CD4+CD25+
and CD4+CD25- fractions
by positive selection of CD25+ cells using
magnetic labeling. Average purity of
CD4+CD25- and
CD4+CD25+ were 88 and 82%,
respectively (data not shown). Cells from both fractions were cultured
and stimulated with plate-bound anti-CD3 and soluble anti-CD28
Abs for 72 h. The culture supernatants were removed and assayed
for IFN-, TGF-, and IL-10.
CD4+25+ lymphocytes secrete
IL-10 and TGF-, but no IFN-, as shown in Fig. 2D. This
is in contrast to CD4+25-
lymphocytes, which secrete large amounts of IFN-, but little TGF-
and IL-10.
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secretion by
activated CD8+ T lymphocytes and helper
CD4+25- lymphocytes
We assessed the suppressor function of
CD4+25+
Treg from cancer patients and normal donors by
coculturing CD8+ or
CD4+25- cells with
CD4+25+ cells. Each type of
lymphocyte was isolated from the peripheral blood of cancer patients
and normal donors as described in Materials and
Methods, and resuspended in culture medium containing rIL-2,
anti-CD28 Ab, and 2% autologous serum. Either
CD8+ or
CD4+25- lymphocytes were
cocultured with the indicated ratio of
CD4+25+ cells in
anti-CD3-coated 96-well plates. After 72 h of coculture,
concentration of IFN- in the medium was measured by ELISA. Cell
proliferation was determined by incorporation of
[3H]thymidine. Representative results from 14
cancer patients and 5 normal donors are depicted in Fig. 3. The data for all other patients and
normal donors not represented in the Fig. 3 are presented in Table II.
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To test the hypothesis that Treg infiltrate
the tumor microenvironment, we isolated lymphocytes from 20 fresh
breast and pancreas cancer specimens and tumor-infiltrated lymph nodes,
and measured the prevalence of
CD4+25+ cells. In Fig. 4, A and B are
representative results of flow cytometry analyses from TIL and LNL.
There was a selection bias toward patients bearing larger and more
advanced tumors in the 20 patients from whom we were able to collect
tumor samples and tumor-infiltrated lymph nodes. This may partly
explain the very high prevalence of Treg in the
TIL and LNL.
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To confirm that
CD4+25+ lymphocytes derived
from tumor microenvironment and draining lymph nodes exhibit the
Treg phenotype, we isolated
CD4+ lymphocytes from two breast cancer specimens
and tumor-draining lymph nodes from two pancreas cancer patients. The
CD4+ cells were fractionated into
CD25+ and CD25- fractions
by using CD25 microbeads and grown in cell culture as described in
Materials and Methods. After 72 h of culture, culture
supernatant was analyzed by ELISA for IFN-, IL-10, and TGF-. The
results are shown in Fig. 4
D.
CD4+25+ lymphocytes from tumor-draining lymph nodes suppress activation of CD4+25- cells
Lymph nodes that are present within the immediate drainage basin
of the tumor are likely sites of tumor-specific CTL proliferation.
Presence of Treg in these lymph nodes may inhibit
such CTL proliferation. To test the hypothesis that
Treg inhibit Th cell function in the draining
lymph nodes, we isolated Treg from draining lymph
nodes of two pancreas cancer patients, and analyzed the secreted
cytokine profile and in vitro suppression activity on
CD4+ cells. The cytokine profile reveals similar
characteristics to peripheral blood-derived Treg
(Fig. 4D) and suppressor activity on
CD4+ cell proliferation and IFN- secretion
(Fig. 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Current research on immunotherapy for cancer mainly focuses on
generation of T cell-mediated tumor lysis by using vaccination
strategies. Such a strategy remains largely unsuccessful in eliciting
clinically significant regression of established tumors even in
patients with detectable vaccine-induced tumor-specific CTL. A few
documented cases of tumor regression remain the exception rather than
the rule. Explanations offered for this marginal success of
immunotherapy include "tolerance" development due to lack of
costimulatory molecules on tumors, down-regulation of signal
transduction molecules in T cells, apoptosis of T cells upon contact
with tumor, tumor-induced dysfunction of APCs, secreted
immunosuppressive proteins such as TGF- by tumor, and emergence of
Ag loss variants. However, virtually no experimental evidence on a role
for Treg in inhibiting immune responses against
human cancer exists.
