This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Onizuka, S. Articles by Nakayama, E. Search for Related Content PubMed PubMed Citation Articles by Onizuka, S. Articles by Nakayama, E.

Tumor Rejection by in Vivo Administration of Anti-CD25 (Interleukin-2 Receptor ) 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

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 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 1 .

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

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Effect on Tumor Growth of in Vivo Administration of Anti-CD25 (IL-2R) 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. 1 and Fig. 2 , 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.

View larger version (49K): [in this window] [in a new window]   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.

View larger version (15K): [in this window] [in a new window]   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. 1 . Each experimental group consisted of three mice. Values, means ± SD.

View larger version (31K): [in this window] [in a new window]   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.

View larger version (34K): [in this window] [in a new window]   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.

View larger version (22K): [in this window] [in a new window]   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.

View this table: [in this window] [in a new window]   Table 2 Tumor regression by in vivo administration of anti-CD25 (IL-2R) mAb (PC61)

Effect of CD4 and/or CD8 Depletion on Tumor Regression by Anti-CD25 (IL-2R) mAb (PC61).

View larger version (25K): [in this window] [in a new window]   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) mAb (PC61).

View larger version (29K): [in this window] [in a new window]   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) () cells 4–6 weeks after primary tumor rejection. and , 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

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.

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.

