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Technology Insight: ECP for the treatment of GvHD—can we offer selective immune control without generalized immunosuppression?

Nature Clinical Practice Oncology volume 3, pages 302–314 (2006)Cite this article

Abstract

Hematopoietic stem-cell transplantation remains an important curative therapy for many conditions and its use is increasing annually. Graft-versus-host disease (GvHD) is the major cause of mortality and suffering following allogeneic hematopoietic stem-cell transplantation. Conventional treatments are associated with multiple side effects and are often ineffective. New therapeutic approaches for the control of GvHD are desperately required. Extracorporeal photochemotherapy (ECP) was developed in the 1970s for the treatment of cutaneous T-cell lymphoma and was approved by the FDA as the first selective immunotherapy for a cancer. ECP has also proved an effective therapy for immune-related conditions, particularly GvHD, even in patients refractory to conventional therapies. The treatment involves the mechanical separation of circulating white cells, which are exposed to psoralen and UVA light and then returned to the patient. ECP is extremely well tolerated with minimal side effects and is not associated with the increased rates of infection or relapse of malignant disease typical of conventional immunosuppressive agents. Thus, ECP appears to offer selective immune modulation without generalized immunosuppression, but its mechanism of action remains poorly understood. This review discusses the development of ECP, its use in the treatment of GvHD, as well as current theories of its mechanism of action.

Key Points

  • Graft-versus-host disease (GvHD) remains the major cause of non-relapse morbidity and mortality following allogeneic hematopoietic stem-cell transplantation

  • Extracorporeal photochemotherapy (ECP) was developed for the treatment of cutaneous T-cell lymphoma and was found to have activity in other T-cell-mediated diseases

  • ECP is a novel approach to GvHD therapy that appears to offer control of GvHD without generalized immunosuppression and its associated complications

  • There is reasonable evidence to support the use of ECP for the treatment of steroid-refractory chronic GvHD and increasing evidence for its use in steroid-refractory acute GvHD

  • ECP is well tolerated with minimal side-effects during therapy and no reported long term side effects

  • The mechanism of action of ECP in GvHD remains poorly characterized, but in vitro studies indicate that the therapy might boost natural mechanisms of tolerance

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Figure 1: Diagram to illustrate the extracorporeal photochemotherapy procedure.
Figure 2: Proposed mechanistic pathways of extracorporeal photochemotherapy.

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References

  1. Gratwohl A et al. (2002) Current trends in hematopoietic stem cell transplantation in Europe. Blood 100: 2374–2388

    Article  CAS  PubMed  Google Scholar 

  2. Devergie A (2004) Graft vs Host Disease, 163–176. Genoa: Forum Service Editore

    Google Scholar 

  3. Chau NJ (2004) Pharmacology and the use of immunosuppressive agents after hematopoietic cell transplantation. In Thomas' Hematopoietic Cell Transplantation, 209 (eds Blume KG et al.) Oxford: Blackwell

    Google Scholar 

  4. Fefer A (2004) Graft-versus-tumour response. In Thomas' Hematopoietic Stem Cell Transplantation (eds Blume KG et al.) Oxford: Blackwell 369

    Google Scholar 

  5. Bacigalupo A and Palandri F (2004) Management of acute graft versus host disease (GvHD). Hematol J 5: 189–196

    Article  CAS  PubMed  Google Scholar 

  6. Lee SJ et al. (2003) Chronic graft-versus-host disease. Biol Blood Marrow Transplant 9: 215–233

    Article  CAS  PubMed  Google Scholar 

  7. Ullrich SE (2005) Mechanisms underlying UV-induced immune suppression. Mutat Res 571: 185–205

    Article  CAS  PubMed  Google Scholar 

  8. Cridland NA and Saunders RD (1994) Cellular and molecular effects of UVA and UVB. Norwich: HMSO

    Google Scholar 

  9. Fahmy IR and Abushady H (1947) Ammi majus Linn: pharmacological study and isolation of a cristalline constituent, ammoidin. Q J Pharm Pharmacol 20: 281–291

    CAS  PubMed  Google Scholar 

  10. Heshmati F (2003) Mechanisms of action of extracorporeal photochemotherapy. Transfus Apher Sci 29: 61–70

    Article  CAS  PubMed  Google Scholar 

  11. Parrish JA et al. (1974) Photochemotherapy of psoriasis with oral methoxalen and long wavelength ultraviolet light. N Engl J Med 29: 1207–1211