Tumor-induced tolerance mediated by T cells has been demonstrated in a variety of tumor types in mice. This has been well-documented in a large body of literature which has been reviewed by R. J. North (24). Until recently, the suppressor population was not defined by the coexpression of CD4 and CD25 markers. Identification of CD4+25+ Treg will now allow us to determine whether the previously described suppressor T cells are indeed the CD4+25+ Treg.
Experimental evidence suggests that down-regulation of immune response to cancer by concomitant development of suppressor cells may allow progressive local growth of tumors (25). When tumor cells are implanted in mice, an initial slow period of growth is followed by a rapid growth period with local invasion and metastatic spread. The phase of rapid growth and metastatic spread has been shown to be synchronous with the development of CD4+ suppressor T cells. These suppressor cells, when adaptively transferred, can suppress immune response to the same tumor in a previously immune mouse (26). Mice rendered immunodeficient by thymectomy or gamma irradiation are better able to reject transplanted tumors when infused with tumor-specific T cells than their immunocompetent counterparts (27). These immunocompromised mice were unable to develop suppressor T cells, allowing adoptively transferred cytotoxic T cells to lyse tumor efficiently. Depletion of suppressor cells with cytotoxic agents such as cyclophosphamide (28) and vinblastin (23) appear to have cytolytic effect on suppressor T cells resulting in T cell-mediated tumor rejection.
Our findings provide no mechanistic explanation for the increased prevalence of Treg in patients with invasive cancer. Future studies will explore two possible mechanisms: 1) tumor-mediated induction of Treg expansion, or 2) physiologic expansion of the Treg repertoire as a response to mostly self Ags born by cancer cells. No experimental evidence is currently available to favor either mechanism. However, by using an animal model, one can attempt to answer this question experimentally. If the emergence of Treg is physiological due to the immune response generated against tumor, nonimmunogenic tumors will cause minimal expansion of Treg. However, if the alternative hypothesis of tumor-induced expansion of Treg as a mechanism of immune evasion is correct, one would expect to see increased prevalence of Treg in mice even with nonimmunogenic tumors.
Our findings may have direct clinical implications on design and implementation of future immunotherapy-based clinical trials. Our findings enhance the significance of the observation made by Sutmuller et al. (12) that therapy with anti-CD25 and anti-CD152 (CTLA-4) Abs led to tumor rejection. Because the prevalence of Treg is increased in human cancer patients, a strategy of treating cancer patients with Abs targeting Treg-bearing CD25 and CD152 molecules offer promise. Furthermore, the efficacy of any vaccine-based immunotherapy may be greatly enhanced by combining such vaccines with Abs that deplete Treg.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. David C. Linehan, Alvin J. Siteman Cancer Center, Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Box 8109, St. Louis, MO 63110. E-mail address: linehand{at}surgery.wustl.edu
3 Abbreviations used in this paper: Treg, regulatory T cell; TIL, tumor-infiltrating lymphocyte; LNL, lymph node lymphocyte.
Received for publication January 8, 2002. Accepted for publication June 27, 2002.
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K. S. Sfanos, T. C. Bruno, C. H. Maris, L. Xu, C. J. Thoburn, A. M. DeMarzo, A. K. Meeker, W. B. Isaacs, and C. G. Drake Phenotypic Analysis of Prostate-Infiltrating Lymphocytes Reveals TH17 and Treg Skewing Clin. Cancer Res., June 1, 2008; 14(11): 3254 - 3261. [Abstract] [Full Text] [PDF]
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S. Mittal, N. A. Marshall, L. Duncan, D. J. Culligan, R. N. Barker, and M. A. Vickers Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma Blood, June 1, 2008; 111(11): 5359 - 5370. [Abstract] [Full Text] [PDF]
