Skip to main content
SpringerLink
Log in

CD4+CD25+ Regulatory T Cells as Adoptive Cell Therapy for Autoimmune Disease and for the Treatment of Graft-Versus-Host Disease

  • Chapter
  • First Online:
Regulatory T Cells and Clinical Application

  • 692 Accesses

Abstract

Researchers in the field of T cell biology, pharmacology, molecular biology and genetic strategies have, over the past several years, systematically developed therapeutic approaches to tackle systemic and organ-specific autoimmune diseases, and treatment with general immunosupressants may soon be replaced by novel therapies based upon this research. Recently, interest in the field of regulatory T cells along with accumulated information that these cells play significant roles in preventing autoimmunity, may revolutionize the field of autoimmune disease therapy. Numerous research groups worldwide have combined forces to develop successful adoptive transfer methods so that regulatory T cells expanded in vivo or ex vivo, as antigen specific or polyclonal, can be used to treat autoimmune diseases. This chapter discusses the evolution of therapeutics for the treatment of autoimmune diseases with particular focus on regulatory T cell therapy using adoptive cell transfer and its treatment for graft-versus-host disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases. Autoimmunity Reviews 2003; 2:119–125

    Article  PubMed  Google Scholar 

  2. Sela M, Teitelbaum D. Glatiramer acetate in the treatment of multiple sclerosis. Expert Opinion on Pharmacotherapy 2001; 2:1149–1165

    Article  PubMed  CAS  Google Scholar 

  3. Steinman L. Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nature Reviews 2005; 4:510–518

    Article  PubMed  CAS  Google Scholar 

  4. Gonsette RE. Mitoxantrone immunotherapy in multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England) 1996; 1:329–332

    CAS  Google Scholar 

  5. Maini RN, Brennan FM, Williams R, et al. TNF-alpha in rheumatoid arthritis and prospects of anti-TNF therapy. Clinical and Experimental Rheumatology 1993; 11 Suppl 8:S173-S175

    PubMed  CAS  Google Scholar 

  6. Shoda LK, Young DL, Ramanujan S, et al. A comprehensive review of interventions in the NOD mouse and implications for translation. Immunity 2005; 23:115–126

    Article  PubMed  CAS  Google Scholar 

  7. Bielekova B, Goodwin B, Richert N, et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nature Medicine 2000; 6:1167–1175

    Article  PubMed  CAS  Google Scholar 

  8. Panitch HS, Hirsch RL, Haley AS, Johnson KP. Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet 1987; 1:893–895

    Article  PubMed  CAS  Google Scholar 

  9. Bartt RE. Multiple sclerosis, natalizumab therapy, and progressive multifocal leukoencephalopathy. Current Opinion in Neurology 2006; 19:341–349

    Article  PubMed  Google Scholar 

  10. Ransohoff RM. Natalizumab and PML. Nature Neuroscience 2005; 8:1275

    Article  PubMed  CAS  Google Scholar 

  11. Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. The New England Journal of Medicine 2006; 355: 1018–1028

    Article  PubMed  CAS  Google Scholar 

  12. Blanas E, Carbone FR, Allison J, Miller JF, Heath WR. Induction of autoimmune diabetes by oral administration of autoantigen. Science 1996; 274:1707–1709

    Article  PubMed  CAS  Google Scholar 

  13. Desquenne-Clark L, Esch TR, Otvos L, Jr., Heber-Katz E. T-cell receptor peptide immunization leads to enhanced and chronic experimental allergic encephalomyelitis. Proceedings of the National Academy of Sciences of the United States of America 1991; 88:7219–7223

    Article  PubMed  CAS  Google Scholar 

  14. Perrin PJ, Scott D, June CH, Racke MK. B7-mediated costimulation can either provoke or prevent clinical manifestations of experimental allergic encephalomyelitis. Immunologic Research 1995; 14:189–199

    Article  PubMed  CAS  Google Scholar 

  15. Robinson WH, Fontoura P, Lee BJ, et al. Protein microarrays guide tolerizing DNA vaccine treatment of autoimmune encephalomyelitis. Nature Biotechnology 2003; 21:1033–1039

    Article  PubMed  CAS  Google Scholar 

  16. Roffe E, Souza AL, Caetano BC, et al. A DNA vaccine encoding CCL4/MIP-1beta enhances myocarditis in experimental Trypanosoma cruzi infection in rats. Microbes and infection/Institut Pasteur 2006; 8:2745–2755

