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[Cancer Research 59, 3128-3133, July 1, 1999]
© 1999 American Association for Cancer Research

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[Cancer Research 59, 3128-3133, July 1, 1999]
© 1999 American Association for Cancer Research


Immunology

Tumor Rejection by in Vivo Administration of Anti-CD25 (Interleukin-2 Receptor {alpha}) Monoclonal Antibody1

Shozaburo Onizuka, Isao Tawara, Jun Shimizu, Shimon Sakaguchi, Teizo Fujita and Eiichi Nakayama2

Department of Parasitology and Immunology, Okayama University Medical School, Okayama 700-8558 [S. O., I. T., E. N.]; Department of Oncology, Nagasaki University School of Medicine, Nagasaki 852-8523 [S. O.]; Department of Immunopathology, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015 [J. S., S. S.]; and Department of Biochemistry, Fukushima Medical College, Fukushima 960-1295 [T. F.], Japan


    ABSTRACT
 Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Immune regulation has been shown to be involved in the progressive growth of some murine tumors. In this study, we demonstrated that a single in vivo administration of an amount less than 0.125 mg of anti-CD25 interleukin 2 receptor {alpha} monoclonal antibody (mAb; PC61) caused the regression of tumors that grew progressively in syngeneic mice. The tumors used were five leukemias, a myeloma, and two sarcomas derived from four different inbred mouse strains. Anti-CD25 mAb (PC61) showed an effect in six of the eight tumors. Administration of anti-CD25 mAb (PC61) caused a reduction in the number of CD4+CD25+ cells in the peripheral lymphoid tissues. The findings suggested that CD4+CD25+ immunoregulatory cells were involved in the growth of those tumors. Kinetic analysis showed that the administration of anti-CD25 mAb (PC61) later than day 2 after tumor inoculation caused no tumor regression, irrespective of depletion of CD4+CD25+ immunoregulatory cells. Two leukemias, on which the PC61-treatment had no effect, seemed to be incapable of eliciting effective rejection responses in the recipient mice because of low or no antigenicity.


    INTRODUCTION
 Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Immune regulation has been shown to be involved in the progressive growth of some murine tumors. North and Bursuker (1) demonstrated that CD4+ T cells from BALB/c mice carrying syngeneic methylcholanthrene-induced Meth A sarcoma down-regulated the activation of immune effector cells against the tumor. Similar findings were obtained with other murine tumors (2, 3, 4) . We previously demonstrated a dominant antigen peptide, pRL1a, that was recognized by cytotoxic T lymphocytes on BALB/c radiation-induced leukemia RL1 (5) . The pRL1a peptide was derived from the 5'-untranslated region of c-akt that became translated by insertion of the long terminal repeat (6) . Overexpression of the altered Akt molecules seemed to induce CD4+ immunoregulatory cells, which resulted in progressive RL1 growth in BALB/c mice. In vivo depletion of CD4+ T cells from BALB/c mice caused RL1 regression (7) .

Recently, CD4+CD25+ cells have been shown to represent a unique population of immunoregulatory cells (8, 9, 10, 11, 12, 13) . Transfer of BALB/c spleen cells depleted of CD25+ cells into BALB/c nu/nu mice induced various autoimmune diseases (11) . In addition, in vivo administration of anti-CD25 mAb3 induced autoimmune diseases in (B6 x A/J)F1 mice (14) .

In this study, we investigated the effect of in vivo administration of anti-CD25 mAb on the growth of eight tumors—RL1 and four other leukemias, a myeloma, and two fibrosarcomas—that grew progressively in syngeneic mice. We found that a single injection of less than 0.125 mg of anti-CD25 mAb (PC61) caused regression in six of the eight tumors, including RL1. After antibody treatment, a reduction in the number of CD4+CD25+ cells was observed by flow cytometry, which suggested that effective tumor rejection responses resulted from a depletion of CD4+CD25+ immunoregulatory cells.


