SEARCH:   Advanced

Blood, 1 March 2004, Vol. 103, No. 5, pp. 1755-1762. Prepublished online as a Blood First Edition Paper on November 6, 2003; DOI 10.1182/blood-2003-07-2594. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-07-2594v1 103/5/1755    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Marshall, N. A. Articles by Vickers, M. A. Search for Related Content PubMed PubMed Citation Articles by Marshall, N. A. Articles by Vickers, M. A. Related Collections Immunobiology Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma Neil A. Marshall, Linsey E. Christie, Laura R. Munro, Dominic J. Culligan, Peter W. Johnston, Robert N. Barker, and Mark A. Vickers From the Department of Medicine and Therapeutics, Department of Haematology, and Department of Pathology, University of Aberdeen, Aberdeen, United Kingdom. Although immunosuppression has long been recognized in Hodgkin lymphoma (HL), the underlying basis for the lack of an effective immune response against the tumor remains unclear. The aim was to test our hypothesis that regulatory T cells dominate involved lymph nodes. The approach was to assay CD4+ T-cell function in HL-infiltrating lymphocytes (HLILs) and paired peripheral blood mononuclear cells (PBMCs) of 24 patients. Strikingly, unlike PBMCs, HLILs were anergic to stimulation with mitogen, primary, or recall antigens, mounting no proliferative responses and only rare T-helper 1 (Th1) or Th2 cytokine responses. Mixing paired HLILs and PBMCs showed the anergic effect was dominant and suppressed PBMC responses. Furthermore, flow cytometry demonstrated that HLILs contained large populations of both interleukin-10 (IL-10)–secreting T-regulatory 1 (Tr1) and CD4+CD25+ regulatory T cells. We found evidence for 3 mechanisms of action implicated in the suppressive functions of regulatory T cells: the inhibition of PBMCs by HLILs was ameliorated by neutralizing IL-10, by preventing cell-to-cell contact, and by blocking anti–cytotoxic T lymphocyte–associated antigen 4 (anti–CTLA-4). Thus, HLILs are highly enriched for regulatory T cells, which induce a profoundly immunosuppressive environment and so provide an explanation for the ineffective immune clearance of Hodgkin-Reed Sternberg cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Regulatory T cells in Hodgkin lymphoma Sibrand Poppema Blood 2004 103: 1565-1566. [Full Text] [PDF] This article has been cited by other articles: K. R.N. Baumforth, A. Birgersdotter, G. M. Reynolds, W. Wei, G. Kapatai, J. R. Flavell, E. Kalk, K. Piper, S. Lee, L. Machado, et al. Expression of the Epstein-Barr Virus-Encoded Epstein-Barr Virus Nuclear Antigen 1 in Hodgkin's Lymphoma Cells Mediates Up-Regulation of CCL20 and the Migration of Regulatory T Cells Am. J. Pathol., July 1, 2008; 173(1): 195 - 204. [Abstract] [Full Text] [PDF] S. Mittal, N. A. Marshall, L. Duncan, D. J. Culligan, R. N. Barker, and M. A. Vickers Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma Blood, June 1, 2008; 111(11): 5359 - 5370. [Abstract] [Full Text] [PDF] M. E. C. Lutsiak, Y. Tagaya, A. J. Adams, J. Schlom, and H. Sabzevari Tumor-Induced Impairment of TCR Signaling Results in Compromised Functionality of Tumor-Infiltrating Regulatory T Cells J. Immunol., May 1, 2008; 180(9): 5871 - 5881. [Abstract] [Full Text] [PDF] R. Yamamoto, M. Nishikori, T. Kitawaki, T. Sakai, M. Hishizawa, M. Tashima, T. Kondo, K. Ohmori, M. Kurata, T. Hayashi, et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma Blood, March 15, 2008; 111(6): 3220 - 3224. [Abstract] [Full Text] [PDF] T. Alvaro, M. Lejeune, J. F. Garcia, Ma. T. Salvado, C. Lopez, R. Bosch, J. Jaen, P. Escriva, and L. E. Pons Tumor-Infiltrated Immune Response