    Article  PubMed  CAS  Google Scholar 

  17. Miura K, Bowman ED, Simon R, et al. Laser capture microdissection and microarray expression analysis of lung adenocarcinoma reveals tobacco smoking- and prognosis-related molecular profiles. Cancer Research 2002; 62:3244–3250

    PubMed  CAS  Google Scholar 

  18. Stosiek C, Garaschuk O, Holthoff K, Konnerth A. In vivo two-photon calcium imaging of neuronal networks. Proceedings of the National Academy of Sciences of the United States of America 2003; 100:7319–7324

    Article  PubMed  CAS  Google Scholar 

  19. Medh RD. Microarray-based expression profiling of normal and malignant immune cells. Endocrine Reviews 2002; 23:393–400

    Article  PubMed  CAS  Google Scholar 

  20. Rajan AJ, Gao YL, Raine CS, Brosnan CF. A pathogenic role for gamma delta T cells in relapsing-remitting experimental allergic encephalomyelitis in the SJL mouse. Journal of Immunology 1996; 157:941–949

    CAS  Google Scholar 

  21. El Behi M, Dubucquoi S, Lefranc D, et al. New insights into cell responses involved in experimental autoimmune encephalomyelitis and multiple sclerosis. Immunology Letters 2005; 96:11–26

    Article  PubMed  CAS  Google Scholar 

  22. Thorbecke GJ, Schwarcz R, Leu J, Huang C, Simmons WJ. Modulation by cytokines of induction of oral tolerance to type II collagen. Arthritis and Rheumatism 1999; 42:110–118

    Article  PubMed  CAS  Google Scholar 

  23. Maron R, Blogg NS, Polanski M, Hancock W, Weiner HL. Oral tolerance to insulin and the insulin B-chain: cell lines and cytokine patterns. Annals of the New York Academy of Sciences 1996; 778:346–357

    Article  PubMed  CAS  Google Scholar 

  24. Weiner HL, Mackin GA, Matsui M, et al. Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science 1993; 259:1321–1324

    Article  PubMed  CAS  Google Scholar 

  25. Blaha P, Bigenzahn S, Koporc Z, et al. The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade. Blood 2003; 101:2886–2893

    Article  PubMed  CAS  Google Scholar 

  26. Khoury SJ, Hancock WW, Weiner HL. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain. The Journal of Experimental Medicine 1992; 176:1355–1364

    Article  PubMed  CAS  Google Scholar 

  27. Wekerle T, Kurtz J, Bigenzahn S, Takeuchi Y, Sykes M. Mechanisms of transplant tolerance induction using costimulatory blockade. Current Opinion in Immunology 2002; 14:592–600

    Article  PubMed  CAS  Google Scholar 

  28. Mor F. Preparation of lymphocytes for autolymphocyte therapy in metastatic renal carcinoma. Lancet 1990; 336:62

    Google Scholar 

  29. Ben-Nun A, Cohen IR. Vaccination against autoimmune encephalomyelitis (EAE): attenuated autoimmune T lymphocytes confer resistance to induction of active EAE but not to EAE mediated by the intact T lymphocyte line. European Journal of Immunology 1981; 11: 949–952

    Article  PubMed  CAS  Google Scholar 

  30. Vandenbark AA, Hashim G, Offner H. Immunization with a synthetic T-cell receptor V-region peptide protects against experimental autoimmune encephalomyelitis. Nature 1989; 341: 541–544

    Article  PubMed  CAS  Google Scholar 

  31. Cohen IR, Quintana FJ, Mimran A. Tregs in T cell vaccination: exploring the regulation of regulation. The Journal of Clinical Investigation 2004; 114:1227–1232

    PubMed  CAS  Google Scholar 

  32. Hellings N, Raus J, Stinissen P. T-cell vaccination in multiple sclerosis: update on clinical application and mode of action. Autoimmunity Reviews 2004; 3:267–275

    Article  PubMed  Google Scholar 

  33. Hafler DA, Cohen I, Benjamin DS, Weiner HL. T cell vaccination in multiple sclerosis: a preliminary report. Clinical Immunology and Immunopathology 1992; 62:307–313