    Article  Google Scholar 

  12. Morison WL (2004) Psoralen ultraviolet A therapy in 2004. Photodermatol Photoimmunol Photomed 20: 315–320

    Article  PubMed  Google Scholar 

  13. Edelson R et al. (1987) Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy: preliminary results. N Engl J Med 316: 297–303

    Article  CAS  PubMed  Google Scholar 

  14. Heald P et al. (1992) Treatment of erythrodermic cutaneous T-cell lymphoma with extracorporeal photochemotherapy. J Am Acad Dermatol 27: 427–433

    Article  CAS  PubMed  Google Scholar 

  15. Lundin J and Osterborg A (2004) Therapy for mycosis fungoides. Curr Treat Options Oncol 5: 203–214

    Article  PubMed  Google Scholar 

  16. Berger CL et al. (2005) Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells. Blood 105: 1640–1647

    Article  CAS  PubMed  Google Scholar 

  17. Knobler R and Girardi M (2001) Extracorporeal photochemoimmunotherapy in cutaneous T cell lymphomas. Ann NY Acad Sci 941: 123–138

    Article  CAS  PubMed  Google Scholar 

  18. Schooneman F (2003) Extracorporeal photopheresis technical aspects. Transfus Apheresis Sci 28: 51–61

    Article  CAS  Google Scholar 

  19. Barr ML et al. (1998) Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group. N Engl J Med 339: 1744–1751

    Article  CAS  PubMed  Google Scholar 

  20. Andreu G et al. (1995) Extracorporeal photochemotherapy treatment for acute lung rejection episode. J Heart Lung Transplant 14: 793–796

    CAS  PubMed  Google Scholar 

  21. Horina JH et al. (1995) Photopheresis for renal allograft rejection. Lancet 346: 61

    Article  CAS  PubMed  Google Scholar 

  22. Menkes CJ et al. (1992) Extracorporeal photochemotherapy. Br J Rheumatol 31: 789–790

    Article  CAS  PubMed  Google Scholar 

  23. Rook AH et al. (1992) Treatment of systemic sclerosis with extracorporeal photochemotherapy. Results of a multicenter trial. Arch Dermatol 128: 337–346

    Article  CAS  PubMed  Google Scholar 

  24. Knobler RM (1994) Extracorporeal photochemotherapy for the treatment of lupus erythematosus: preliminary observations. Springer Semin Immunopathol 16: 323–325

    Article  CAS  PubMed  Google Scholar 

  25. Rook AH et al. (1990) Extracorporeal photochemotherapy for drug-resistant pemphigus vulgaris. Ann Intern Med 112: 303–305

    Article  CAS  PubMed  Google Scholar 

  26. de Misa RF et al. (1992) Extracorporeal photochemotherapy in the treatment of severe psoriatic arthropathy. Br J Dermatol 127: 448

    Article  CAS  PubMed  Google Scholar 

  27. Prinz B et al. (1994) Treatment of severe atopic dermatitis with extracorporeal photopheresis. Arch Dermatol Res 287: 48–52

    Article  CAS  PubMed  Google Scholar 

  28. Reinisch W et al. (2001) Extracorporeal photochemotherapy in patients with steroid-dependent Crohn's disease: a prospective pilot study. Aliment Pharmacol Ther 15: 1313–1322

    Article  CAS  PubMed  Google Scholar 

  29. Rossetti F et al. (1996) Extracorporeal photochemotherapy for the treatment of graft-versus-host disease. Bone Marrow Transplant 18 (Suppl 2): S175–S181

    Google Scholar 

  30. Dall'Amico R and Messina C (2002) Extracorporeal photochemotherapy for the treatment of graft-versus-host disease. Ther Apher 6: 296–304

    Article  CAS  PubMed  Google Scholar 

  31. Carpenter PA and Sanders JE (2003) Steroid-refractory graft-vs.-host disease: past, present and future. Pediatr Transplant 7: 19–31

    Article  PubMed  Google Scholar 

  32. Messina C et al. (2003) Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell transplantation. Br J Haematol 122: 118–127

    Article  CAS  PubMed  Google Scholar 

  33. Smith EP et al. (1998) Extracorporeal photochemotherapy for treatment of drug-resistant graft-vs.-host disease. Biol Blood Marrow Transplant 4: 27–37

