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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2409-2414.
Prepublished online as a Blood First Edition Paper on November 22, 2005; DOI 10.1182/blood-2005-06-2399.
Previous Article | Table of Contents | Next Article 
IMMUNOBIOLOGY
IL-2 administration increases CD4+CD25hi Foxp3+ regulatory T cells in cancer patients
Mojgan Ahmadzadeh, and
Steven A. Rosenberg
From the Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Interleukin-2 (IL-2) is historically known as a T-cell growth factor. Accumulating evidence from knockout mice suggests that IL-2 is crucial for the homeostasis and function of CD4+CD25+ regulatory T cells in vivo. However, the impact of administered IL-2 in an immune intact host has not been studied in rodents or humans. Here, we studied the impact of IL-2 administration on the frequency and function of human CD4+CD25hi T cells in immune intact patients with melanoma or renal cancer. We found that the frequency of CD4+CD25hi T cells was significantly increased after IL-2 treatment, and these cells expressed phenotypic markers associated with regulatory T cells. In addition, both transcript and protein levels of Foxp3, a transcription factor exclusively expressed on regulatory T cells, were consistently increased in CD4 T cells following IL-2 treatment. Functional analysis of the increased number of CD4+CD25hi T cells revealed that this population exhibited potent suppressive activity in vitro. Collectively, our results demonstrate that administration of high-dose IL-2 increased the frequency of circulating CD4+CD25hi Foxp3+ regulatory T cells. Our findings suggest that selective inhibition of IL-2-mediated enhancement of regulatory T cells may improve the therapeutic effectiveness of IL-2 administration. (Blood. 2006;107:2409-2414)

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182(7):
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|
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|
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|
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|
 |
|

|
 |

|
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|
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|

|
 |

|
 |
 
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69(2):
599 - 608.
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[Full Text]
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|
 |
|

|
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|
 |
 
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14(24):
8314 - 8320.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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112(13):
4953 - 4960.
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[Full Text]
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|
 |
|

|
 |

|
 |
 
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181(10):
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[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
T. Y. Wuest, J. Willette-Brown, S. K. Durum, and A. A. Hurwitz
The influence of IL-2 family cytokines on activation and function of naturally occurring regulatory T cells
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84(4):
973 - 980.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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181(6):
3784 - 3792.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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Tris (Dibenzylideneacetone) Dipalladium, a N-Myristoyltransferase-1 Inhibitor, Is Effective against Melanoma Growth In vitro and In vivo
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14(18):
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[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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112(6):
2205 - 2213.
[Abstract]
[Full Text]
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|
 |
|

|
 |

|
 |
 
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J. Immunol.,
September 1, 2008;
181(5):
3323 - 3335.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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68(15):
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[Full Text]
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|
 |
|

|
 |

|
 |
 
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205(7):
1701 - 1714.
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[Full Text]
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|
 |
|

|
 |

|
 |
 
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68(11):
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[Full Text]
[PDF]
|
 |
|

|
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|
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|

|
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|
 |
 
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180(7):
5118 - 5129.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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31(3):
555 - 562.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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14(4):
1032 - 1040.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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]
|
 |
|

|
 |

|
 |
 
A. A. Hombach, D. Kofler, A. Hombach, G. Rappl, and H. Abken
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J. Immunol.,
December 1, 2007;
179(11):
7924 - 7931.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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]
|
 |
|

|
 |

|
 |
 
C. Quintarelli, J. F. Vera, B. Savoldo, G. M. P. Giordano Attianese, M. Pule, A. E. Foster, H. E. Heslop, C. M. Rooney, M. K. Brenner, and G. Dotti
Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes
Blood,
October 15, 2007;
110(8):
2793 - 2802.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
H. Guan, P. S. Nagarkatti, and M. Nagarkatti
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J. Immunol.,
September 15, 2007;
179(6):
3715 - 3723.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
D. F. McDermott and M. B. Atkins
More Support for the Judicious Use of High-Dose Interleukin-2 in Patients With Advanced Melanoma
J. Clin. Oncol.,
September 1, 2007;
25(25):
3791 - 3793.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. Clayton, J. P. Mitchell, J. Court, M. D. Mason, and Z. Tabi
Human Tumor-Derived Exosomes Selectively Impair Lymphocyte Responses to Interleukin-2
Cancer Res.,
August 1, 2007;
67(15):
7458 - 7466.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
S. Wei, I. Kryczek, R. P. Edwards, L. Zou, W. Szeliga, M. Banerjee, M. Cost, P. Cheng, A. Chang, B. Redman, et al.
Interleukin-2 Administration Alters the CD4+FOXP3+ T-Cell Pool and Tumor Trafficking in Patients with Ovarian Carcinoma
Cancer Res.,
August 1, 2007;
67(15):
7487 - 7494.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
Y. Kato, K. Yoshimura, T. Shin, H. Verheul, H. Hammers, T. B. Sanni, B. C. Salumbides, K. Van Erp, R. Schulick, and R. Pili
Synergistic In vivo Antitumor Effect of the Histone Deacetylase Inhibitor MS-275 in Combination with Interleukin 2 in a Murine Model of Renal Cell Carcinoma
Clin. Cancer Res.,
August 1, 2007;
13(15):
4538 - 4546.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
S. Tuyaerts, S. Van Meirvenne, A. Bonehill, C. Heirman, J. Corthals, H. Waldmann, K. Breckpot, K. Thielemans, and J. L. Aerts
Expression of human GITRL on myeloid dendritic cells enhances their immunostimulatory function but does not abrogate the suppressive effect of CD4+CD25+ regulatory T cells
J. Leukoc. Biol.,
July 1, 2007;
82(1):
93 - 105.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Beyer and J. L. Schultze
CD4+CD25highFOXP3+ Regulatory T Cells in Peripheral Blood Are Primarily of Effector Memory Phenotype
J. Clin. Oncol.,
June 20, 2007;
25(18):
2628 - 2630.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
I. Kryczek, S. Wei, L. Zou, S. Altuwaijri, W. Szeliga, J. Kolls, A. Chang, and W. Zou
Cutting Edge: Th17 and Regulatory T Cell Dynamics and the Regulation by IL-2 in the Tumor Microenvironment
J. Immunol.,
June 1, 2007;
178(11):
6730 - 6733.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
L.-X. Wang, S. Shu, M. L. Disis, and G. E. Plautz
Adoptive transfer of tumor-primed, in vitro activated, CD4+ T effector cells (TEs) combined with CD8+ TEs provides intratumoral TE proliferation and synergistic antitumor response
Blood,
June 1, 2007;
109(11):
4865 - 4876.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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]
|
 |
|