    Article  PubMed  CAS  Google Scholar 

  34. Achiron A, Kishner I, Sarova-Pinhas I, et al. Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: a randomized, double-blind, placebo-controlled trial. Archives of Neurology 2004; 61:1515–1520

    Article  PubMed  Google Scholar 

  35. Tuohy VK, Mathisen PM. T cell design for therapy in autoimmune demyelinating disease. Journal of Neuroimmunology 2000; 107:226–232

    Article  PubMed  CAS  Google Scholar 

  36. Setoguchi K, Misaki Y, Araki Y, et al. Antigen-specific T cells transduced with IL-10 ameliorate experimentally induced arthritis without impairing the systemic immune response to the antigen. Journal of Immunology 2000; 165:5980–5986

    CAS  Google Scholar 

  37. Nakajima A, Seroogy CM, Sandora MR, et al. Antigen-specific T cell-mediated gene therapy in collagen-induced arthritis. The Journal of Clinical Investigation 2001; 107: 1293–1301

    Article  PubMed  CAS  Google Scholar 

  38. Rabinovich GA, Daly G, Dreja H, et al. Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis. The Journal of Experimental Medicine 1999; 190:385–398

    Article  PubMed  CAS  Google Scholar 

  39. Dreja H, Annenkov A, Chernajovsky Y. Soluble complement receptor 1 (CD35) delivered by retrovirally infected syngeneic cells or by naked DNA injection prevents the progression of collagen-induced arthritis. Arthritis and Rheumatism 2000; 43:1698–1709

    Article  PubMed  CAS  Google Scholar 

  40. Croxford B, Tham KW, Young A, Oreszczyn T, Wyon D. A study of local electrostatic filtration and main pre-filtration on airborne and surface dust levels in air-conditioned office premises. Indoor Air 2000; 10:170–177

    Article  PubMed  CAS  Google Scholar 

  41. Fiehn C, Wettschureck N, Krauthoff A, Haas R, Ho AD. Bone marrow-derived cells as carriers of recombinant immunomodulatory cytokine genes to lymphoid organs. Cancer Gene Therapy 2000; 7:1105–1112

    Article  PubMed  CAS  Google Scholar 

  42. Kim SH, Kim S, Evans CH, et al. Effective treatment of established murine collagen-induced arthritis by systemic administration of dendritic cells genetically modified to express IL-4. Journal of Immunology 2001; 166:3499–3505

    CAS  Google Scholar 

  43. Morita Y, Yang J, Gupta R, et al. Dendritic cells genetically engineered to express IL-4 inhibit murine collagen-induced arthritis. The Journal of Clinical Investigation 2001; 107: 1275–1284

    Article  PubMed  CAS  Google Scholar 

  44. Falqui L, Martinenghi S, Severini GM, et al. Reversal of diabetes in mice by implantation of human fibroblasts genetically engineered to release mature human insulin. Human Gene Therapy 1999; 10:1753–1762

    Article  PubMed  CAS  Google Scholar 

  45. Lee HC, Kim SJ, Kim KS, Shin HC, Yoon JW. Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue. Nature 2000; 408:483–488

    Article  PubMed  CAS  Google Scholar 

  46. Woods JM, Katschke KJ, Volin MV, et al. IL-4 adenoviral gene therapy reduces inflammation, proinflammatory cytokines, vascularization, and bony destruction in rat adjuvant-induced arthritis. Journal of Immunology 2001; 166:1214–1222

    CAS  Google Scholar 

  47. Martino G, Furlan R, Brambilla E, et al. Cytokines and immunity in multiple sclerosis: the dual signal hypothesis. Journal of Neuroimmunology 2000; 109:3–9

    Article  PubMed  CAS  Google Scholar 

  48. Cottard V, Mulleman D, Bouille P, et al. Adeno-associated virus-mediated delivery of IL-4 prevents collagen-induced arthritis. Gene Therapy 2000; 7:1930–1939

    Article  PubMed  CAS  Google Scholar 

  49. Kim SH, Evans CH, Kim S, et al. Gene therapy for established murine collagen-induced arthritis by local and systemic adenovirus-mediated delivery of interleukin-4. Arthritis Research 2000; 2:293–302

    Article  PubMed  CAS  Google Scholar 

  50. Batteux F, Trebeden H, Charreire J, Chiocchia G. Curative treatment of experimental autoimmune thyroiditis by in vivo administration of plasmid DNA coding for interleukin-10. European Journal of Immunology 1999; 29:958–963