Correlates with Alterations in the Apoptotic and Cell Cycle Pathways in Hodgkin and Reed-Sternberg Cells Clin. Cancer Res., February 1, 2008; 14(3): 685 - 691. [Abstract] [Full Text] [PDF] A. Tzankov, C. Meier, P. Hirschmann, P. Went, S. A. Pileri, and S. Dirnhofer Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin's lymphoma Haematologica, February 1, 2008; 93(2): 193 - 200. [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] J. M. Chemnitz, D. Eggle, J. Driesen, S. Classen, J. L. Riley, S. Debey-Pascher, M. Beyer, A. Popov, T. Zander, and J. L. Schultze RNA fingerprints provide direct evidence for the inhibitory role of TGF{beta} and PD-1 on CD4+ T cells in Hodgkin lymphoma Blood, November 1, 2007; 110(9): 3226 - 3233. [Abstract] [Full Text] [PDF] C. Atayar, A. van den Berg, T. Blokzijl, M. Boot, R. D Gascoyne, L. Visser, and S. Poppema Hodgkin's lymphoma associated T-cells exhibit a transcription factor profile consistent with distinct lymphoid compartments J. Clin. Pathol., October 1, 2007; 60(10): 1092 - 1097. [Abstract] [Full Text] [PDF] T. Tanijiri, T. Shimizu, K. Uehira, T. Yokoi, H. Amuro, H. Sugimoto, Y. Torii, K. Tajima, T. Ito, R. Amakawa, et al. Hodgkin's Reed-Sternberg cell line (KM-H2) promotes a bidirectional differentiation of CD4+CD25+Foxp3+ T cells and CD4+ cytotoxic T lymphocytes from CD4+ naive T cells J. Leukoc. Biol., September 1, 2007; 82(3): 576 - 584. [Abstract] [Full Text] [PDF] A. Merlo, C. Calcaterra, S. Menard, and A. Balsari Cross-talk between Toll-like receptors 5 and 9 on activation of human immune responses J. Leukoc. Biol., September 1, 2007; 82(3): 509 - 518. [Abstract] [Full Text] [PDF] P. Juszczynski, J. Ouyang, S. Monti, S. J. Rodig, K. Takeyama, J. Abramson, W. Chen, J. L. Kutok, G. A. Rabinovich, and M. A. Shipp The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma PNAS, August 7, 2007; 104(32): 13134 - 13139. [Abstract] [Full Text] [PDF] S Hohaus, M Giachelia, A Di Febo, M Martini, G Massini, B Vannata, F D'Alo', F Guidi, M Greco, F Pierconti, et al. Polymorphism in cytokine genes as prognostic markers in Hodgkin's lymphoma Ann. Onc., August 1, 2007; 18(8): 1376 - 1381. [Abstract] [Full Text] [PDF] W. J. Pickford, A. J.M. Watson, and R. N. Barker Different Forms of Helper Tolerance to Carcinoembryonic Antigen: Ignorance and Regulation Clin. Cancer Res., August 1, 2007; 13(15): 4528 - 4537. [Abstract] [Full Text] [PDF] A. Diepstra, G. W. van Imhoff, H. E. Karim-Kos, A. van den Berg, G. J. te Meerman, M. Niens, I. M. Nolte, E. Bastiaannet, M. Schaapveld, E. Vellenga, et al. HLA Class II Expression by Hodgkin Reed-Sternberg Cells Is an Independent Prognostic Factor in Classical Hodgkin's Lymphoma J. Clin. Oncol., July 20, 2007; 25(21): 3101 - 3108. [Abstract] [Full Text] [PDF] S. Tuve, B.-M. Chen, Y. Liu, T.-L. Cheng, P. Toure, P. S. Sow, Q. Feng, N. Kiviat, R. Strauss, S. Ni, et al. Combination of Tumor Site-Located CTL-Associated Antigen-4 Blockade and Systemic Regulatory T-Cell Depletion Induces Tumor-Destructive Immune Responses Cancer Res., June 15, 2007; 67(12): 5929 - 5939. [Abstract] [Full Text] [PDF] 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] S. P. Hilchey, A. De, L. M. Rimsza, R. B. Bankert, and S. H. Bernstein Follicular Lymphoma Intratumoral CD4+CD25+GITR+ Regulatory T Cells Potently Suppress CD3/CD28-Costimulated Autologous and Allogeneic CD8+CD25- and CD4+CD25- T Cells J. Immunol., April 1, 2007; 178(7): 4051 - 4061. [Abstract] [Full Text] [PDF] 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] V. C. Liu, L. Y. Wong, T. Jang, A. H. Shah, I. Park, X. Yang, Q. Zhang, S. Lonning, B. A. Teicher, and C. Lee Tumor Evasion of the Immune System by