Skip to main content

Advertisement

SpringerLink
Log in

Restoration of peripheral blood T cell repertoire complexity during remission in advanced cutaneous T cell lymphoma

  • Original Paper
  • Published:
Archives of Dermatological Research Aims and scope Submit manuscript

Abstract

In advanced stages, cutaneous T cell lymphomas (CTCL) are associated with increased mortality from infections and also increased susceptibility to skin malignancies. In this study, we analyzed the complexity of the peripheral blood T cell repertoire with a sensitive b-variable (BV) complementarity-determining region 3 (CDR3) spectratyping analysis and flow cytometry in three-stage IV CTCL/Sezary syndrome patients who achieved complete clinical remission after therapy. The T cell repertoire of peripheral blood T cells before treatment was profoundly abnormal across multiple BV subfamilies. Following treatment, CDR3 spectratype patterns showed dramatic restoration of normal diversity and complexity. However, absolute CD4 counts across multiple BV families remained low for many months, even after identifiable circulating malignant T cell populations were eliminated. These data suggest that the diversity of the T cell repertoire can be recovered after successful treatment of even advanced CTCL.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

CTCL:

Cutaneous T cell lymphoma

TREC:

T cell receptor excision circle

IL:

Interleukin

T reg:

Regulatory T cell

BV:

b-Variable

CDR3:

Complementarity-determining region 3

ECP:

Extracorporeal photopheresis

IFN:

Interferon

References

  1. Asadullah K, Haeussler A, Friedrich M, Siegling A, Olaizola-Horn S, Trefzer U, Volk HD, Sterry W (1996) IL-7 mRNA is not overexpressed in mycosis fungoides and pleomorphic T-cell lymphoma and is likely to be an autocrine growth factor in vivo. Arch Dermatol Res 289:9–13

    Article  CAS  PubMed  Google Scholar 

  2. Axelrod PI, Lorber B, Vonderheid EC (1992) Infections complicating mycosis fungoides and Sezary syndrome. JAMA 267:1354–1358

    Article  CAS  PubMed  Google Scholar 

  3. Berger CL, Tigelaar R, Cohen J, Mariwalla K, Trinh J, Wang N, Edelson RL (2005) Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells. Blood 105:1640–1647

    Article  CAS  PubMed  Google Scholar 

  4. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, Nguyen PL, Khoruts A, Larson M, Haase AT, Douek DC (2004) CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 200:749–759

    Article  CAS  PubMed  Google Scholar 

  5. Brownell I, Etzel CJ, Yang DJ, Taylor SH, Duvic M (2008) Increased malignancy risk in the cutaneous T-cell lymphoma patient population. Clin Lymphoma Myeloma 8:100–105

    Article  PubMed  Google Scholar 

  6. Dummer R, Heald PW, Nestle FO, Ludwig E, Laine E, Hemmi S, Burg G (1996) Sezary syndrome T-cell clones display T-helper 2 cytokines and express the accessory factor-1 (interferon-gamma receptor beta-chain). Blood 88:1383–1389

    CAS  PubMed  Google Scholar 

  7. Ehrhard S, Wernli M, Kaufmann G, Pantaleo G, Rizzardi GP, Gudat F, Erb P, Battegay M (2008) Effect of antiretroviral therapy on apoptosis markers and morphology in peripheral lymph nodes of HIV-infected individuals. Infection 36:120–129

    Article  CAS  PubMed  Google Scholar 

  8. Evans a V, Scarisbrick JJ, Child FJ, Acland KM, Whittaker SJ, Russell-Jones R (2004) Cutaneous malignant melanoma in association with mycosis fungoides. J Am Acad Dermatol 50:701–705

    Article  PubMed  Google Scholar 

  9. Ferenczi K, Mckee P, Kupper TS (2000) Cutaneous lymphoma. Atlas of clinical oncology. BC Decker, Hamilton, ON, pp 85–117

  10. Ferenczi K, Yawalkar N, Jones D, Kupper TS (2003) Monitoring the decrease of circulating malignant T cells in cutaneous T-cell lymphoma during photopheresis and interferon therapy. Arch Dermatol 139:909–913

    Article  PubMed  Google Scholar 

  11. Goldgeier MH, Cohen SR, Braverman IM, Stenn KS (1981) An unusual and fatal case of disseminated cutaneous herpes simplex. Infection in a patient with cutaneous T cell lymphoma (mycosis fungoides). J Am Acad Dermatol 4:176–180