    Article  PubMed  CAS  Google Scholar 

  51. Koh JJ, Ko KS, Lee M, et al. Degradable polymeric carrier for the delivery of IL-10 plasmid DNA to prevent autoimmune insulitis of NOD mice. Gene Therapy 2000; 7:2099–2104

    Article  PubMed  CAS  Google Scholar 

  52. Lechman ER, Jaffurs D, Ghivizzani SC, et al. Direct adenoviral gene transfer of viral IL-10 to rabbit knees with experimental arthritis ameliorates disease in both injected and contralateral control knees. Journal of Immunology 1999; 163:2202–2208.

    Google Scholar 

  53. Whalen JD, Lechman EL, Carlos CA, et al. Adenoviral transfer of the viral IL-10 gene periarticularly to mouse paws suppresses development of collagen-induced arthritis in both injected and uninjected paws. Journal of Immunology 1999; 162:3625–3632

    CAS  Google Scholar 

  54. Kim KN, Watanabe S, Ma Y, et al. Viral IL-10 and soluble TNF receptor act synergistically to inhibit collagen-induced arthritis following adenovirus-mediated gene transfer. Journal of Immunology 2000; 164:1576–1581

    CAS  Google Scholar 

  55. Bessis N, Honiger J, Damotte D, et al. Encapsulation in hollow fibres of xenogeneic cells engineered to secrete IL-4 or IL-13 ameliorates murine collagen-induced arthritis (CIA). Clinical and Experimental Immunology 1999; 117:376–382

    Article  PubMed  CAS  Google Scholar 

  56. Chang Y, Prud'homme GJ. Intramuscular administration of expression plasmids encoding interferon-gamma receptor/IgG1 or IL-4/IgG1 chimeric proteins protects from autoimmunity. The Journal of Gene Medicine 1999; 1:415–423

    Article  PubMed  CAS  Google Scholar 

  57. Piccirillo CA, Prud'homme GJ. Prevention of experimental allergic encephalomyelitis by intramuscular gene transfer with cytokine-encoding plasmid vectors. Human Gene Therapy 1999; 10:1915–1922

    Article  PubMed  CAS  Google Scholar 

  58. Quattrocchi E, Walmsley M, Browne K, et al. Paradoxical effects of adenovirus-mediated blockade of TNF activity in murine collagen-induced arthritis. Journal of Immunology 1999; 163:1000–1009

    CAS  Google Scholar 

  59. Prud'homme GJ, Chang Y. Prevention of autoimmune diabetes by intramuscular gene therapy with a nonviral vector encoding an interferon-gamma receptor/IgG1 fusion protein. Gene Therapy 1999; 6:771–777

    Article  PubMed  Google Scholar 

  60. Lawson BR, Prud'homme GJ, Chang Y, et al. Treatment of murine lupus with cDNA encoding IFN-gammaR/Fc. The Journal of Clinical Investigation 2000; 106:207–215

    Article  PubMed  CAS  Google Scholar 

  61. Costa GL, Sandora MR, Nakajima A, et al. Adoptive immunotherapy of experimental autoimmune encephalomyelitis via T cell delivery of the IL-12 p40 subunit. Journal of Immunology 2001; 167:2379–2387

    CAS  Google Scholar 

  62. Lubberts E, Joosten LA, Chabaud M, et al. IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion. The Journal of Clinical Investigation 2000; 105:1697–1710

    Article  PubMed  CAS  Google Scholar 

  63. Zhang HG, Fleck M, Kern ER, et al. Antigen presenting cells expressing Fas ligand down-modulate chronic inflammatory disease in Fas ligand-deficient mice. The Journal of Clinical Investigation 2000; 105:813–821

    Article  PubMed  CAS  Google Scholar 

  64. Tarner IH, Nakajima A, Seroogy CM, et al. Retroviral gene therapy of collagen-induced arthritis by local delivery of IL-4. Clinical Immunology (Orlando, Fla) 2002; 105:304–314

    Article  CAS  Google Scholar 

  65. Smith R, Tarner IH, Hollenhorst M, et al. Localized expression of an anti-TNF single-chain antibody prevents development of collagen-induced arthritis. Gene Therapy 2003; 10: 1248–1257