    Article  CAS  PubMed  Google Scholar 

  34. Miller JL et al. (1998) Extracorporeal photochemotherapy in the treatment of graft-versus-host disease. In Abstract Book of the International Bone Marrow Transplant Registry/Autologous Bone Marrow Transplant Registry Meeting: Keystone Resort Colorado, 7a

    Google Scholar 

  35. Salvaneschi L et al. (2001) Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood. Transfusion 41: 1299–1305

    Article  CAS  PubMed  Google Scholar 

  36. Besnier DP et al. (1997) Treatment of graft-versus-host disease by extracorporeal photochemotherapy: a pilot study. Transplantation 64: 49–54

    Article  CAS  PubMed  Google Scholar 

  37. Child FJ et al. (1999) Extracorporeal photopheresis (ECP) in the treatment of chronic graft-versus-host disease (GVHD) [see comment]. Bone Marrow Transplant 23: 881–887

    Article  CAS  PubMed  Google Scholar 

  38. Apisarnthanarax N et al. (2003) Extracorporeal photopheresis therapy in the management of steroid-refractory or steroid-dependent cutaneous chronic graft-versus-host disease after allogeneic stem cell transplantation: feasibility and results. Bone Marrow Transplant 31: 459–465

    Article  CAS  PubMed  Google Scholar 

  39. Zic JA et al. (1999) The North American experience with photopheresis. Ther Apher 3: 50–62

    Article  CAS  PubMed  Google Scholar 

  40. Martin PJ et al. (1991) A retrospective analysis of therapy for acute graft-versus-host disease: secondary treatment. Blood 77: 1821–1828

    CAS  PubMed  Google Scholar 

  41. Besnier DP et al. (1997) Treatment of graft-versus-host disease by extracorporeal photochemotherapy: a pilot study. Transplantation 64: 49–54

    Article  CAS  PubMed  Google Scholar 

  42. Greinix HT et al. (1998) Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood 92: 3098–3104

    CAS  PubMed  Google Scholar 

  43. Kanold J et al. (2003) Extracorporeal photochemotherapy for graft versus host disease in pediatric patients. Transfus Apheresis Sci 28: 71–80

    Article  Google Scholar 

  44. Bisaccia E et al. (2003) Treating refractory chronic graft-versus-host disease with extracorporeal photochemotherapy. Bone Marrow Transplant 31: 291–294

    Article  CAS  PubMed  Google Scholar 

  45. Rubegni P et al. (2005) Role of extracorporeal photochemotherapy in patients with refractory chronic graft-versus-host disease. Br J Haematol 130: 271–275

    Article  CAS  PubMed  Google Scholar 

  46. Foss F et al. (2005) Prospective study of extracorporeal photophoresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors. Bone Marrow Transplant 35: 1187–1193

    Article  CAS  PubMed  Google Scholar 

  47. Greinix HT et al. (2000) Extracorporeal photochemotherapy in the treatment of severe steroid-refractory acute graft-versus-host disease: a pilot study. Blood 96: 2426–2431

    CAS  PubMed  Google Scholar 

  48. Ullrich SE (1991) Photoinactivation of T-cell function with psoralen and UVA irradiation suppresses the induction of experimental murine graft-versus-host disease across major histocompatability barriers. J Invest Dermatol 96: 303–308

    Article  CAS  PubMed  Google Scholar 

  49. Miller KB et al. (2004) A novel reduced intensity regimen for allogeneic hematopoietic stem cell transplantation associated with a reduced incidence of graft-versus-host disease. Bone Marrow Transplant 33: 881–889

    Article  CAS  PubMed  Google Scholar 

  50. Shaughnessy PJ et al. (2004) A multi-institutional study of extracorporeal photoimmune therapy with UVADEX® for the prevention of acute GVHD in patients undergoing standard myeloablative conditioning and allogeneic hematopoietic stem cell transplantation [abstract #1230]. Blood 104

  51. Kanold J et al. (2005) Update on extracorporeal photochemotherapy for graft-versus-host disease treatment. Bone Marrow Transplant 35 (Suppl 1): S69–S71