    Article  CAS  PubMed  Google Scholar 

  12. Hochberg EP, Chillemi AC, Wu CJ, Neuberg D, Canning C, Hartman K, Alyea EP, Soiffer RJ, Kalams SA, Ritz J (2001) Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation in adults. Blood 98:1116–1121

    Article  CAS  PubMed  Google Scholar 

  13. Kim EJ, Hess S, Richardson SK, Newton S, Showe LC, Benoit BM, Ubriani R, Vittorio CC, Junkins-Hopkins JM, Wysocka M, Rook AH (2005) Immunopathogenesis and therapy of cutaneous T cell lymphoma. J Clin Invest 115:798–812

    CAS  PubMed  Google Scholar 

  14. Mukai H, Noguchi T, Kamimura K, Nishioka K, Nishiyama S (1990) Significance of elevated serum LDH (lactate dehydrogenase) activity in atopic dermatitis. J Dermatol 17:477–481

    CAS  PubMed  Google Scholar 

  15. Nguyen V, Huggins RH, Lertsburapa T, Bauer K, Rademaker A, Gerami P, Guitart J (2008) Cutaneous T-cell lymphoma and Staphylococcus aureus colonization. J Am Acad Dermatol 59:949–952

    Article  PubMed  Google Scholar 

  16. Pielop JA, Brownell I, Duvic M (2003) Mycosis fungoides associated with malignant melanoma and dysplastic nevus syndrome. Int J Dermatol 42:116–122

    Article  CAS  PubMed  Google Scholar 

  17. Poznansky MC, Evans RH, Foxall RB, Olszak IT, Piascik AH, Hartman KE, Brander C, Meyer TH, Pykett MJ, Chabner KT, Kalams SA, Rosenzweig M, Scadden DT (2000) Efficient generation of human T cells from a tissue-engineered thymic organoid. Nat Biotechnol 18:729–734

    Article  CAS  PubMed  Google Scholar 

  18. Raaphorst FM, Schelonka RL, Rusnak J, Infante AJ, Teale JM (2002) TCRBV CDR3 diversity of CD4+ and CD8+ T-lymphocytes in HIV-infected individuals. Hum Immunol 63:51–60

    Article  CAS  PubMed  Google Scholar 

  19. Resino S, Correa R, Bellon JM, Munoz-Fernandez MA (2003) Preserved immune system in long-term asymptomatic vertically HIV-1 infected children. Clin Exp Immunol 132:105–112

    Article  CAS  PubMed  Google Scholar 

  20. Ruiz-Mateos E, De La Rosa R, Franco JM, Martinez-Moya M, Rubio A, Soriano N, Sanchez-Quijano A, Lissen E, Leal M (2003) Endogenous IL-7 is associated with increased thymic volume in adult HIV-infected patients under highly active antiretroviral therapy. Aids 17:947–954

    Article  CAS  PubMed  Google Scholar 

  21. Schelonka RL, Raaphorst FM, Infante D, Kraig E, Teale JM, Infante AJ (1998) T cell receptor repertoire diversity and clonal expansion in human neonates. Pediatr Res 43:396–402

    Article  CAS  PubMed  Google Scholar 

  22. Thomas JM, Newton-Bishop J, A’hern R, Coombes G, Timmons M, Evans J, Cook M, Theaker J, Fallowfield M, O’neill T, Ruka W, Bliss JM (2004) Excision margins in high-risk malignant melanoma. N Engl J Med 350:757–766

    Article  CAS  PubMed  Google Scholar 

  23. Van Grevenynghe J, Halwani R, Chomont N, Ancuta P, Peretz Y, Tanel A, Procopio FA, Shi Y, Said EA, Haddad EK, Sekaly RP (2008) Lymph node architecture collapse and consequent modulation of FOXO3a pathway on memory T- and B-cells during HIV infection. Semin Immunol 20:196–203

    Article  PubMed  Google Scholar 

  24. Vowels BR, Cassin M, Vonderheid EC, Rook AH (1992) Aberrant cytokine production by Sezary syndrome patients: cytokine secretion pattern resembles murine Th2 cells. J Invest Dermatol 99:90–94