    MATERIALS AND METHODS
 Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Mice.
A/St strain of mice was derived from a colony at the Texas University College of Medicine (Houston, TX). BALB/c and B6 mice were purchased from Japan SLC (Shizuoka, Japan). Breeding pairs of AKR/J mice were provided by Dr. T. Shiroishi (National Institute of Genetics, Mishima, Japan). Breeding pairs of CB-17 SCID mice were provided by Dr. K. Kuribayashi (Mie University School of Medicine, Mie, Japan). BALB/c athymic (nu/nu) mice were produced by breeding male athymic (nu/nu) mice with female nu/+ mice at our animal center.

Tumors.
The tumor cell lines used and their derivation are listed in Table 1Citation .


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Table 1 Tumors used in this study

 
Antibodies.
Anti-L3T4 (CD4) mAb GK1.5 (15) was provided by Dr. F. Fitch (University of Chicago, Chicago, IL). Anti-Lyt-2.2 (CD8) mAb 19/178 (16) was provided by Dr. U. Hämmerling (Memorial Sloan-Kettering Cancer Center, New York, NY). Anti-CD25 IL-2R{alpha} mAb produced by hybridoma PC61 (17) was a rat IgG1 antibody. Another anti-CD25 mAb produced by hybridoma, 7D4 (18) , was a rat IgM antibody. For in vivo administration, anti-CD25 mAb (PC61) was used after purification. The hybridoma ascites produced in CB-17 SCID mice was purified to homogeneity by ammonium sulfate precipitation, followed by chromatography on a DEAE Toyopearl 650S column (Tosoh, Tokyo, Japan). The concentration of IgG was determined from its absorbance at 280 nm as an absorption coefficient value of 1.5.

Anti-L3T4 (CD4) mAb and anti-Lyt-2.2 (CD8) mAb were used in the form of ascites from hybridoma-bearing mice as described previously (19) . Depletion of CD4 and/or CD8 T cells by in vivo administration of its respective mAb was confirmed as described previously (19) . Normal rat IgG was obtained from Caltag (Burlingame, CA).

Flow Cytometry.
Cells (1 x 106) were washed and incubated with mAb for 30 min at 4°C in 2% FCS-containing PBS. The following mAbs were used: (a) PE-conjugated anti-L3T4 (CD4) mAb (GK1.5; Becton Dickinson Co., Mountain View, CA); (b) PE-conjugated anti-Lyt-2.2 (CD8) mAb (KT15; Serotec Ltd., Kidlington, Oxford, England); (c) PE-conjugated anti-CD3{epsilon} mAb (145-2C11); and (d) FITC-conjugated anti-CD25 (IL-2R{alpha}) mAb (7D4; PharMingen Co., San Diego, CA). After treatment, the cells were washed, suspended in PBS, and analyzed on a FACScan (Becton Dickinson).

Tumor Assay.
Tumor cells (in 0.2 ml) were injected intradermally into the backs of mice with a 27-gauge needle. Before inoculation of tumor cells, the hair was cut with clippers. The diameter of the tumors was measured with Vernier calipers twice at right angles to calculate the mean diameter.

Antibody Administration.
The mice were anesthetized with ether, and a volume of 0.2 ml of mAb diluted in PBS was injected through the retrobulbar venous plexus.


    RESULTS
 Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Effect on Tumor Growth of in Vivo Administration of Anti-CD25 (IL-2R{alpha}) mAb (PC61).
We first investigated the effect of the in vivo administration of anti-CD25 mAb (PC61) on a CD25+ population in lymphoid tissues. PC61 antibody blocks IL-2 binding to the receptor (17) , and anti-CD25 mAb 7D4 does not block IL-2 binding (18) . For detection of CD25+ cells in lymph node cells from PC61-treated mice, we used 7D4 with flow cytometry. As shown in Fig. 1Citation and Fig. 2Citation , CD25+ cells consisted of ~10% CD4+ cells and less than 1% CD8+ cells among the lymph node cells from untreated mice, which was consistent with previous results (11, 12, 13) . CD4+CD25+ cells reduced maximally on days 3–4 and fully recovered by day 9 after a single in vivo administration of 0.25 mg anti-CD25 mAb (PC61). The reduction was observed in the range of 70–80% at doses between 0.125 and 0.75 mg. For subsequent analyses, we used a single injection of 0.25 mg PC61 on day -4 unless otherwise stated.