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S. Ladoire, L. Arnould, L. Apetoh, B. Coudert, F. Martin, B. Chauffert, P. Fumoleau, and F. Ghiringhelli Pathologic Complete Response to Neoadjuvant Chemotherapy of Breast Carcinoma Is Associated with the Disappearance of Tumor-Infiltrating Foxp3+ Regulatory T Cells Clin. Cancer Res., April 15, 2008; 14(8): 2413 - 2420. [Abstract] [Full Text] [PDF]
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L. Strauss, C. Bergmann, M. J. Szczepanski, S. Lang, J. M. Kirkwood, and T. L. Whiteside Expression of ICOS on Human Melanoma-Infiltrating CD4+CD25highFoxp3+ T Regulatory Cells: Implications and Impact on Tumor-Mediated Immune Suppression J. Immunol., March 1, 2008; 180(5): 2967 - 2980. [Abstract] [Full Text] [PDF]
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J. Yokokawa, V. Cereda, C. Remondo, J. L. Gulley, P. M. Arlen, J. Schlom, and K. Y. Tsang Enhanced Functionality of CD4+CD25highFoxP3+ Regulatory T Cells in the Peripheral Blood of Patients with Prostate Cancer Clin. Cancer Res., February 15, 2008; 14(4): 1032 - 1040. [Abstract] [Full Text] [PDF]
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J. Haas, L. Schopp, B. Storch-Hagenlocher, B. Fritzsching, C. Jacobi, L. Milkova, B. Fritz, A. Schwarz, E. Suri-Payer, M. Hensel, et al. Specific recruitment of regulatory T cells into the CSF in lymphomatous and carcinomatous meningitis Blood, January 15, 2008; 111(2): 761 - 766. [Abstract] [Full Text] [PDF]
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Y. Li and C. Yee IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes Blood, January 1, 2008; 111(1): 229 - 235. [Abstract] [Full Text] [PDF]
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P. Zhou, L. L'italien, D. Hodges, and X. M. Schebye Pivotal Roles of CD4+ Effector T cells in Mediating Agonistic Anti-GITR mAb-Induced-Immune Activation and Tumor Immunity in CT26 Tumors J. Immunol., December 1, 2007; 179(11): 7365 - 7375. [Abstract] [Full Text] [PDF]
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J.-R. Pallandre, E. Brillard, G. Crehange, A. Radlovic, J.-P. Remy-Martin, P. Saas, P.-S. Rohrlich, X. Pivot, X. Ling, P. Tiberghien, et al. Role of STAT3 in CD4+CD25+FOXP3+ Regulatory Lymphocyte Generation: Implications in Graft-versus-Host Disease and Antitumor Immunity J. Immunol., December 1, 2007; 179(11): 7593 - 7604. [Abstract] [Full Text] [PDF]
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L. Strauss, C. Bergmann, W. Gooding, J. T. Johnson, and T. L. Whiteside The Frequency and Suppressor Function of CD4+CD25highFoxp3+ T Cells in the Circulation of Patients with Squamous Cell Carcinoma of the Head and Neck Clin. Cancer Res., November 1, 2007; 13(21): 6301 - 6311. [Abstract] [Full Text] [PDF]
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M. T. Litzinger, R. Fernando, T. J. Curiel, D. W. Grosenbach, J. Schlom, and C. Palena IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity Blood, November 1, 2007; 110(9): 3192 - 3201. [Abstract] [Full Text] [PDF]
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A. Joetham, K. Takeda, N. Miyahara, S. Matsubara, H. Ohnishi, T. Koya, A. Dakhama, and E. W. Gelfand Activation of naturally occurring lung CD4+CD25+ regulatory T cells requires CD8 and MHC I interaction PNAS, September 18, 2007; 104(38): 15057 - 15062. [Abstract] [Full Text] [PDF]
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S. Hinz, L. Pagerols-Raluy, H.-H. Oberg, O. Ammerpohl, S. Grussel, B. Sipos, R. Grutzmann, C. Pilarsky, H. Ungefroren, H.-D. Saeger, et al. Foxp3 Expression in Pancreatic Carcinoma Cells as a Novel Mechanism of Immune Evasion in Cancer Cancer Res., September 1, 2007; 67(17): 8344 - 8350. [Abstract] [Full Text] [PDF]