    Article  CAS  PubMed  Google Scholar 

  25. Wu CJ, Chillemi A, Alyea EP, Orsini E, Neuberg D, Soiffer RJ, Ritz J (2000) Reconstitution of T-cell receptor repertoire diversity following T-cell depleted allogeneic bone marrow transplantation is related to hematopoietic chimerism. Blood 95:352–359

    CAS  PubMed  Google Scholar 

  26. Yamanaka K, Clark R, Dowgiert R, Hurwitz D, Shibata M, Rich BE, Hirahara K, Jones DA, Eapen S, Mizutani H, Kupper TS (2006) Expression of interleukin-18 and caspase-1 in cutaneous T-cell lymphoma. Clin Cancer Res 12:376–382

    Article  CAS  PubMed  Google Scholar 

  27. Yamanaka K, Clark R, Rich B, Dowgiert R, Hirahara K, Hurwitz D, Shibata M, Mirchandani N, Jones DA, Goddard DS, Eapen S, Mizutani H, Kupper TS (2006) Skin-derived interleukin-7 contributes to the proliferation of lymphocytes in cutaneous T-cell lymphoma. Blood 107:2440–2445

    Article  CAS  PubMed  Google Scholar 

  28. Yamanaka K, Yawalkar N, Jones DA, Hurwitz D, Ferenczi K, Eapen S, Kupper TS (2005) Decreased T-cell receptor excision circles in cutaneous T-cell lymphoma. Clin Cancer Res 11:5748–5755

    Article  CAS  PubMed  Google Scholar 

  29. Yawalkar N, Ferenczi K, Jones DA, Yamanaka K, Suh KY, Sadat S, Kupper TS (2003) Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma. Blood 102:4059–4066

    Article  CAS  PubMed  Google Scholar 

  30. Yoo EK, Cassin M, Lessin SR, Rook AH (2001) Complete molecular remission during biologic response modifier therapy for Sezary syndrome is associated with enhanced helper T type 1 cytokine production and natural killer cell activity. J Am Acad Dermatol 45:208–216

    Article  CAS  PubMed  Google Scholar 

  31. Yoshimoto T, Mizutani H, Tsutsui H, Noben-Trauth N, Yamanaka K, Tanaka M, Izumi S, Okamura H, Paul WE, Nakanishi K (2000) IL-18 induction of IgE: dependence on CD4+ T cells, IL-4 and STAT6. Nat Immunol 1:132–137

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

Grant support: SPORE in Skin Cancer from the NCI/NIH.

Conflicts of interest statement

None identified.

Author information

Authors and Affiliations

  1. Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women’s Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA

    Kei-ichi Yamanaka, Robert C. Fuhlbrigge & Thomas S. Kupper

  2. Department of Dermatology, Graduate School of Medicine, Mie University, 2-174, Edobashi, Tsu, Mie, 514-8507, Japan

    Kei-ichi Yamanaka & Hitoshi Mizutani

Authors
  1. Kei-ichi Yamanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert C. Fuhlbrigge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hitoshi Mizutani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas S. Kupper
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas S. Kupper.

Electronic supplementary material

Below is the link to the electronic supplementary material.

403_2009_1023_MOESM1_ESM.pdf

Supplementary material 1 (pdf 122 kb) Analysis of Patient B shows a markedly reduced spectratype complexity (Panel a) and an expandedmalignant clone (BV 14, Panel c). Analysis of the same patient after CR shows improved CDR3spectratype (Panel b) with the restriction of diverse T cells in the peripheral blood (Panel d)

403_2009_1023_MOESM2_ESM.pdf

Supplementary material 2 (pdf 115 kb) Analysis of Patient C shows a markedly reduced spectratype complexity (Panel a), but dominantclones were undetectable with our panel of TCR BV antibodies (Panel c). Analysis of the patient Cafter CR shows improved CDR3 spectratype (Panel b) with the restriction of diverse T cells in theperipheral blood (Panel d)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamanaka, Ki., Fuhlbrigge, R.C., Mizutani, H. et al. Restoration of peripheral blood T cell repertoire complexity during remission in advanced cutaneous T cell lymphoma. Arch Dermatol Res 302, 453–459 (2010). https://doi.org/10.1007/s00403-009-1023-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-009-1023-x

Keywords

Search

Navigation