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Fig. 1. Flow cytometry analysis. Lymph node cells from BALB/c mice that were untreated or treated with 0.25 mg PC61 on day -4 were analyzed by FACScan.

 


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Fig. 2. CD4+CD25+ cells (%) 1, 3, 5, 7, and 9 days after the administration of 0.25 mg PC61 (A) and those on day 3 after the administration of various doses of PC61 (B) in lymph node cells from BALB/c mice. Assays were done by FACScan as shown in Fig. 1Citation . Each experimental group consisted of three mice. Values, means ± SD.

 
The tumors used were listed in Table 1Citation . We used two spontaneously occurring leukemias, two radiation-induced leukemias, a dimethylbenzanthracene-induced leukemia, a mineral oil-induced myeloma and two methylcholanthrene-induced sarcomas. As shown in Fig. 3Citation and 4Citation , all of the tumors grew progressively in syngeneic mice and eventually killed them. A single administration of 0.25 mg anti-CD25 mAb (PC61) on day -4 caused regression in six of the eight tumors. Administration of normal (control) rat IgG had no effect. No recurrence of tumors was observed thereafter. Among the tumors used, only ASL1 and RL1 expressed CD25 on the cell surface. Administration of anti-CD25 mAb (PC61) had no effect on the growth of tumors with either CD25+ or CD25- phenotype in BALB/c nu/nu mice.



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Fig. 3. Effect of in vivo administration of anti-CD25 mAb (PC61) on tumor growth. RL1 (2 x 105), MOPC-70A (5 x 105) or Meth A (2 x 105) cells were inoculated into the backs of BALB/c or BALB/c nu/nu mice treated with PBS (control) or PC61 on day -4, and the tumor growth was observed. Each experimental group consisted of five to six mice. *, the death of all of the mice in the experimental group. Values, means ± SD.

 


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Fig. 4. Effect of in vivo administration of anti-CD25 mAb (PC61) on tumor growth. ASL1 (1 x 106), AKSL2 (2 x 105), RL8 (2 x 105), EL4 (1 x 105), and CMS17 (2 x 106) cells were inoculated into the backs of the mice indicated, treated with PBS (control) or PC61 on day -4. Meth A (2 x 105) cells were inoculated into the backs of BALB/c mice treated with PC61 or normal rat IgG. Each experimental group consisted of five to six mice. *, the death of all of the mice in the experimental group. Values, means ± SD.

 
Next, the timing of the administration of anti-CD25 mAb (PC61) on tumor growth was examined. As shown in Fig. 5Citation , administration on days -4, -2, 0, and 1, but not later than day 2, even with reduction of CD4+CD25+ T cells after MOPC-70A inoculation, caused regression.



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Fig. 5. A, effect of timing of in vivo administration with anti-CD25 mAb (PC61) on tumor growth. MOPC-70A (5 x 105) cells were inoculated into the backs of BALB/c mice treated with the mAb on day -4 to day 6 after tumor inoculation. Each experimental group consisted of three mice. *, the death of all of the mice in the experimental group. Values represent the mean. B, reduction in CD4+CD25+ cells by PC61-treatment on days 0, 1, 2, and 4 after MOPC-70A inoculation. Assays were done on day 3 after the mAb treatment by FACScan.

 
The dose effect of anti-CD25 mAb (PC61) on tumor growth was then examined. As shown in Table 2Citation , a single administration of 0.125, 0.25, 0.5, or 0.75 mg on day -4 caused MOPC-70A regression. At doses of 0.03 and 0.06 mg, regression was observed in 0 of 3 and 2 of 3 mice inoculated with the tumor, respectively.