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T. Tanijiri, T. Shimizu, K. Uehira, T. Yokoi, H. Amuro, H. Sugimoto, Y. Torii, K. Tajima, T. Ito, R. Amakawa, et al. Hodgkin's Reed-Sternberg cell line (KM-H2) promotes a bidirectional differentiation of CD4+CD25+Foxp3+ T cells and CD4+ cytotoxic T lymphocytes from CD4+ naive T cells J. Leukoc. Biol., September 1, 2007; 82(3): 576 - 584. [Abstract] [Full Text] [PDF]
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S. Hao, Y. Liu, J. Yuan, X. Zhang, T. He, X. Wu, Y. Wei, D. Sun, and J. Xiang Novel Exosome-Targeted CD4+ T Cell Vaccine Counteracting CD4+25+ Regulatory T Cell-Mediated Immune Suppression and Stimulating Efficient Central Memory CD8+ CTL Responses J. Immunol., September 1, 2007; 179(5): 2731 - 2740. [Abstract] [Full Text] [PDF]
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J. Nitcheu-Tefit, M.-S. Dai, R. J. Critchley-Thorne, F. Ramirez-Jimenez, M. Xu, S. Conchon, N. Ferry, H. J. Stauss, and G. Vassaux Listeriolysin O Expressed in a Bacterial Vaccine Suppresses CD4+CD25high Regulatory T Cell Function In Vivo J. Immunol., August 1, 2007; 179(3): 1532 - 1541. [Abstract] [Full Text] [PDF]
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R. Shaykhiev and R. Bals Interactions between epithelial cells and leukocytes in immunity and tissue homeostasis J. Leukoc. Biol., July 1, 2007; 82(1): 1 - 15. [Abstract] [Full Text] [PDF]
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G. Cesana and H. L. Kaufman In Reply J. Clin. Oncol., June 20, 2007; 25(18): 2630 - 2632. [Full Text] [PDF]
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S. Tuve, B.-M. Chen, Y. Liu, T.-L. Cheng, P. Toure, P. S. Sow, Q. Feng, N. Kiviat, R. Strauss, S. Ni, et al. Combination of Tumor Site-Located CTL-Associated Antigen-4 Blockade and Systemic Regulatory T-Cell Depletion Induces Tumor-Destructive Immune Responses Cancer Res., June 15, 2007; 67(12): 5929 - 5939. [Abstract] [Full Text] [PDF]
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B. G. Molenkamp, P. A.M. van Leeuwen, S. Meijer, B. J.R. Sluijter, P. G.J.T.B. Wijnands, A. Baars, A. J.M. van den Eertwegh, R. J. Scheper, and T. D. de Gruijl Intradermal CpG-B Activates Both Plasmacytoid and Myeloid Dendritic Cells in the Sentinel Lymph Node of Melanoma Patients Clin. Cancer Res., May 15, 2007; 13(10): 2961 - 2969. [Abstract] [Full Text] [PDF]
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S. A. Perez, M. V. Karamouzis, D. V. Skarlos, A. Ardavanis, N. N. Sotiriadou, E. G. Iliopoulou, M. L. Salagianni, G. Orphanos, C. N. Baxevanis, G. Rigatos, et al. CD4+CD25+ Regulatory T-Cell Frequency in HER-2/neu (HER)-Positive and HER-Negative Advanced-Stage Breast Cancer Patients Clin. Cancer Res., May 1, 2007; 13(9): 2714 - 2721. [Abstract] [Full Text] [PDF]
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S. P. Hilchey, A. De, L. M. Rimsza, R. B. Bankert, and S. H. Bernstein Follicular Lymphoma Intratumoral CD4+CD25+GITR+ Regulatory T Cells Potently Suppress CD3/CD28-Costimulated Autologous and Allogeneic CD8+CD25- and CD4+CD25- T Cells J. Immunol., April 1, 2007; 178(7): 4051 - 4061. [Abstract] [Full Text] [PDF]
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A. Berhanu, J. Huang, S. C. Watkins, H. Okada, and W. J. Storkus Treatment-Enhanced CD4+Foxp3+ Glucocorticoid-Induced TNF Receptor Family RelatedHigh Regulatory Tumor-Infiltrating T Cells Limit the Effectiveness of Cytokine-Based Immunotherapy J. Immunol., March 15, 2007; 178(6): 3400 - 3408. [Abstract] [Full Text] [PDF]
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V. C. Liu, L. Y. Wong, T. Jang, A. H. Shah, I. Park, X. Yang, Q. Zhang, S. Lonning, B. A. Teicher, and C. Lee Tumor Evasion of the Immune System by Converting CD4+CD25- T Cells into CD4+CD25+ T Regulatory Cells: Role of Tumor-Derived TGF-beta J. Immunol., March 1, 2007; 178(5): 2883 - 2892. [Abstract] [Full Text] [PDF]
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S. Liu, D. R. Breiter, G. Zheng, and A. Chen Enhanced Antitumor Responses Elicited by Combinatorial Protein Transfer of Chemotactic and Costimulatory Molecules J. Immunol., March 1, 2007; 178(5): 3301 - 3306. [Abstract] [Full Text] [PDF]
