Abstract
Narrowband ultraviolet B phototherapy (NB-UVB) is a therapeutic alternative for haematopoietic stem cell transplantation-related skin graft-versus-host disease (GVHD). The beneficial effects of this intervention may be induced by direct irradiation of inflammatory cells in the skin; however, the putative involvement of indirect effects on systemic immunity has not been elucidated. To address this issue, 11 acute skin GVHD patients refractory to standard corticosteroid treatment and with no gut/liver involvement were treated with NB-UVB irradiation. The median number of treatments was 10 times, with a mean cumulative exposure of 6.36 J/cm2. No other immunosuppressive therapy was initiated during irradiation. Eight patients achieved an objective complete response, two had a partial response, and one showed no change. None of the patients experienced progressive skin GVHD or newly diagnosed gut/liver GVHD. NB-UVB was well tolerated, with no patients discontinuing irradiation due to toxicity. We additionally demonstrated by flow cytometry that NB-UVB irradiation induces the increment of the proportion of regulatory T cell (Tregs) in patients’ peripheral blood. These results suggest that NB-UVB may exert beneficial effects on steroid-refractory skin GVHD through the expansion of Tregs.
Similar content being viewed by others
References
Ferrara JL, Deeg HJ. Graft-versus-host disease. N Engl J Med. 1991;324:667–74.
Barrett J. Graft-versus-host disease. In: Barrett AJ, Treleaven J, editors. Bone marrow transplantation in practice. Edinburgh: Churchill Linvingstone; 1992. p. 257.
Klingebiel T, Schlegel PG. GVHD: overview on pathophysiology, incidence, clinical and biological features. Bone Marrow Transplant. 1998;21(Suppl 2):S45–9.
Weisdorf D, Haake R, Blazar B, Miller W, McGlave P, Ramsay N, et al. Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome. Blood. 1990;75:1024–30.
Martin PJ, Schoch G, Fisher L, Byers V, Anasetti C, Appelbaum FR, et al. A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment. Blood. 1990;76:1464–72.
Teshima T, Ferrara JL. Understanding the alloresponse: new approaches to graft-versus-host disease prevention. Semin Hematol. 2002;39:15–22.
Ferrara JL, Levy R, Chao NJ. Pathophysiologic mechanisms of acute graft-vs.-host disease. Biol Blood Marrow Transplant. 1999;5:347–56.
Martin PJ, Schoch G, Fisher L, Byers V, Appelbaum FR, McDonald GB, et al. A retrospective analysis of therapy for acute graft-versus-host disease: secondary treatment. Blood. 1991;77:1821–8.
Hymes SR, Morison WL, Farmer ER, Walters LL, Tutschka PJ, Santos GW. Methoxsalen and ultraviolet A radiation in treatment of chronic cutaneous graft-versus-host reaction. J Am Acad Dermatol. 1985;12:30–7.
Vogelsang GB, Wolff D, Altomonte V, Farmer E, Morison WL, Corio R, et al. Treatment of chronic graft-versus-host disease with ultraviolet irradiation and psoralen (PUVA). Bone Marrow Transplant. 1996;17:1061–7.
Furlong T, Leisenring W, Storb R, Anasetti C, Appelbaum FR, Carpenter PA, et al. Psoralen and ultraviolet A irradiation (PUVA) as therapy for steroid-resistant cutaneous acute graft-versus-host disease. Biol Blood Marrow Transplant. 2002;8:206–12.
Grundmann-Kollmann M, Martin H, Ludwig R, Klein S, Boehncke WH, Hoelzer D, et al. Narrowband UV-B phototherapy in the treatment of cutaneous graft versus host disease. Transplantation. 2002;74:1631–4.
Feldstein JV, Bolanos-Meade J, Anders VL, Abuav R. Narrowband ultraviolet B phototherapy for the treatment of steroid-refractory and steroid-dependent acute graft-versus-host disease of the skin. J Am Acad Dermatol. 2011;65:733–8.
Coimbra S, Oliveira H, Reis F, Belo L, Rocha S, Quintanilha A, et al. Interleukin (IL)-22, IL-17, IL-23, IL-8, vascular endothelial growth factor and tumour necrosis factor-alpha levels in patients with psoriasis before, during and after psoralen-ultraviolet A and narrowband ultraviolet B therapy. Br J Dermatol. 2010;163:1282–90.
Shin HJ, Baker J, Leveson-Gower DB, Smith AT, Sega EI, Negrin RS. Rapamycin and IL-2 reduce lethal acute graft-versus-host disease associated with increased expansion of donor type CD4+CD25+Foxp3+ regulatory T cells. Blood. 2011;118:2342–50.
Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP 3rd, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365:2055–66.
Ngoma AM, Ikeda K, Hashimoto Y, Mochizuki K, Takahashi H, Sano H, et al. Impaired regulatory T cell reconstitution in patients with acute graft-versus-host disease and cytomegalovirus infection after allogeneic bone marrow transplantation. Int J Hematol. 2012;95:86–94.
Westin JR, Saliba RM, De Lima M, Alousi A, Hosing C, Qazilbash MH, et al. Steroid-refractory acute GVHD: predictors and outcomes. Adv Hematol. 2011;2011:601953.
Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–87.
Hart JW, Shiue LH, Shpall EJ, Alousi AM. Extracorporeal photopheresis in the treatment of graft-versus-host disease: evidence and opinion. Ther Adv Hematol. 2013;4:320–34.
Kreutz M, Karrer S, Hoffmann P, Gottfried E, Szeimies RM, Hahn J, et al. Whole-body UVB irradiation during allogeneic hematopoietic cell transplantation is safe and decreases acute graft-versus-host disease. J Invest Dermatol. 2012;132:179–87.
Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003;198:1875–86.
Lee HS, Kooshesh F, Sauder DN, Kondo S. Modulation of TGF-beta 1 production from human keratinocytes by UVB. Exp Dermatol. 1997;6:105–10.
Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003;9:1144–50.
Larko O. Treatment of psoriasis with a new UVB-lamp. Acta Derm Venereol. 1989;69:357–9.
Acknowledgments
We appreciate the assistance of the physicians, physician assistants, nurses, and support staff on the transplantation units.
Conflict of interest
This manuscript has not been published or submitted for publication elsewhere. All authors have contributed significantly and are in agreement with the content of the manuscript. We declare that there are no financial support or relationships that may pose conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
12185_2014_1530_MOESM1_ESM.pptx
Supplemental Figure 1. The flowcytometric panels (case #1122) to show changes before and after treatment of the NB-UVB (PPTX 2053 kb)
12185_2014_1530_MOESM2_ESM.pptx
Supplemental Figure 2. Serum TGF-β levels monitoring in five patients with aGVHD. Statistical comparisons were made using the paired t test (p = 0.0390) (PPTX 55 kb)
12185_2014_1530_MOESM3_ESM.pptx
Supplemental Figure 3. Immunohistochemical staining using anti-CD1a antibodies. Complete depletion of the LCs was observed after treatment in two patients (PPTX 12747 kb)
About this article
Cite this article
Iyama, S., Murase, K., Sato, T. et al. Narrowband ultraviolet B phototherapy ameliorates acute graft-versus-host disease by a mechanism involving in vivo expansion of CD4+CD25+Foxp3+ regulatory T cells. Int J Hematol 99, 471–476 (2014). https://doi.org/10.1007/s12185-014-1530-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-014-1530-1