Skip to main content

Advertisement

SpringerLink
Log in

Alefacept therapy reduces the effector T-cell population in lesional psoriatic epidermis

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

Abstract

Alefacept, a LFA-3/IgG1 fusion protein, interferes with the activation and proliferation of T cells by binding to the CD2 receptor on their surfaces. The clinical efficacy of this drug has been demonstrated in chronic plaque psoriasis. We performed a single-center, open-label study to investigate the immunohistochemical effects in psoriatic lesional skin. A group of 11 patients with plaque psoriasis all received 12 weekly doses of 7.5 mg alefacept intravenously. Skin biopsies were obtained at baseline and on days 8, 43 and 92, and were evaluated by digital image analysis after immunohistochemical staining. After completion of treatment, 8 out of the 11 patients experienced a reduction in PASI of 50% or more compared to baseline. Immunohistochemical analysis displayed a gradual decrease in the number of cutaneous T cells during therapy, with a significant reduction in epidermal CD8+ cells and dermal CD4+ cells on day 92. Patients with a reduction in PASI of 50% or more after therapy had a clearance of effector/memory T cells from the epidermis, in contrast to patients with a reduction in PASI of less than 50%. These findings support the hypothesis that effector/memory T cells play a prominent role in the pathogenesis of psoriasis, and that alefacept is capable of reducing these cells in lesional psoriatic skin.

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. 2a–d
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Austin LM, Coven TR, Bhardwaj N, Steinman R, Krueger JG (1998) Intraepidermal lymphocytes in psoriatic lesions are activated GMP-17 (TIA-1)+CD8+CD3+ CTLs as determined by phenotypic analysis. J Cutan Pathol 25:79–88

    CAS  PubMed  Google Scholar 

  • Baker BS, Swain AF, Fry L, Valdimarsson H (1984) Epidermal T lymphocytes and HLA-DR expression in psoriasis. Br J Dermatol 110:555–564

    CAS  PubMed  Google Scholar 

  • Baker BS, Griffiths CEM, Lambert S, Powles AV, Leonard JN, Valdimarsson H, Fry L (1987) The effects of cyclosporin A on T lymphocytes and dendritic cell sub-populations in psoriasis. Br J Dermatol 116:503–510

    CAS  PubMed  Google Scholar 

  • Bjerke JR (1982) In situ characterization and counting of mononuclear cells in lesions of different clinical forms of psoriasis. Acta Derm Venereol 62:93–100

    CAS  PubMed  Google Scholar 

  • Bjerke JR, Krogh H-K, Matre R (1978) Characterization of mononuclear cell infiltrates in psoriatic lesions. J Invest Dermatol 71:340–343

    CAS  PubMed  Google Scholar 

  • Bos JD, Hulsebosch HJ, Krieg SR, Bakker PM, Cormane RH (1983) Immunocompetent cells in psoriasis. In situ phenotyping by monoclonal antibodies. Arch Dermatol Res 275:181–189

    CAS  PubMed  Google Scholar 

  • Bos JD, Hagenaars C, Das PK, Krieg SR, Voorn WJ, Kapsenberg ML (1989) Predominance of “memory” T cells (CD4+, CDw29+) over “naive” T cells (CD4+, CD45R+) in both normal and diseased human skin. Arch Dermatol Res 281:24–30

    CAS  PubMed  Google Scholar 

  • Cooper JC, Morgan G, Harding S, Subramanyam M, Majeau GR, Moulder K, Alexander DR (2003) Alefacept selectively promotes NK cell-mediated deletion of CD45R0+ human T cells. Eur J Immunol 33:666–675

    Article  CAS  PubMed  Google Scholar 

  • Danielian S, Fagard R, Alcover A, Acuto O, Fischer S (1991) The tyrosine kinase activity of p56lck is increased in human T cells activated via CD2. Eur J Immunol 21:1967–1970

    CAS  PubMed  Google Scholar 

  • Da Silva AJ, Brickelmaier M, Majeau GR, Li Z, Su L, Hsu Y-M, Hochman PS (2002) Alefacept, an immunomodulatory recombinant LFA-3/IgG1 fusion protein, induces CD16 signalling and CD2/CD16-dependent apoptosis of CD2+ cells. J Immunol 168:4462–4471

    PubMed  Google Scholar 

  • Dustin ML, Springer TA (1991) Role of lymphocyte adhesion receptors in transient interactions and cell locomotion. Annu Rev Immunol 9:27–66

    Article  CAS  PubMed  Google Scholar 

  • Dustin ML, Sanders ME, Shaw S, Springer TA (1987) Purified lymphocyte function-associated antigen-3 (LFA-3) binds to CD2 and mediates T lymphocyte adhesion. J Exp Med 165:677–692