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Table 2 Tumor regression by in vivo administration of anti-CD25 (IL-2R{alpha}) mAb (PC61)

 
Effect of CD4 and/or CD8 Depletion on Tumor Regression by Anti-CD25 (IL-2R{alpha}) mAb (PC61).
To investigate the involvement of CD4 and CD8 T cells in tumor regression caused by the administration of anti-CD25 mAb (PC61), the effect of the coadministration of anti-CD25 mAb (PC61) and anti-CD4 mAb and/or anti-CD8 mAb was investigated. We showed previously (20 , 21) that in high responder (BALB/c x B6)F1 mice, CD8 T cells were required for rejection in all of the seven tumors from the BALB/c, B6, and (BALB/c x B6)F1 mice investigated, but the requirement of CD4 T cells differed depending on the tumor. Meth A and MOPC-70A were representative tumors that did and did not require CD4 T cells, respectively. As shown in Fig. 6Citation , in the case of MOPC-70A, coadministration with anti-Lyt-2.2 (CD8) mAb, but not anti-L3T4 (CD4) mAb, inhibited the regression by anti-CD25 mAb (PC61). On the other hand, in the case of Meth A, coadministration with either anti-Lyt-2.2 (CD8) mAb or anti-L3T4 (CD4) mAb inhibited the regression.



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Fig. 6. Effect of CD4 and/or CD8 depletion on tumor rejection by PC61. MOPC-70A (5 x 105) and Meth A (2 x 105) cells were inoculated into the backs of BALB/c mice treated with PC61 on day -4, and anti-L3T4 (CD4) mAb and/or anti-Lyt-2.2 (CD8) mAb on day -7 and day -4. Each experimental group consisted of five to six mice. *, the death of all of the mice in the experimental group. Values, means ± SD.

 
Secondary Response in Mice That Rejected Tumors by Anti-CD25 (IL-2R{alpha}) mAb (PC61).
As shown in Fig. 7Citation , no MOPC-70A or RL1 growth was observed even at higher doses in BALB/c mice that rejected MOPC-70A or RL1, respectively, by anti-CD25 mAb (PC61).



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Fig. 7. Secondary tumor rejection response in PC61-treated mice. MOPC-70A (5 x 105) and RL1 (2 x 105) cells were inoculated into the backs of BALB/c mice treated with PBS (control) and PC61 on day -4. Mice treated with PC61 were challenged with MOPC-70A (1 x 106) (•) or RL1 (1 x 106) ({blacksquare}) cells 4–6 weeks after primary tumor rejection. {circ} and {square}, normal (control) BALB/c mice. Each experimental group consisted of five to six mice. *, the death of all of the mice in the experimental group. Values, means ± SD.

 

    DISCUSSION
 Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this study, we demonstrated that in vivo administration of anti-CD25 mAb (PC61) caused regression of tumors that grew progressively in syngeneic mice and killed them eventually. The tumors used were five leukemias, a myeloma, and two sarcomas derived from four different inbred mouse strains. The effect of anti-CD25 mAb (PC61) was observed on six of the eight tumors. Administration of anti-CD25 mAb (PC61) resulted in a reduction in CD4+CD25+ cells in the peripheral lymphoid tissues. These findings suggested that CD4+CD25+ immunoregulatory cells were involved in the growth of those tumors. Tumor regression was observed even 2–3 months after PC61-treatment. Kinetic analysis showed that the administration of anti-CD25 mAb (PC61) later than day 2 after tumor inoculation caused no tumor regression. This could be due to an insufficient activation of effector cells for proliferating tumor cells by late depletion of CD4+CD25+ T cells. Alternatively, it could be due to a failure in the activation of effector cells by depletion of CD4+CD25+ immunoregulatory cells after tumor antigen stimulation.

We previously identified a dominant rejection antigen peptide recognized by CTL on RL1 leukemia cells (5) . Irrespective of the presence of the rejection antigen, RL1 continued to grow in syngeneic BALB/c mice and killed them eventually. Depletion of CD4+ T cells from the mice resulted in tumor regression (7) , consistent with the present findings.