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K.-Y. Lin, D. Lu, C.-F. Hung, S. Peng, L. Huang, C. Jie, F. Murillo, J. Rowley, Y.-C. Tsai, L. He, et al. Ectopic Expression of Vascular Cell Adhesion Molecule-1 as a New Mechanism for Tumor Immune Evasion Cancer Res., February 15, 2007; 67(4): 1832 - 1841. [Abstract] [Full Text] [PDF]
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A. Chen, S. Liu, D. Park, Y. Kang, and G. Zheng Depleting Intratumoral CD4+CD25+ Regulatory T Cells via FasL Protein Transfer Enhances the Therapeutic Efficacy of Adoptive T Cell Transfer Cancer Res., February 1, 2007; 67(3): 1291 - 1298. [Abstract] [Full Text] [PDF]
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N. Kobayashi, N. Hiraoka, W. Yamagami, H. Ojima, Y. Kanai, T. Kosuge, A. Nakajima, and S. Hirohashi FOXP3+ Regulatory T Cells Affect the Development and Progression of Hepatocarcinogenesis Clin. Cancer Res., February 1, 2007; 13(3): 902 - 911. [Abstract] [Full Text] [PDF]
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M. Kurooka and Y. Kaneda Inactivated Sendai Virus Particles Eradicate Tumors by Inducing Immune Responses through Blocking Regulatory T Cells Cancer Res., January 1, 2007; 67(1): 227 - 236. [Abstract] [Full Text] [PDF]
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L. Strauss, T. L. Whiteside, A. Knights, C. Bergmann, A. Knuth, and A. Zippelius Selective Survival of Naturally Occurring Human CD4+CD25+Foxp3+ Regulatory T Cells Cultured with Rapamycin J. Immunol., January 1, 2007; 178(1): 320 - 329. [Abstract] [Full Text] [PDF]
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G. J. Bates, S. B. Fox, C. Han, R. D. Leek, J. F. Garcia, A. L. Harris, and A. H. Banham Quantification of Regulatory T Cells Enables the Identification of High-Risk Breast Cancer Patients and Those at Risk of Late Relapse J. Clin. Oncol., December 1, 2006; 24(34): 5373 - 5380. [Abstract] [Full Text] [PDF]
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A. M. Miller, K. Lundberg, V. Ozenci, A. H. Banham, M. Hellstrom, L. Egevad, and P. Pisa CD4+CD25high T Cells Are Enriched in the Tumor and Peripheral Blood of Prostate Cancer Patients J. Immunol., November 15, 2006; 177(10): 7398 - 7405. [Abstract] [Full Text] [PDF]
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D. J. Powell Jr., M. E. Dudley, K. A. Hogan, J. R. Wunderlich, and S. A. Rosenberg Adoptive Transfer of Vaccine-Induced Peripheral Blood Mononuclear Cells to Patients with Metastatic Melanoma following Lymphodepletion J. Immunol., November 1, 2006; 177(9): 6527 - 6539. [Abstract] [Full Text] [PDF]
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J. Carreras, A. Lopez-Guillermo, B. C. Fox, L. Colomo, A. Martinez, G. Roncador, E. Montserrat, E. Campo, and A. H. Banham High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma Blood, November 1, 2006; 108(9): 2957 - 2964. [Abstract] [Full Text] [PDF]
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N. Hiraoka, K. Onozato, T. Kosuge, and S. Hirohashi Prevalence of FOXP3+ Regulatory T Cells Increases During the Progression of Pancreatic Ductal Adenocarcinoma and Its Premalignant Lesions. Clin. Cancer Res., September 15, 2006; 12(18): 5423 - 5434. [Abstract] [Full Text] [PDF]
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K. L. Knutson, C. J. Krco, C. L. Erskine, K. Goodman, L. E. Kelemen, P. J. Wettstein, P. S. Low, L. C. Hartmann, and K. R. Kalli T-Cell Immunity to the Folate Receptor Alpha Is Prevalent in Women With Breast or Ovarian Cancer J. Clin. Oncol., September 10, 2006; 24(26): 4254 - 4261. [Abstract] [Full Text] [PDF]
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C. T. Viehl, T. T. Moore, U. K. Liyanage, D. M. Frey, J. P. Ehlers, T. J. Eberlein, P. S. Goedegebuure, and D. C. Linehan Depletion of CD4+CD25+ Regulatory T Cells Promotes a Tumor-Specific Immune Response in Pancreas Cancer-Bearing Mice Ann. Surg. Oncol., September 1, 2006; 13(9): 1252 - 1258. [Abstract] [Full Text] [PDF]
