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Immunology |
) Monoclonal Antibody1
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 |
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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 |
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1 (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 RL
1 growth in BALB/c mice. In vivo depletion of CD4+ T cells from BALB/c mice caused RL
1 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 tumorsRL
1 and four other leukemias, a myeloma, and two fibrosarcomasthat 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 RL
1. 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 |
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Tumors.
The tumor cell lines used and their derivation are listed in Table 1
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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
mAb (145-2C11); and (d) FITC-conjugated anti-CD25 (IL-2R
) 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 |
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) mAb (PC61).
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 34 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 7080% 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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1 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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) mAb (PC61).
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) mAb (PC61).
1 growth was observed even at higher doses in BALB/c mice that rejected MOPC-70A or RL
1, respectively, by anti-CD25 mAb (PC61).
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| DISCUSSION |
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We previously identified a dominant rejection antigen peptide recognized by CTL on RL
1 leukemia cells (5)
. Irrespective of the presence of the rejection antigen, RL
1 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 RL
8, 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 |
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| FOOTNOTES |
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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. ![]()
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. ![]()
3 The abbreviations used are: mAb, monoclonal antibody; B6, C57BL/6; SCID, severe combined immunodeficient; IL, interleukin; IL-2R
, IL-2 receptor
; FACS, fluorescence-activated cell sorting; PE, phycoerythrin. ![]()
Received 1/19/99. Accepted 4/27/99.
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E. A. Wohlfert, F. C. Nichols, E. Nevius, and R. B. Clark Peroxisome Proliferator-Activated Receptor {gamma} (PPAR{gamma}) and Immunoregulation: Enhancement of Regulatory T Cells through PPAR{gamma}-Dependent and -Independent Mechanisms J. Immunol., April 1, 2007; 178(7): 4129 - 4135. [Abstract] [Full Text] [PDF] |
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S. A. Siddiqui, X. Frigola, S. Bonne-Annee, M. Mercader, S. M. Kuntz, A. E. Krambeck, S. Sengupta, H. Dong, J. C. Cheville, C. M. Lohse, et al. Tumor-Infiltrating Foxp3-CD4+CD25+ T Cells Predict Poor Survival in Renal Cell Carcinoma Clin. Cancer Res., April 1, 2007; 13(7): 2075 - 2081. [Abstract] [Full Text] [PDF] |
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H. J.J. van derVliet, H. B. Koon, S. C. Yue, B. Uzunparmak, V. Seery, M. A. Gavin, A. Y. Rudensky, M. B. Atkins, S. P. Balk, and M. A. Exley Effects of the Administration of High-Dose Interleukin-2 on Immunoregulatory Cell Subsets in Patients with Advanced Melanoma and Renal Cell Cancer Clin. Cancer Res., April 1, 2007; 13(7): 2100 - 2108. [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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F. v. Rhee Idiotype Vaccination Strategies in Myeloma: How to Overcome a Dysfunctional Immune System Clin. Cancer Res., March 1, 2007; 13(5): 1353 - 1355. [Full Text] [PDF] |
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Y. Sakoda, D. Hashimoto, S. Asakura, K. Takeuchi, M. Harada, M. Tanimoto, and T. Teshima Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease Blood, February 15, 2007; 109(4): 1756 - 1764. [Abstract] [Full Text] [PDF] |
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J. Kotner and R. Tarleton Endogenous CD4+ CD25+ Regulatory T Cells Have a Limited Role in the Control of Trypanosoma cruzi Infection in Mice Infect. Immun., February 1, 2007; 75(2): 861 - 869. [Abstract] [Full Text] [PDF] |
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E. M. Gabriel and E. C. Lattime Anti-CTL-Associated Antigen 4: Are Regulatory T Cells a Target? Clin. Cancer Res., February 1, 2007; 13(3): 785 - 788. [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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K. F. May Jr., X. Chang, H. Zhang, K. D. Lute, P. Zhou, E. Kocak, P. Zheng, and Y. Liu B7-Deficient Autoreactive T Cells Are Highly Susceptible to Suppression by CD4+CD25+ Regulatory T Cells J. Immunol., February 1, 2007; 178(3): 1542 - 1552. [Abstract] [Full Text] [PDF] |