Thymectomy at day 3 after birth caused various autoimmune diseases (9 , 22, 23, 24) . CD4+CD25- T cells were shown to be responsible for causing the diseases (8 , 9) . Transfer of CD4+CD25+ cells to those mice inhibited the occurrence of the autoimmune diseases (9) . The CD4+CD25+ cells that appeared to represent a distinct lineage (11, 12, 13) down-regulated the induction and/or activation of those autoreactive CD4+ T cells from the CD4+CD25- cell pool. Thymectomy at day 3 resulted in the disappearance of CD4+CD25+ cells, which constituted ~10% of the CD4+ T cells in the peripheral lymphoid tissues, which suggests that those cells migrated from the thymus to those tissues on about day 3 after birth (9) .

Taguchi and Takahashi (14) demonstrated the depletion of CD25+ cells and the occurrence of autoimmune diseases in (B6 x A/J)F1 mice by in vivo administration of anti-CD25 mAb (PC61) 11 consecutive times every other day at a dose of 2 mg. In our study, a single injection at a dose of 0.125 mg was sufficient to cause regression of the tumors, and no histological indication of autoimmune disease and no autoantibody formation were observed in the mice 3 months after the antibody treatment (data not shown). These findings suggested that the effect of the PC61-treatment seemed to differ between the multitargeted autoimmune responses and the responses against the tumor.

Although the exact mechanisms of suppression by CD4+CD25+ cells in vivo are presently unknown, the in vitro studies by Thornton and Shevach (12) and Takahashi et al. (13) demonstrated that CD4+CD25+ cells suppressed the proliferation of CD4+CD25- cells by specifically inhibiting the production of IL-2. Moreover, the inhibition required the activation of CD4+CD25+ suppressor cells via T-cell receptor for antigen, and mediation by cell contact but not by cytokines.

Coadministration with anti-CD8 mAb inhibited tumor regression by anti-CD25 mAb (PC61) alone, which suggests that CD8 T cells were responsible for those tumor regressions. Coadministration with anti-CD4 mAb had no effect on the regression of MOPC-70A but inhibited the regression of Meth A by PC61 alone. This suggested that the relative involvement of CD4+ T cells depended on the tumor, probably as helper T cells for the generation of CD8 effector cells, and was consistent with our previous results (20 , 21) . The lack of regression of AKSL2, a spontaneous leukemia derived from an AKR mouse and a RL8, a radiation-induced leukemia derived from a BALB/c mouse by PC61-treatment, together with the normal expression of H-2 class I antigens on those tumors (data not shown) suggested low or no antigenicity of those tumors for eliciting effective rejection responses in syngeneic mice.


    ACKNOWLEDGMENTS
 
We thank Drs. O. Taguchi and T. Takahashi (Aichi Cancer Institute, Nagoya, Japan) for providing antibodies. We also thank M. Isobe for excellent technical assistance and J. Mizuuchi for preparation of the manuscript.


    FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports and Culture, Japan and by the Research Grant for Longevity Sciences (10C-01) from the Ministry of Health and Welfare of Japan. Back

2 To whom requests for reprints should be addressed, at Department of Parasitology and Immunology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Back

3 The abbreviations used are: mAb, monoclonal antibody; B6, C57BL/6; SCID, severe combined immunodeficient; IL, interleukin; IL-2R{alpha}, IL-2 receptor {alpha}; FACS, fluorescence-activated cell sorting; PE, phycoerythrin. Back

Received 1/19/99. Accepted 4/27/99.