    Article  PubMed  Google Scholar 

  52. Seaton ED et al. (2003) Influence of extracorporeal photopheresis on clinical and laboratory parameters in chronic graft-versus-host disease and analysis of predictors of response. Blood 102: 1217–1223

    Article  CAS  PubMed  Google Scholar 

  53. Lim HW and Edelson RL (1995) Photopheresis for the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 9: 1117–1126

    Article  CAS  PubMed  Google Scholar 

  54. Suchin KR et al. (1999) Extracorporeal photochemotherapy does not suppress T- or B-cell responses to novel or recall antigens. J Am Acad Dermatol 41: 980–986

    Article  CAS  PubMed  Google Scholar 

  55. Laroche L et al. (1991) Antigen-specific tolerance induced by autoimmunization with photoinactivated syngeneic effector cells. Ann NY Acad Sci 636: 113–123

    Article  CAS  PubMed  Google Scholar 

  56. Perez M et al. (1992) Induction of a cell-transferable suppression of alloreactivity by photodamaged lymphocytes. Transplantation 54: 896–903

    Article  CAS  PubMed  Google Scholar 

  57. Maeda A et al. (2005) Intravenous infusion of syngeneic apoptotic cells by photopheresis induces antigen-specific regulatory T cells. J Immunol 174: 5968–5976

    Article  CAS  PubMed  Google Scholar 

  58. Perez MR et al. (1989) Inhibition of anti-skin allograft immunity by infusion with syngeneic photoinactivated effector lymphocytes. J Invest Dermatol 92: 669–676

    Article  CAS  PubMed  Google Scholar 

  59. Yoo EK et al. (1996) Apoptosis induction of ultraviolet light A and photochemotherapy in cutaneous T-cell lymphoma: relevance to mechanism of therapeutic action. J Invest Dermatol 107: 235–242

    Article  CAS  PubMed  Google Scholar 

  60. Tambur AR et al. (2000) Extracorporeal photopheresis induces lymphocyte but not monocyte apoptosis. Transplant Proc 32: 747–748

    Article  CAS  PubMed  Google Scholar 

  61. Berger CL et al. (2001) Induction of human tumor-loaded dendritic cells. Int J Cancer 91: 438–447

    Article  CAS  PubMed  Google Scholar 

  62. French LE et al. (2002) Identification of amplified clonal T cell populations in the blood of patients with chronic graft-versus-host disease: positive correlation with response to photopheresis. Bone Marrow Transplant 30: 509–515

    Article  CAS  PubMed  Google Scholar 

  63. Tokura Y (1999) Modulation of cytokine production by 8-methoxypsoralen and UVA. J Dermatol Sci 19: 114–122

    Article  CAS  PubMed  Google Scholar 

  64. Kim EJ et al. (2005) Immunopathogenesis and therapy of cutaneous T cell lymphoma. J Clin Invest 115: 798–812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Craciun LI et al. (2002) Increased production of interleukin-10 and interleukin-1 receptor antagonist after extracorporeal photochemotherapy in chronic graft-versus-host disease. Transplantation 74: 995–1000

    Article  CAS  PubMed  Google Scholar 

  66. Savill J et al. (2002) A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2: 965–975

    Article  CAS  PubMed  Google Scholar 

  67. Sakaguchi S et al. (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155: 1151–1164

    CAS  PubMed  Google Scholar 

  68. Edinger M et al. (2003) CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 9: 1144–1150

    Article  CAS  PubMed  Google Scholar 

  69. Clark FJ et al. (2004) Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25 high regulatory T-cells. Blood 103: 2410–2416

    Article  CAS  PubMed  Google Scholar 

  70. Lamioni A et al. (2005) The immunological effects of extracorporeal photopheresis unraveled: induction of tolerogenic dendritic cells in vitro and regulatory T cells in vivo. Transplantation 79: 846–850

    Article  PubMed  Google Scholar 

  71. Gimmi CD et al. (1993) Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation. Proc Natl Acad Sci USA 90: 6586–6590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Fresnay S et al. (2003) Can tolerogenic dendritic cells help to modulate allo-immune responses in the setting of hematopoietic cell transplantation? Transplant Immunol 11: 259–266

    Article  CAS  Google Scholar 

  73. Liu YJ et al. (2001) Dendritic cell lineage, plasticity and cross-regulation. Nat Immunol 2: 585–589

    Article  CAS  PubMed  Google Scholar 

  74. Gorgun G et al. (2002) Immunological mechanisms of extracorporeal photochemotherapy in chronic graft-versus-host disease. Blood 100: 941–947