|
 |

|
 |
 
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]
|
 |
|

|
 |

|
 |
 
Y. Dang, K. L. Knutson, V. Goodell, C. dela Rosa, L. G. Salazar, D. Higgins, J. Childs, and M. L. Disis
Tumor Antigen-Specific T-Cell Expansion Is Greatly Facilitated by In vivo Priming
Clin. Cancer Res.,
March 15, 2007;
13(6):
1883 - 1891.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
Y. Zhang, D. Wakita, K. Chamoto, Y. Narita, N. Matsubara, H. Kitamura, and T. Nishimura
Th1 cell adjuvant therapy combined with tumor vaccination: a novel strategy for promoting CTL responses while avoiding the accumulation of Tregs
Int. Immunol.,
February 1, 2007;
19(2):
151 - 161.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
N. Ralainirina, A. Poli, T. Michel, L. Poos, E. Andres, F. Hentges, and J. Zimmer
Control of NK cell functions by CD4+CD25+ regulatory T cells
J. Leukoc. Biol.,
January 1, 2007;
81(1):
144 - 153.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
I. Goldstein, S. Ben-Horin, A. Koltakov, H. Chermoshnuk, V. Polevoy, Y. Berkun, N. Amariglio, and I. Bank
{alpha}1beta1 Integrin+ and Regulatory Foxp3+ T Cells Constitute Two Functionally Distinct Human CD4+ T Cell Subsets Oppositely Modulated by TNF{alpha} Blockade
J. Immunol.,
January 1, 2007;
178(1):
201 - 210.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. Yang
In Reply
J. Clin. Oncol.,
December 1, 2006;
24(34):
5470 - 5471.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
K. D. Khan, C. Emmanouilides, D. M. Benson Jr., D. Hurst, P. Garcia, G. Michelson, S. Milan, A. K. Ferketich, L. Piro, J. P. Leonard, et al.
A Phase 2 Study of Rituximab in Combination with Recombinant Interleukin-2 for Rituximab-Refractory Indolent Non-Hodgkin's Lymphoma
Clin. Cancer Res.,
December 1, 2006;
12(23):
7046 - 7053.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
D. K. Banerjee, M. V. Dhodapkar, E. Matayeva, R. M. Steinman, and K. M. Dhodapkar
Expansion of FOXP3high regulatory T cells by human dendritic cells (DCs) in vitro and after injection of cytokine-matured DCs in myeloma patients
Blood,
October 15, 2006;
108(8):
2655 - 2661.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
E. Zorn and J. Ritz
Studying Human Regulatory T Cells In vivo.
Clin. Cancer Res.,
September 15, 2006;
12(18):
5265 - 5267.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
E. Zorn, E. A. Nelson, M. Mohseni, F. Porcheray, H. Kim, D. Litsa, R. Bellucci, E. Raderschall, C. Canning, R. J. Soiffer, et al.
IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo
Blood,
September 1, 2006;
108(5):
1571 - 1579.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
K. Rezvani, S. Mielke, M. Ahmadzadeh, Y. Kilical, B. N. Savani, J. Zeilah, K. Keyvanfar, A. Montero, N. Hensel, R. Kurlander, et al.
High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT
Blood,
August 15, 2006;
108(4):
1291 - 1297.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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]
|
 |
|

|
 |

|
 |
 
G. Cesana, S. Kim-Schulze, and H. L. Kaufman
In Reply
J. Clin. Oncol.,
July 10, 2006;
24(20):
e35 - e36.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
T. Manigold, E.-C. Shin, E. Mizukoshi, K. Mihalik, K. K. Murthy, C. M. Rice, C. A. Piccirillo, and B. Rehermann
Foxp3+CD4+CD25+ T cells control virus-specific memory T cells in chimpanzees that recovered from hepatitis C
Blood,
June 1, 2006;
107(11):
4424 - 4432.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
P. A. Antony, C. M. Paulos, M. Ahmadzadeh, A. Akpinarli, D. C. Palmer, N. Sato, A. Kaiser, C. Heinrichs, C. A. Klebanoff, Y. Tagaya, et al.
Interleukin-2-Dependent Mechanisms of Tolerance and Immunity In Vivo
J. Immunol.,
May 1, 2006;
176(9):
5255 - 5266.
[Abstract]
[Full Text]
[PDF]
|
 |
|
|
|