    REFERENCES
 Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Cancer Res.Home page
H. Nishikawa, T. Kato, M. Hirayama, Y. Orito, E. Sato, N. Harada, S. Gnjatic, L. J. Old, and H. Shiku
Regulatory T Cell-Resistant CD8+ T Cells Induced by Glucocorticoid-Induced Tumor Necrosis Factor Receptor Signaling
Cancer Res., July 15, 2008; 68(14): 5948 - 5954.
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J. Immunol.Home page
L. Gil-Guerrero, J. Dotor, I. L. Huibregtse, N. Casares, A. B. Lopez-Vazquez, F. Rudilla, J. I. Riezu-Boj, J. Lopez-Sagaseta, J. Hermida, S. Van Deventer, et al.
In Vitro and In Vivo Down-Regulation of Regulatory T Cell Activity with a Peptide Inhibitor of TGF-{beta}1
J. Immunol., July 1, 2008; 181(1): 126 - 135.
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J. Immunol.Home page
M. B. F. Werneck, G. Lugo-Villarino, E. S. Hwang, H. Cantor, and L. H. Glimcher
T-Bet Plays a Key Role in NK-Mediated Control of Melanoma Metastatic Disease
J. Immunol., June 15, 2008; 180(12): 8004 - 8010.
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J. Immunol.Home page
Y. Cao, J. Zhao, Z. Lei, S. Shen, C. Liu, D. Li, J. Liu, G.-X. Shen, G.-M. Zhang, Z.-H. Feng, et al.
Local Accumulation of FOXP3+ Regulatory T Cells: Evidence for an Immune Evasion Mechanism in Patients with Large Condylomata Acuminata
J. Immunol., June 1, 2008; 180(11): 7681 - 7686.
[Abstract] [Full Text] [PDF]


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Clin. Cancer Res.Home page
J. Kline, I. E. Brown, Y.-Y. Zha, C. Blank, J. Strickler, H. Wouters, L. Zhang, and T. F. Gajewski
Homeostatic Proliferation Plus Regulatory T-Cell Depletion Promotes Potent Rejection of B16 Melanoma
Clin. Cancer Res., May 15, 2008; 14(10): 3156 - 3167.
[Abstract] [Full Text] [PDF]


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QJMHome page
J. King, J. Waxman, and H. Stauss
Advances in tumour immunotherapy
QJM, May 13, 2008; (2008) hcn050v1.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
A. Jorritsma, A. D. Bins, T. N.M. Schumacher, and J. B.A.G. Haanen
Skewing the T-Cell Repertoire by Combined DNA Vaccination, Host Conditioning, and Adoptive Transfer
Cancer Res., April 1, 2008; 68(7): 2455 - 2462.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
M. Terme, N. Chaput, B. Combadiere, A. Ma, T. Ohteki, and L. Zitvogel
Regulatory T Cells Control Dendritic Cell/NK Cell Cross-Talk in Lymph Nodes at the Steady State by Inhibiting CD4+ Self-Reactive T Cells
J. Immunol., April 1, 2008; 180(7): 4679 - 4686.
[Abstract] [Full Text] [PDF]


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Clin. Cancer Res.Home page
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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BloodHome page
H. Nishikawa, T. Tsuji, E. Jager, G. Briones, G. Ritter, L. J. Old, J. E. Galan, H. Shiku, and S. Gnjatic
Induction of regulatory T cell-resistant helper CD4+ T cells by bacterial vector
Blood, February 1, 2008; 111(3): 1404 - 1412.
[Abstract] [Full Text] [PDF]


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Clin. Cancer Res.Home page
P. Hu, R. S. Arias, R. E. Sadun, Y.-C. Nien, N. Zhang, H. Sabzevari, M.E. C. Lutsiak, L. A. Khawli, and A. L. Epstein
Construction and Preclinical Characterization of Fc-mGITRL for the Immunotherapy of Cancer
Clin. Cancer Res., January 15, 2008; 14(2): 579 - 588.
[Abstract] [Full Text] [PDF]


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BloodHome page
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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BloodHome page
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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J. Immunol.Home page
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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Clin. Cancer Res.Home page
Y. Kiniwa, Y. Miyahara, H. Y. Wang, W. Peng, G. Peng, T. M. Wheeler, T. C. Thompson, L. J. Old, and R.-F. Wang
CD8+ Foxp3+ Regulatory T Cells Mediate Immunosuppression in Prostate Cancer
Clin. Cancer Res., December 1, 2007; 13(23): 6947 - 6958.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
K. Leon, K. Garcia, J. Carneiro, and A. Lage
How Regulatory CD25+CD4+ T Cells Impinge on Tumor Immunobiology: The Differential Response of Tumors to Therapies
J. Immunol., November 1, 2007; 179(9): 5659 - 5668.
[Abstract] [Full Text] [PDF]