    Article  PubMed  CAS  Google Scholar 

  66. Urbanek-Ruiz I, Ruiz PJ, Paragas V, et al. Immunization with DNA encoding an immunodominant peptide of insulin prevents diabetes in NOD mice. Clinical Immunology (Orlando, Fla) 2001; 100:164–171

    Article  CAS  Google Scholar 

  67. Marson A, Kretschmer K, Frampton GM, et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 2007; 445:931–935.

    Google Scholar 

  68. Szanya V, Ermann J, Taylor C, Holness C, Fathman CG. The subpopulation of CD4+CD25+ splenocytes that delays adoptive transfer of diabetes expresses L-selectin and high levels of CCR7. Journal of Immunology 2002; 169:2461–2465

    CAS  Google Scholar 

  69. Ermann J, Hoffmann P, Edinger M, et al. Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood 2005; 105:2220–2226

    Article  PubMed  CAS  Google Scholar 

  70. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. The Journal of Experimental Medicine 2002; 196:389–399

    Article  PubMed  CAS  Google Scholar 

  71. Hanash AM, Levy RB. Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation. Blood 2005; 105: 1828–1836

    Article  PubMed  CAS  Google Scholar 

  72. Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nature Medicine 2003; 9:1144–1150

    Article  PubMed  CAS  Google Scholar 

  73. Trenado A, Charlotte F, Fisson S, et al. Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia. The Journal of Clinical Investigation 2003; 112:1688–1696

    PubMed  CAS  Google Scholar 

  74. Taylor PA, Lees CJ, Blazar BR. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 2002; 99:3493–3499

    Article  PubMed  CAS  Google Scholar 

  75. Godfrey WR, Ge YG, Spoden DJ, et al. In vitro-expanded human CD4(+)CD25(+) T-regulatory cells can markedly inhibit allogeneic dendritic cell-stimulated MLR cultures. Blood 2004; 104:453–461

    Article  PubMed  CAS  Google Scholar 

  76. Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. Type 1 T regulatory cells. Immunological Reviews 2001; 182:68–79

    Article  PubMed  CAS  Google Scholar 

  77. Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM. CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. The Journal of Experimental Medicine 2004; 199:1467–1477

    Article  PubMed  CAS  Google Scholar 

  78. Maus MV, Thomas AK, Leonard DG, et al. Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB. Nature Biotechnology 2002; 20:143–148

    Article  PubMed  CAS  Google Scholar 

  79. Dutt S, Ermann J, Tseng D, et al. L-selectin and beta7 integrin on donor CD4 T cells are required for the early migration to host mesenteric lymph nodes and acute colitis of graft-versus-host disease. Blood 2005; 106:4009–4015

    Article  PubMed  CAS  Google Scholar 

  80. Su L, Creusot RJ, Gallo EM, et al. Murine CD4+CD25+ regulatory T cells fail to undergo chromatin remodeling across the proximal promoter region of the IL-2 gene. Journal of Immunology 2004; 173:4994–5001

    CAS  Google Scholar 

  81. Sweeney TJ, Mailander V, Tucker AA, et al. Visualizing the kinetics of tumor-cell clearance in living animals. Proceedings of the National Academy of Sciences of the United States of America 1999; 96:12044–12049

    Article  PubMed  CAS  Google Scholar 

  82. Cao D, van Vollenhoven R, Klareskog L, Trollmo C, Malmstrom V. CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Research and Therapy 2004; 6:R335–R346

    Article  PubMed  CAS  Google Scholar 

  83. Beilhack A, Schulz S, Baker J, et al. In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets. Blood 2005; 106:1113–1122

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Medicine, Stanford University, Palo Alto, CA 94305, USA

    C. Garrison Fathman

Authors
  1. Swati Acharya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Garrison Fathman
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2008 Springer Science+Business Media, LLC

    About this chapter

    Cite this chapter

    Acharya, S., Fathman, C.G. (2008). CD4+CD25+ Regulatory T Cells as Adoptive Cell Therapy for Autoimmune Disease and for the Treatment of Graft-Versus-Host Disease. In: Jiang, S. (eds) Regulatory T Cells and Clinical Application. Springer, New York, NY. https://doi.org/10.1007/978-0-387-77909-6_11

    Download citation

    Publish with us

    Policies and ethics

    Search

    Navigation