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K. Lahl, C. Loddenkemper, C. Drouin, J. Freyer, J. Arnason, G. Eberl, A. Hamann, H. Wagner, J. Huehn, and T. Sparwasser Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease J. Exp. Med., January 22, 2007; 204(1): 57 - 63. [Abstract] [Full Text] [PDF] |
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J. Vieweg, Z. Su, P. Dahm, and S. Kusmartsev Reversal of Tumor-Mediated Immunosuppression Clin. Cancer Res., January 15, 2007; 13(2): 727s - 732s. [Abstract] [Full Text] [PDF] |
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S. Nair, D. Boczkowski, M. Fassnacht, D. Pisetsky, and E. Gilboa Vaccination against the Forkhead Family Transcription Factor Foxp3 Enhances Tumor Immunity Cancer Res., January 1, 2007; 67(1): 371 - 380. [Abstract] [Full Text] [PDF] |
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A. Charalambous, M. Oks, G. Nchinda, S. Yamazaki, and R. M. Steinman Dendritic Cell Targeting of Survivin Protein in a Xenogeneic Form Elicits Strong CD4+ T Cell Immunity to Mouse Survivin J. Immunol., December 15, 2006; 177(12): 8410 - 8421. [Abstract] [Full Text] [PDF] |
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Z.-Z. Yang, A. J. Novak, S. C. Ziesmer, T. E. Witzig, and S. M. Ansell Attenuation of CD8+ T-Cell Function by CD4+CD25+ Regulatory T Cells in B-Cell Non-Hodgkin's Lymphoma. Cancer Res., October 15, 2006; 66(20): 10145 - 10152. [Abstract] [Full Text] [PDF] |
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L. Melencio, R. J. McKallip, H. Guan, R. Ramakrishnan, R. Jain, P. S. Nagarkatti, and M. Nagarkatti Role of CD4+CD25+ T regulatory cells in IL-2-induced vascular leak Int. Immunol., October 1, 2006; 18(10): 1461 - 1471. [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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A. Vojdani and J. Erde Regulatory T Cells, a Potent Immunoregulatory Target for CAM Researchers: Modulating Tumor Immunity, Autoimmunity and Alloreactive Immunity (III) Evid. Based Complement. Altern. Med., September 1, 2006; 3(3): 309 - 316. [Abstract] [Full Text] [PDF] |
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F. Billiard, E. Litvinova, D. Saadoun, F. Djelti, D. Klatzmann, J. L. Cohen, G. Marodon, and B. L. Salomon Regulatory and Effector T Cell Activation Levels Are Prime Determinants of In Vivo Immune Regulation J. Immunol., August 15, 2006; 177(4): 2167 - 2174. [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. Maksimow, M. Miiluniemi, F. Marttila-Ichihara, S. Jalkanen, and A. Hanninen Antigen targeting to endosomal pathway in dendritic cell vaccination activates regulatory T cells and attenuates tumor immunity Blood, August 15, 2006; 108(4): 1298 - 1305. [Abstract] [Full Text] [PDF] |
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D. T. Nardelli, T. F. Warner, S. M. Callister, and R. F. Schell Anti-CD25 Antibody Treatment of Mice Vaccinated and Challenged with Borrelia spp. Does Not Exacerbate Arthritis but Inhibits Borreliacidal Antibody Production. Clin. Vaccine Immunol., August 1, 2006; 13(8): 884 - 891. [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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D. Valmori, V. Tosello, N. E. Souleimanian, E. Godefroy, L. Scotto, Y. Wang, and M. Ayyoub Rapamycin-Mediated Enrichment of T Cells with Regulatory Activity in Stimulated CD4+ T Cell Cultures Is Not Due to the Selective Expansion of Naturally Occurring Regulatory T Cells but to the Induction of Regulatory Functions in Conventional CD4+ T Cells J. Immunol., July 15, 2006; 177(2): 944 - 949. [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. Oniki, H. Nagai, T. Horikawa, J. Furukawa, M. L. Belladonna, T. Yoshimoto, I. Hara, and C. Nishigori Interleukin-23 and interleukin-27 exert quite different antitumor and vaccine effects on poorly immunogenic melanoma. Cancer Res., June 15, 2006; 66(12): 6395 - 6404. [Abstract] [Full Text] [PDF] |
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M. Kaparakis, K. L. Laurie, O. Wijburg, J. Pedersen, M. Pearse, I. R. van Driel, P. A. Gleeson, and R. A. Strugnell CD4+ CD25+ Regulatory T Cells Modulate the T-Cell and Antibody Responses in Helicobacter-Infected BALB/c Mice. Infect. Immun., June 1, 2006; 74(6): 3519 - 3529. [Abstract] [Full Text] [PDF] |
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W. Li and W. R. Green The Role of CD4 T Cells in the Pathogenesis of Murine AIDS. J. Virol., June 1, 2006; 80(12): 5777 - 5789. [Abstract] [Full Text] [PDF] |