	REFERENCES

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. North R. J., Bursuker I. Generation and decay of the immune response to a progressive fibrosarcoma. I. Ly-1⁺2^- suppressor T cells down-regulate the generation of Ly-1^-2⁺ effector T cells. J. Exp. Med., 54: 1295-1311, 1984.
2. Awwad M., North R. J. Immunologically mediated regression of a murine lymphoma after treatment with anti-L3T4 antibody. A consequence of removing L3T4⁺ suppressor T cells from a host generating predominantly Lyt-2⁺ T cell-mediated immunity. J. Exp. Med., 168: 2193-2206, 1988.[Abstract/Free Full Text]
3. North R. J., Dye E. S. Ly-1⁺2^- suppressor T cells down-regulate the generation of Ly-1^-2⁺ effector T cells during progressive growth of the P815 mastocytoma. Immunology, 54: 47-56, 1985.[Medline]
4. Rakhmilevich A. L., North R. J., Dye E. S. Presence of CD4⁺ T suppressor cells in mice rendered unresponsive to tumor antigens by intravenous injection of irradiated tumor cells. Int. J. Cancer, 55: 338-343, 1993.[Medline]
5. Uenaka A., Ono T., Akisawa T., Wada H., Yasuda T., Nakayama E. Identification of a unique antigen peptide pRL1 on BALB/c RL1 leukemia recognized by cytotoxic T lymphocytes and its relation of the akt oncogene. J. Exp. Med., 180: 1599-1607, 1994.[Abstract/Free Full Text]
6. Wada H., Matsuo M., Uenaka A., Shimbara N., Shimizu K., Nakayama E. Rejection antigen peptides on BALB/c RL1 leukemia recognized by cytotoxic T lymphocytes: derivation from the normally untranslated 5' region of the c-akt proto-oncogene activated by long terminal repeat. Cancer Res., 55: 4780-4783, 1995.[Abstract/Free Full Text]
7. Matsuo, M., Wada, H., Honda, S., Tawara, I., Uenaka, A., Kanematsu, T., and Nakayama, E. Expression of multiple unique rejection antigens on murine leukemia BALB/c RL1 and the role of dominant Akt antigen for tumor escape. J. Immunol., in press, 1999.
8. Sakaguchi S., Fukuma K., Kuribayashi K., Masuda T. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J. Exp. Med., 161: 72-82, 1985.[Abstract/Free Full Text]
9. Asano M., Toda M., Sakaguchi N., Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med., 184: 387-396, 1996.[Abstract/Free Full Text]
10. Suri-Payer E., Amer A. Z., Thornton A. M., Shevach E. M. CD4⁺CD25⁺ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. J. Immunol., 160: 1212-1218, 1998.[Abstract/Free Full Text]
11. Sakaguchi S., Sakaguchi N., Asano M., Itoh M., Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor -chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol., 155: 1151-1164, 1995.[Abstract]
12. Thornton A. M., Shevach E. M. CD4⁺CD25⁺ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med., 188: 287-296, 1998.[Abstract/Free Full Text]
13. Takahashi T., Kuniyasu Y., Toda M., Sakaguchi N., Itoh M., Iwata M., Shimizu J., Sakaguchi S. Immunologic self-tolerance maintained by CD25⁺CD4⁺ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int. Immunol., 10: 1969-1980, 1998.[Abstract/Free Full Text]
14. Taguchi O., Takahashi T. Administration of anti-interleukin-2 receptor antibody in vivo induces localized autoimmune disease. Eur. J. Immunol., 26: 1608-1612, 1996.[Medline]
15. Dialynas D. P., Quan Z. S., Wall K. A., Pierres A., Quintans J., Loken M. R., Pierres M., Fitch F. W. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule. J. Immunol., 131: 2445-2451, 1983.[Abstract]
16. Nakayama E., Dippold W., Shiku H., Oettgen H. F., Old L. J. Alloantigen-induced T-cell proliferation: Lyt phenotype of responding cells and blocking of proliferation by Lyt antisera. Proc. Natl. Acad. Sci. USA., 77: 2890-2894, 1980.[Abstract/Free Full Text]
17. Lowenthal J. W., Corthesy P., Tougne C., Lees R., MacDonald H. R., Nabholz M. High and low affinity IL-2 receptors: analysis by IL-2 dissociation rate and reactivity with monoclonal anti-receptor antibody PC61. J. Immunol., 135: 3988-3994, 1985.[Abstract]
18. Ortega G., Robb R. J., Shevach E. M., Malek T. R. The murine IL-2 receptor. I. Monoclonal antibodies that define distinct functional epitopes on activated T cells and react with activated B cells. J. Immunol., 133: 1970-1975, 1984.[Abstract]
19. Yoshimura A., Shiku H., Nakayama E. Rejection of an IA⁺ variant line of FBL-3 leukemia by cytotoxic T lymphocytes with CD4⁺ and CD4^-CD8^- T cell receptor-ß phenotypes generated in CD8-depleted C57BL/6 mice. J. Immunol., 150: 4900-4910, 1993.[Abstract]
20. Udono H., Mieno M., Shiku H., Nakayama E. The roles of CD8⁺ and CD4⁺ cells in tumor rejection. Jpn. J. Cancer Res., 80: 649-654, 1989.[Medline]
21. Harutsumi M., Aji T., Manki A., Hikida M., Omori H., Watanabe Y., Teramura Y., Kuribayashi K., Seino Y., Nakayama E. Rejection of parental Meth A tumor on concomitant inoculation of Meth A cells infected retrovirally with the interferon- gene into (BALB/c x C57BL/6)F₁ mice. Int. J. Oncol., 7: 233-238, 1995.
22. Sakaguchi S., Takahashi T., Nishizuka Y. Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis. J. Exp. Med., 156: 1577-1586, 1982.[Abstract/Free Full Text]
23. Moroda T., Iiai T., Kawachi Y., Kawamura Y. T., Hatakeyama K., Abo T. Restricted appearance of self-reactive clones into T cell receptor intermediate cells in neonatally thymectomized mice with autoimmune disease. Eur. J. Immunol., 26: 3084-3091, 1996.[Medline]
24. Wang J., Griggs N. D., Tung K. S., Klein J. R. Dynamic regulation of gastric autoimmunity by thyroid hormone. Int. Immunol., 10: 231-236, 1998.[Abstract/Free Full Text]
25. Old L. J., Boyse E. A., Stockert E. Antigenic properties of experimental leukemias. I. Serological studies in vitro with spontaneous and radiation-induced leukemias. J. Natl. Cancer Inst., 31: 977-986, 1963.
26. Stockert E., DeLeo A. B., O’Donnell P. V., Obata Y., Old L. J. A new cell surface antigen of the mouse related to the dualtropic mink cell focus-inducing class of murine leukemia virus detected by naturally occurring antibody. J. Exp. Med., 149: 200-215, 1979.[Abstract/Free Full Text]
27. Nakayama E., Shiku H., Takahashi T., Oettgen H. F., Old L. J. Definition of a unique cell surface antigen of mouse leukemia RL1 by cell-mediated cytotoxicity. Proc. Natl. Acad. Sci. USA, 76: 3486-3490, 1979.[Abstract/Free Full Text]
28. Gorer P. A. Studies in antibody response of mice to tumor inoculation. Br. J. Cancer, 4: 372-379, 1950.[Medline]
29. Potter M. The plasma cell tumors and myeloma protein of mice Busch H. eds. . Methods in Cancer Research, : 106-157, Academic Press, Inc. New York 1967.
30. Old L. J., Boyse E. A., Clarke D. A., Carswell E. A. Antigenic properties of chemically induced tumors. Ann. NY Acad. Sci., 101: 80-106, 1962.
31. DeLeo A. B., Shiku H., Takahashi T., John M., Old L. J. Cell surface antigens of chemically induced sarcomas of the mouse. I. Murine leukemia virus-related antigens and alloantigens on cultured fibroblasts and sarcoma cells: description of a unique antigen on BALB/c Meth A sarcoma. J. Exp. Med., 146: 720-734, 1977.[Abstract/Free Full Text]

This article has been cited by other articles:

				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. [Abstract] [Full Text] [PDF]

				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. [Abstract] [Full Text] [PDF]

				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. [Abstract] [Full Text] [PDF]

				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]

				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]

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

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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. 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]

				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]

				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]

				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]

				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]

				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. [Full Text] [PDF]

				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]

				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]

				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]

				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]