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BloodHome page
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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Ann Rheum DisHome page
R. Sutmuller, A. Garritsen, and G. J Adema
Regulatory T cells and toll-like receptors: regulating the regulators
Ann Rheum Dis, November 1, 2007; 66(suppl_3): iii91 - iii95.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
N. Chaput, G. Darrasse-Jeze, A.-S. Bergot, C. Cordier, S. Ngo-Abdalla, D. Klatzmann, and O. Azogui
Regulatory T Cells Prevent CD8 T Cell Maturation by Inhibiting CD4 Th Cells at Tumor Sites
J. Immunol., October 15, 2007; 179(8): 4969 - 4978.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
C. E. Clark, S. R. Hingorani, R. Mick, C. Combs, D. A. Tuveson, and R. H. Vonderheide
Dynamics of the Immune Reaction to Pancreatic Cancer from Inception to Invasion
Cancer Res., October 1, 2007; 67(19): 9518 - 9527.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
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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J. Immunol.Home page
N. Hyka-Nouspikel, L. Lucian, E. Murphy, T. McClanahan, and J. H. Phillips
DAP10 Deficiency Breaks the Immune Tolerance against Transplantable Syngeneic Melanoma
J. Immunol., September 15, 2007; 179(6): 3763 - 3771.
[Abstract] [Full Text] [PDF]


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BloodHome page
O. Cao, E. Dobrzynski, L. Wang, S. Nayak, B. Mingle, C. Terhorst, and R. W. Herzog
Induction and role of regulatory CD4+CD25+ T cells in tolerance to the transgene product following hepatic in vivo gene transfer
Blood, August 15, 2007; 110(4): 1132 - 1140.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
A. T. Hagymasi, A. M. Slaiby, M. A. Mihalyo, H. Z. Qui, D. J. Zammit, L. Lefrancois, and A. J. Adler
Steady State Dendritic Cells Present Parenchymal Self-Antigen and Contribute to, but Are Not Essential for, Tolerization of Naive and Th1 Effector CD4 Cells
J. Immunol., August 1, 2007; 179(3): 1524 - 1531.
[Abstract] [Full Text] [PDF]


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JCOHome page
E. Yakirevich and M. B. Resnick
Regulatory T Lymphocytes: Pivotal Components of the Host Antitumor Response
J. Clin. Oncol., June 20, 2007; 25(18): 2506 - 2508.
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J. Immunol.Home page
K. G. Elpek, C. Lacelle, N. P. Singh, E. S. Yolcu, and H. Shirwan
CD4+CD25+ T Regulatory Cells Dominate Multiple Immune Evasion Mechanisms in Early but Not Late Phases of Tumor Development in a B Cell Lymphoma Model
J. Immunol., June 1, 2007; 178(11): 6840 - 6848.
[Abstract] [Full Text] [PDF]


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BloodHome page
Y. H. Kim, M. Duvic, E. Obitz, R. Gniadecki, L. Iversen, A. Osterborg, S. Whittaker, T. M. Illidge, T. Schwarz, R. Kaufmann, et al.
Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma
Blood, June 1, 2007; 109(11): 4655 - 4662.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
L. Weng, J. Dyson, and F. Dazzi
Low-intensity transplant regimens facilitate recruitment of donor-specific regulatory T cells that promote hematopoietic engraftment
PNAS, May 15, 2007; 104(20): 8415 - 8420.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
P. Sinha, V. K. Clements, A. M. Fulton, and S. Ostrand-Rosenberg
Prostaglandin E2 Promotes Tumor Progression by Inducing Myeloid-Derived Suppressor Cells
Cancer Res., May 1, 2007; 67(9): 4507 - 4513.
[Abstract] [Full Text] [PDF]