    CAS  PubMed  Google Scholar 

  • Ellis CN, Krueger GG (2001) Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. New Engl J Med 345:248–255

    Article  CAS  PubMed  Google Scholar 

  • Ferenczi K, Burack L, Pope M, Krueger JG, Austin LM (2000) CD69, HLA-DR and the IL-2R identify persistently activated T cells in psoriasis vulgaris lesional skin: blood and skin comparisons by flow cytometry. J Autoimmun 14:63–78

    Article  CAS  PubMed  Google Scholar 

  • Gottlieb AB, Lifshitz B, Fu SM, Staiano-Coico L, Wang CY, Carter DM (1986) Expression of HLA-DR molecules by keratinocytes, and presence of Langerhans cells in the dermal infiltrate of active psoriatic plaques. J Exp Med 164:1013–1028

    CAS  PubMed  Google Scholar 

  • Gottlieb AB, Grossman RM, Khandke L, Carter DM, Sehgal PB, Fu SM, Granelli-Piperno A, Rivas M, Barazani L, Krueger JG (1992) Studies of the effect of cyclosporine in psoriasis in vivo: combined effects on activated T lymphocytes and epidermal regenerative maturation. J Invest Dermatol 98:302–309

    CAS  PubMed  Google Scholar 

  • Gottlieb AB, Krueger JG, Wittkowski K, Dedrick R, Walicke PA, Garovoy M (2002) Psoriasis as a model for T-cell mediated disease. Immunobiologic and clinical effects of treatment with multiple doses of Efalizumab, an anti-CD11a antibody. Arch Dermatol 138:591–600

    CAS  PubMed  Google Scholar 

  • Gottlieb SL, Gilleaudeau P, Johnson R, Estes L, Woodworth TG, Gottlieb AB, Krueger JG (1995) Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat Med 1:442–447

    CAS  PubMed  Google Scholar 

  • Griffiths CEM, Voorhees JJ, Nickoloff BJ (1989) Characterization of ICAM-1 and HLA-DR expression in normal and inflamed skin: modulation by recombinant IFN-gamma and TNF-alpha. J Am Acad Dermatol 20:617–629

    CAS  PubMed  Google Scholar 

  • Hammar H, Gu S-Q, Johannesson A, Sundkvist K-G, Biberfeld P (1984) Subpopulations of mononuclear cells in microscopic lesions of psoriatic patients. Selective accumulation of suppressor/cytotoxic T cells in epidermis during evolution of the lesion. J Invest Dermatol 83:416–420

    CAS  PubMed  Google Scholar 

  • Henseler T, Christophers E (1985) Psoriasis of early and late-onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol 13:450–456

    CAS  PubMed  Google Scholar 

  • June CH, Fletcher MC, Ledbetter JA, Samelson LE (1990) Increases in tyrosine phosphorylation are detectable before phospholipase C activation after T cell receptor stimulation. J Immunol 144:1591–1599

    CAS  PubMed  Google Scholar 

  • Kobayashi S, Sugiyama H, Gyulai R, McCormick T, Korman N, Stevens S, Cooper K, Vaishnaw A, Shrager D (2001) Alefacept treatment for psoriasis reduces the number of infiltrating IFN-γ+-producing T cells in lesional skin (abstract). J Invest Dermatol 117:546

    Google Scholar 

  • Kraan MC, Haringman JJ, Ahern MJ, Breedveld FC, Smith MD, Tak PP (2000) Quantification of the cell infiltrate in synovial tissue by digital image analysis. Rheumatology (Oxford) 39:43–49

  • Kraan MC, van Kuijk AWR, Dinant HJ, Goedkoop, Smeets TJM, de Rie MA, Dijkmans BAC, Vaishnaw AK, Bos JD, Tak PP (2002) Alefacept treatment in psoriatic arthritis. Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis. Arthritis Rheum 46:2776–2784

    Article  CAS  PubMed  Google Scholar 

  • Krueger JG, Wolfe JT, Nabeya RT, Vallat VP, Gilleaudeau P, Heftler NS, Austin LM, Gottlieb AB (1995) Successful ultraviolet B treatment of psoriasis is accompanied by a reversal of keratinocyte pathology and by selective depletion of intraepidermal T cell. J Exp Med 182:2057–2068

    CAS  PubMed  Google Scholar 

  • Krueger JG, Gilleaudeau P, Kikuchi T, Lee E (2002) Alefacept selectively reduces subpopulations of memory CD4+ and CD8+ T cells (abstract). J Invest Dermatol 119:759