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G. Lizee, L. G. Radvanyi, W. W. Overwijk, and P. Hwu Improving Antitumor Immune Responses by Circumventing Immunoregulatory Cells and Mechanisms. Clin. Cancer Res., August 15, 2006; 12(16): 4794 - 4803. [Abstract] [Full Text] [PDF]
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M. Beyer and J. L. Schultze Regulatory T cells in cancer Blood, August 1, 2006; 108(3): 804 - 811. [Abstract] [Full Text] [PDF]
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J. D. Bui, R. Uppaluri, C.-S. Hsieh, and R. D. Schreiber Comparative Analysis of Regulatory and Effector T Cells in Progressively Growing versus Rejecting Tumors of Similar Origins. Cancer Res., July 15, 2006; 66(14): 7301 - 7309. [Abstract] [Full Text] [PDF]
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P. E. Fecci, A. E. Sweeney, P. M. Grossi, S. K. Nair, C. A. Learn, D. A. Mitchell, X. Cui, T. J. Cummings, D. D. Bigner, E. Gilboa, et al. Systemic Anti-CD25 Monoclonal Antibody Administration Safely Enhances Immunity in Murine Glioma without Eliminating Regulatory T Cells. Clin. Cancer Res., July 15, 2006; 12(14): 4294 - 4305. [Abstract] [Full Text] [PDF]
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S. Wei, I. Kryczek, and W. Zou Regulatory T-cell compartmentalization and trafficking Blood, July 15, 2006; 108(2): 426 - 431. [Abstract] [Full Text] [PDF]
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S. F. Hussain, D. Yang, D. Suki, K. Aldape, E. Grimm, and A. B. Heimberger The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses Neuro-oncol, July 1, 2006; 8(3): 261 - 279. [Abstract] [Full Text] [PDF]
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G. Zheng, S. Liu, P. Wang, Y. Xu, and A. Chen Arming Tumor-Reactive T Cells with Costimulator B7-1 Enhances Therapeutic Efficacy of the T Cells. Cancer Res., July 1, 2006; 66(13): 6793 - 6799. [Abstract] [Full Text] [PDF]
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K. L. Knutson, Y. Dang, H. Lu, J. Lukas, B. Almand, E. Gad, E. Azeke, and M. L. Disis IL-2 Immunotoxin Therapy Modulates Tumor-Associated Regulatory T Cells and Leads to Lasting Immune-Mediated Rejection of Breast Cancers in neu-Transgenic Mice J. Immunol., July 1, 2006; 177(1): 84 - 91. [Abstract] [Full Text] [PDF]
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R. Zeiser, V. H. Nguyen, A. Beilhack, M. Buess, S. Schulz, J. Baker, C. H. Contag, and R. S. Negrin Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production Blood, July 1, 2006; 108(1): 390 - 399. [Abstract] [Full Text] [PDF]
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R. Kim, M. Emi, K. Tanabe, and K. Arihiro Tumor-Driven Evolution of Immunosuppressive Networks during Malignant Progression Cancer Res., June 1, 2006; 66(11): 5527 - 5536. [Abstract] [Full Text] [PDF]
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L. Sfondrini, A. Rossini, D. Besusso, A. Merlo, E. Tagliabue, S. Menard, and A. Balsari Antitumor Activity of the TLR-5 Ligand Flagellin in Mouse Models of Cancer. J. Immunol., June 1, 2006; 176(11): 6624 - 6630. [Abstract] [Full Text] [PDF]
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R.-F. Wang Regulatory T cells and toll-like receptors in cancer therapy. Cancer Res., May 15, 2006; 66(10): 4987 - 4990. [Abstract] [Full Text] [PDF]
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M. Beyer, M. Kochanek, T. Giese, E. Endl, M. R. Weihrauch, P. A. Knolle, S. Classen, and J. L. Schultze In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma Blood, May 15, 2006; 107(10): 3940 - 3949. [Abstract] [Full Text] [PDF]
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A. Berhanu, J. Huang, S. M. Alber, S. C. Watkins, and W. J. Storkus Combinational FLt3 Ligand and Granulocyte Macrophage Colony-Stimulating Factor Treatment Promotes Enhanced Tumor Infiltration by Dendritic Cells and Antitumor CD8+ T-Cell Cross-priming but Is Ineffective as a Therapy. Cancer Res., May 1, 2006; 66(9): 4895 - 4903. [Abstract] [Full Text] [PDF]