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T. Nishioka, J. Shimizu, R. Iida, S. Yamazaki, and S. Sakaguchi CD4+CD25+Foxp3+ T Cells and CD4+CD25-Foxp3+ T Cells in Aged Mice. J. Immunol., June 1, 2006; 176(11): 6586 - 6593. [Abstract] [Full Text] [PDF] |
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H. Nishikawa, F. Qian, T. Tsuji, G. Ritter, L. J. Old, S. Gnjatic, and K. Odunsi Influence of CD4+CD25+ Regulatory T Cells on Low/High-Avidity CD4+ T Cells following Peptide Vaccination J. Immunol., May 15, 2006; 176(10): 6340 - 6346. [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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O. Saitoh and Y. Nagayama Regulation of Graves' Hyperthyroidism with Naturally Occurring CD4+CD25+ Regulatory T Cells in a Mouse Model Endocrinology, May 1, 2006; 147(5): 2417 - 2422. [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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G. Lizee, L. G. Radvanyi, W. W. Overwijk, and P. Hwu Immunosuppression in melanoma immunotherapy: potential opportunities for intervention. Clin. Cancer Res., April 1, 2006; 12(7): 2359s - 2365s. [Abstract] [Full Text] [PDF] |
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A. P. Kohm, J. S. McMahon, J. R. Podojil, W. S. Begolka, M. DeGutes, D. J. Kasprowicz, S. F. Ziegler, and S. D. Miller Cutting Edge: Anti-CD25 Monoclonal Antibody Injection Results in the Functional Inactivation, Not Depletion, of CD4+CD25+ T Regulatory Cells J. Immunol., March 15, 2006; 176(6): 3301 - 3305. [Abstract] [Full Text] [PDF] |
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J. Taieb, N. Chaput, N. Schartz, S. Roux, S. Novault, C. Menard, F. Ghiringhelli, M. Terme, A. F. Carpentier, G. Darrasse-Jese, et al. Chemoimmunotherapy of tumors: cyclophosphamide synergizes with exosome based vaccines. J. Immunol., March 1, 2006; 176(5): 2722 - 2729. [Abstract] [Full Text] [PDF] |
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H. Geng, G.-M. Zhang, D. Li, H. Zhang, Y. Yuan, H.-G. Zhu, H. Xiao, L.-F. Han, and Z.-H. Feng Soluble Form of T Cell Ig Mucin 3 Is an Inhibitory Molecule in T Cell-Mediated Immune Response J. Immunol., February 1, 2006; 176(3): 1411 - 1420. [Abstract] [Full Text] [PDF] |
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M. J. Smyth, M. W. L. Teng, J. Swann, K. Kyparissoudis, D. I. Godfrey, and Y. Hayakawa CD4+CD25+ T Regulatory Cells Suppress NK Cell-Mediated Immunotherapy of Cancer J. Immunol., February 1, 2006; 176(3): 1582 - 1587. [Abstract] [Full Text] [PDF] |
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A. Comes, O. Rosso, A. M. Orengo, E. Di Carlo, C. Sorrentino, R. Meazza, T. Piazza, B. Valzasina, P. Nanni, M. P. Colombo, et al. CD25+ Regulatory T Cell Depletion Augments Immunotherapy of Micrometastases by an IL-21-Secreting Cellular Vaccine J. Immunol., February 1, 2006; 176(3): 1750 - 1758. [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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M. Terabe, J. Swann, E. Ambrosino, P. Sinha, S. Takaku, Y. Hayakawa, D. I. Godfrey, S. Ostrand-Rosenberg, M. J. Smyth, and J. A. Berzofsky A nonclassical non-V{alpha}14J{alpha}18 CD1d-restricted (type II) NKT cell is sufficient for down-regulation of tumor immunosurveillance J. Exp. Med., December 19, 2005; 202(12): 1627 - 1633. [Abstract] [Full Text] [PDF] |
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A. S.I. Loskog, M. E. Fransson, and T. T.H. Totterman AdCD40L Gene Therapy Counteracts T Regulatory Cells and Cures Aggressive Tumors in an Orthotopic Bladder Cancer Model Clin. Cancer Res., December 15, 2005; 11(24): 8816 - 8821. [Abstract] [Full Text] [PDF] |
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A. Liu, P. Hu, L. A. Khawli, and A. L. Epstein Combination B7-Fc Fusion Protein Treatment and Treg Cell Depletion Therapy Clin. Cancer Res., December 1, 2005; 11(23): 8492 - 8502. [Abstract] [Full Text] [PDF] |
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Y.-Q. Chen, H.-Z. Shi, X.-J. Qin, W.-N. Mo, X.-D. Liang, Z.-X. Huang, H.-B. Yang, and C. Wu CD4+CD25+ Regulatory T Lymphocytes in Malignant Pleural Effusion Am. J. Respir. Crit. Care Med., December 1, 2005; 172(11): 1434 - 1439. [Abstract] [Full Text] [PDF] |
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L. E. Raez, S. Fein, and E. R. Podack Lung Cancer Immunotherapy Clin. Med. Res., November 1, 2005; 3(4): 221 - 228. [Abstract] [Full Text] [PDF] |
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M. Boudewijns, A. Jeurissen, M. Wuyts, L. Moens, L. Boon, J. J. Van Neerven, A. Kasran, L. Overbergh, C. Lenaerts, M. Waer, et al. Blockade of CTLA-4 (CD152) enhances the murine antibody response to pneumococcal capsular polysaccharides J. Leukoc. Biol., November 1, 2005; 78(5): 1060 - 1069. [Abstract] [Full Text] [PDF] |
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