    Google Scholar 

  • Majeau GR, Meier W, Jimmo B, Kioussis D, Hochman PS (1994) Mechanism of lymphocyte function-associated molecule 3-Ig fusion proteins inhibition of T cell responses. Structure/function analysis in vitro and in human CD2 transgenic mice. J Immunol 152:2753–2767

    CAS  PubMed  Google Scholar 

  • Miller GT, Hochman PS, Meier W, Tizard R, Bixler SA, Rosa MD, Wallner B (1993) Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses. J Exp Med 178:211–222

    CAS  PubMed  Google Scholar 

  • Morganroth GS, Lawrence SC, Weinstein GD, Voorhees JJ, Cooper KD (1991) Proliferating cells in psoriatic dermis are comprised primarily of T cells, endothelial cells, and factor XIIIa+ perivascular cells. J Invest Dermatol 96:333–340

    CAS  PubMed  Google Scholar 

  • Reich K, Mossner R, Koning IR, Westphal G, Ziegler A, Neumann C (2002) Promoter polymorphisms of the genes encoding tumor necrosis factor-α and interleukin-1β are associated with different subtypes of psoriasis characterized by early and late disease onset. J Invest Dermatol 118:155–163

    Google Scholar 

  • Sanders ME, Makgoba MW, Sharrow SO, Stephany D, Springer TA, Young HA, Shaw S (1988) Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and have three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-γ production. J Immunol 140:1401–1407

    CAS  PubMed  Google Scholar 

  • Schlaak JF, Buslau M, Jochum W, Hermann E, Girndt M, Gallati H, Meyer zum Buschenfelde KH, Fleischer B (1994) T cells involved in psoriasis vulgaris belong to the Th1 subset. J Invest Dermatol 102:145–149

    CAS  PubMed  Google Scholar 

  • Springer TA, Dustin ML, Kishimoto TK, Marlin SD (1987) The lymphocyte function-associated LFA-1, CD2, and LFA-3 molecules: cell adhesion receptors of the immune system. Annu Rev Immunol 5:223–252

    CAS  PubMed  Google Scholar 

  • Uyemura K, Yamamura M, Fivenson DF, Modlin RL, Nickoloff BJ (1993) The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J Invest Dermatol 101:701–705

    CAS  PubMed  Google Scholar 

  • Vallat VP, Gilleaudeau P, Battat L, Wolfe J, Nabeya R, Heftler N, Hodak E, Gottlieb AB, Krueger JG (1994) PUVA bath therapy strongly suppresses immunological and epidermal activation in psoriasis: a possible cellular basis for remittive therapy. J Exp Med 180:283–296

    CAS  PubMed  Google Scholar 

  • Wallace DL, Beverley PC (1990) Phenotypic changes associated with activation of CD45RA+ and CD45RO+ T cells. Immunology 69:460–467

    CAS  PubMed  Google Scholar 

  • Wawryk SO, Novotny JR, Wicks IP, Wilkinson D, Maher D, Salvaris E, Welch K, Fecondo J, Boyd AW (1989) The role of the LFA-ICAM-1 interaction in human leukocyte homing and adhesion. Immunol Rev 108:135–161

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This investigator-initiated study was supported by a grant from Biogen Inc., Cambridge, Massachusetts, who also provided the alefacept.

Author information

Authors and Affiliations

  1. Department of Dermatology, Academic Medical Center, University of Amsterdam, P.O. Box 22660, 1100 DD, Amsterdam, The Netherlands

    Amber Y. Goedkoop, Menno A. de Rie, Daisy I. Picavet, Jan D. Bos & Marcel B. M. Teunissen

  2. Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, Academic Medical Center, University of Amsterdam, P.O. Box 22660, 1100 DD, Amsterdam, The Netherlands

    Amber Y. Goedkoop, Maarten C. Kraan, Huib J. Dinant, Arno W. R. van Kuijk & Paul P. Tak

  3. Jan van Breemen Institute, Dr. J. van Breemenstraat 2, 1056 AB, Amsterdam, The Netherlands

    Huib J. Dinant & Arno W. R. van Kuijk

Authors
  1. Amber Y. Goedkoop
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Menno A. de Rie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daisy I. Picavet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maarten C. Kraan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huib J. Dinant
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Arno W. R. van Kuijk
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paul P. Tak
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jan D. Bos
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marcel B. M. Teunissen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amber Y. Goedkoop.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goedkoop, A.Y., de Rie, M.A., Picavet, D.I. et al. Alefacept therapy reduces the effector T-cell population in lesional psoriatic epidermis. Arch Dermatol Res 295, 465–473 (2004). https://doi.org/10.1007/s00403-004-0450-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-004-0450-y

Keywords

Search

Navigation