    Article  CAS  PubMed  Google Scholar 

  75. Plumas J et al. (2003) Mechanisms of action of extracorporeal photochemotherapy in the control of GVHD: involvement of dendritic cells. Leukemia 17: 2061–2062

    Article  CAS  PubMed  Google Scholar 

  76. Banchereau J and Palucka K (2005) Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol 5: 296–306

    Article  CAS  PubMed  Google Scholar 

  77. Berger CL et al. (2002) Transimmunization, a novel approach for tumor immunotherapy. Transfus Apher Sci 26: 205–216

    Article  PubMed  Google Scholar 

  78. Salskov-Iversen M and Berger CL (2005) Rapid construction of dendritic cell vaccine through physical perturbation and apoptotic malignant T cell loading. J Immune Based Ther Vaccines 3: 4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Berger CL et al. (2001) Induction of human tumor-loaded dendritic cells. Int J Cancer 91: 438–447

    Article  CAS  PubMed  Google Scholar 

  80. Spisek R et al. (2006) Maturation state of dendritic cells during the extracorporeal photopheresis and its relevance for the treatment of chronic graft-versus-host disease. Transfusion 46: 55–65

    Article  CAS  PubMed  Google Scholar 

  81. Girardi M et al. (2006) Transimmunization for cutaneous T cell lymphoma: a phase I study. Leuk Lymphoma, in press

    Google Scholar 

  82. Lee S et al. (2004) Extracorporeal photopheresis in graft-versus-host disease: ultraviolet radiation mediates T cell senescence in vivo. Transplantation 78: 484–485

    Article  PubMed  Google Scholar 

  83. Wolnicka-Glubisz A et al. (2002) Apoptosis in leukocytes induced by UVA in the presence of 8-methoxypsoralen, chlorpromazine or 4,6,4'-trimethylangelicin. J Photochem Photobiol B 68: 65–72

    Article  CAS  PubMed  Google Scholar 

  84. van Iperen HP et al. (1996) The lack of efficacy of 4,6,6´-trimethylangelicin to induce immune suppression in an animal model for photopheresis: a comparison with 8-MOP. Photochem Photobiol 63: 577–582

    Article  CAS  PubMed  Google Scholar 

  85. Walterscheid JP et al. (2002) Platelet-activating factor, a molecular sensor for cellular damage, activates systemic immune suppression. J Exp Med 195: 171–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Chung HT et al. (1986) Involvement of prostaglandins in the immune alterations caused by the exposure of mice to ultraviolet radiation. J Immunol 137: 2478–2484

    CAS  PubMed  Google Scholar 

  87. Rivas JM and Ullrich SE (1992) Systemic suppression of delayed-type hypersensitivity by supernatants from UV-irradiated keratinocytes. An essential role for keratinocyte-derived IL-10. J Immunol 149: 3865–3871

    CAS  PubMed  Google Scholar 

  88. Rivas JM and Ullrich SE (1994) The role of IL-4, IL-10, and TNF-alpha in the immune suppression induced by ultraviolet radiation. J Leukoc Biol 56: 769–775

    Article  CAS  PubMed  Google Scholar 

  89. Sniecinski I et al. (1995) Extracorporeal photochemotherapy for treatment of drug resistant chronic graft-vs-host disease. J Clin Apheresis 10: 51–60

    Google Scholar 

  90. Sniecinski I et al. (1998) Extracorporeal photopheresis (EP) is effective treatment for chronic refractory graft versus host disease. Blood 92 (Suppl 1): 454a

    Google Scholar 

  91. Marshall SR et al. (2006) Phase II prospective study of extracorporeal phototherapy for treatment of refractory chronic extensive graft-versus-host disease performed in Newcastle Upon Tyne. Br J Haem 133 (Suppl 1): S5

    Google Scholar 

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  1. specialist registrar in hematology in the Department of Haematological Sciences, School of Clinical and Laboratory Sciences, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK

    Scott R Marshall

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Marshall, S. Technology Insight: ECP for the treatment of GvHD—can we offer selective immune control without generalized immunosuppression?. Nat Rev Clin Oncol 3, 302–314 (2006). https://doi.org/10.1038/ncponc0511

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