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R. Houot, I. Perrot, E. Garcia, I. Durand, and S. Lebecque Human CD4+CD25high Regulatory T Cells Modulate Myeloid but Not Plasmacytoid Dendritic Cells Activation J. Immunol., May 1, 2006; 176(9): 5293 - 5298. [Abstract] [Full Text] [PDF]
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Z.-Z. Yang, A. J. Novak, M. J. Stenson, T. E. Witzig, and S. M. Ansell Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma Blood, May 1, 2006; 107(9): 3639 - 3646. [Abstract] [Full Text] [PDF]
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B. Valzasina, S. Piconese, C. Guiducci, and M. P. Colombo Tumor-Induced Expansion of Regulatory T Cells by Conversion of CD4+CD25- Lymphocytes Is Thymus and Proliferation Independent. Cancer Res., April 15, 2006; 66(8): 4488 - 4495. [Abstract] [Full Text] [PDF]
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P. E. Fecci, D. A. Mitchell, J. F. Whitesides, W. Xie, A. H. Friedman, G. E. Archer, J. E. Herndon II, D. D. Bigner, G. Dranoff, and J. H. Sampson Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res., March 15, 2006; 66(6): 3294 - 3302. [Abstract] [Full Text] [PDF]
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G. C. Cesana, G. DeRaffele, S. Cohen, D. Moroziewicz, J. Mitcham, J. Stoutenburg, K. Cheung, C. Hesdorffer, S. Kim-Schulze, and H. L. Kaufman Characterization of CD4+CD25+ Regulatory T Cells in Patients Treated With High-Dose Interleukin-2 for Metastatic Melanoma or Renal Cell Carcinoma J. Clin. Oncol., March 1, 2006; 24(7): 1169 - 1177. [Abstract] [Full Text] [PDF]
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S. Chattopadhyay, S. Mehrotra, A. Chhabra, U. Hegde, B. Mukherji, and N. G. Chakraborty Effect of CD4+CD25+ and CD4+CD25- T Regulatory Cells on the Generation of Cytolytic T Cell Response to a Self but Human Tumor-Associated Epitope In Vitro J. Immunol., January 15, 2006; 176(2): 984 - 990. [Abstract] [Full Text] [PDF]
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C. Badoual, S. Hans, J. Rodriguez, S. Peyrard, C. Klein, N. E. H. Agueznay, V. Mosseri, O. Laccourreye, P. Bruneval, W. H. Fridman, et al. Prognostic Value of Tumor-Infiltrating CD4+ T-Cell Subpopulations in Head and Neck Cancers Clin. Cancer Res., January 15, 2006; 12(2): 465 - 472. [Abstract] [Full Text] [PDF]
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G. Zhou, C. G. Drake, and H. I. Levitsky Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines Blood, January 15, 2006; 107(2): 628 - 636. [Abstract] [Full Text] [PDF]
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A. N. Saul, T. M. Oberyszyn, C. Daugherty, D. Kusewitt, S. Jones, S. Jewell, W. B. Malarkey, A. Lehman, S. Lemeshow, and F. S. Dhabhar Chronic Stress and Susceptibility to Skin Cancer J Natl Cancer Inst, December 7, 2005; 97(23): 1760 - 1767. [Abstract] [Full Text] [PDF]
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C. A. Wysocki, Q. Jiang, A. Panoskaltsis-Mortari, P. A. Taylor, K. P. McKinnon, L. Su, B. R. Blazar, and J. S. Serody Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease Blood, November 1, 2005; 106(9): 3300 - 3307. [Abstract] [Full Text] [PDF]
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F. Ghiringhelli, C. Menard, M. Terme, C. Flament, J. Taieb, N. Chaput, P. E. Puig, S. Novault, B. Escudier, E. Vivier, et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-{beta}-dependent manner J. Exp. Med., October 17, 2005; 202(8): 1075 - 1085. [Abstract] [Full Text] [PDF]
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F. Ghiringhelli, P. E. Puig, S. Roux, A. Parcellier, E. Schmitt, E. Solary, G. Kroemer, F. Martin, B. Chauffert, and L. Zitvogel Tumor cells convert immature myeloid dendritic cells into TGF-{beta}-secreting cells inducing CD4+CD25+ regulatory T cell proliferation J. Exp. Med., October 3, 2005; 202(7): 919 - 929. [Abstract] [Full Text] [PDF]
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