Converting CD4+CD25- T Cells into CD4+CD25+ T Regulatory Cells: Role of Tumor-Derived TGF-beta J. Immunol., March 1, 2007; 178(5): 2883 - 2892. [Abstract] [Full Text] [PDF] A. M. Miller, K. Lundberg, V. Ozenci, A. H. Banham, M. Hellstrom, L. Egevad, and P. Pisa CD4+CD25high T Cells Are Enriched in the Tumor and Peripheral Blood of Prostate Cancer Patients J. Immunol., November 15, 2006; 177(10): 7398 - 7405. [Abstract] [Full Text] [PDF] 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] C. Smith, L. Cooper, M. Burgess, M. Rist, N. Webb, E. Lambley, J. Tellam, P. Marlton, J. F. Seymour, M. Gandhi, et al. Functional Reversion of Antigen-Specific CD8+ T Cells from Patients with Hodgkin Lymphoma following In Vitro Stimulation with Recombinant Polyepitope J. Immunol., October 1, 2006; 177(7): 4897 - 4906. [Abstract] [Full Text] [PDF] M. K. Gandhi, E. Lambley, J. Duraiswamy, U. Dua, C. Smith, S. Elliott, D. Gill, P. Marlton, J. Seymour, and R. Khanna Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients Blood, October 1, 2006; 108(7): 2280 - 2289. [Abstract] [Full Text] [PDF] 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] M. Beyer and J. L. Schultze Regulatory T cells in cancer Blood, August 1, 2006; 108(3): 804 - 811. [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] A. E. Andaloussi and M. S. Lesniak An increase in CD4+CD25+FOXP3+ regulatory T cells in tumor-infiltrating lymphocytes of human glioblastoma multiforme Neuro-oncol, July 1, 2006; 8(3): 234 - 243. [Abstract] [Full Text] [PDF] D. Xu, J. Fu, L. Jin, H. Zhang, C. Zhou, Z. Zou, J.-M. Zhao, B. Zhang, M. Shi, X. Ding, et al. Circulating and Liver Resident CD4+CD25+ Regulatory T Cells Actively Influence the Antiviral Immune Response and Disease Progression in Patients with Hepatitis B J. Immunol., July 1, 2006; 177(1): 739 - 747. [Abstract] [Full Text] [PDF] M. Kasprzycka, M. Marzec, X. Liu, Q. Zhang, and M. A. Wasik From the Cover: Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3 PNAS, June 27, 2006; 103(26): 9964 - 9969. [Abstract] [Full Text] [PDF] L. Sfondrini, A. Rossini, D. Besusso, A. Merlo, E. Tagliabue, S. Menard, and A. Balsari Antitumor Activity of the TLR-5 Ligand Flagellin in Mouse Models of Cancer. J. Immunol., June 1, 2006; 176(11): 6624 - 6630. [Abstract] [Full Text] [PDF] 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] 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] J. S. Abramson T-cell/histiocyte-rich B-cell lymphoma: biology, diagnosis, and management. Oncologist, April 1, 2006; 11(4): 384 - 392. [Abstract] [Full Text] [PDF] M. Miyara, Z. Amoura, C. Parizot, C. Badoual, K. Dorgham, S. Trad, M. Kambouchner, D. Valeyre, C. Chapelon-Abric, P. Debre, et al. The immune paradox of sarcoidosis and regulatory T cells J. Exp. Med., February 21, 2006; 203(2): 359 - 370. [Abstract] [Full Text] [PDF] H. Williams and D. H. Crawford Epstein-Barr virus: the impact of scientific advances on clinical practice Blood, February 1, 2006; 107(3): 862 - 869. [Abstract] [Full Text] [PDF] J. M. Chemnitz, J. Driesen, S. Classen, J. L. Riley, S. Debey, M. Beyer, A. Popov, T. Zander, and J. L. Schultze Prostaglandin E2 Impairs CD4+ T Cell Activation by Inhibition of lck: Implications in Hodgkin's Lymphoma Cancer Res., January 15, 2006; 66(2): 1114 - 1122. [Abstract] [Full Text] [PDF] 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] K. Karube, K. Ohshima, J. Suzumiya, R. Kawano, M. Kikuchi, and M. Harada Gene expression profile of cytokines and chemokines in microdissected primary Hodgkin and Reed-Sternberg (HRS) cells: high expression of interleukin-11 receptor {alpha} Ann. Onc., January 1, 2006; 17(1): 110 - 116. [Abstract] [Full Text] [PDF]