Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes.

BACKGROUND Psoriatic plaques are characterized by infiltration with CD4+ CD45RO+ and CD8+ CD45RO+ memory effector T lymphocytes. The recombinant protein alefacept binds to CD2 on memory effector T lymphocytes, inhibiting their activation. METHODS In a multicenter, randomized, placebo-controlled, double-blind study, we evaluated alefacept as a treatment for psoriasis. Two hundred twenty-nine patients with chronic psoriasis received intravenous alefacept (0.025, 0.075, or 0.150 mg per kilogram of body weight) or placebo weekly for 12 weeks, with follow-up for 12 additional weeks. Before treatment, the median scores on the psoriasis area-and-severity index were between 14 and 20 in all groups (0 denotes no psoriasis and 72 the most severe disease possible). RESULTS Alefacept was well tolerated and nonimmunogenic. The mean reduction in the score on the psoriasis area-and-severity index two weeks after treatment was greater in the alefacept groups (38, 53, and 53 percent in the groups receiving 0.025, 0.075, and 0.150 mg per kilogram, respectively) than in the placebo group (21 percent, P<0.001). Twelve weeks after treatment, 28 patients who had received alefacept alone were clear or almost clear of psoriasis. Three patients in the placebo group were clear or almost clear; all three had received additional systemic therapy for psoriasis. Alefacept reduced peripheral-blood memory effector T-lymphocyte (CD45RO+) counts, and the reduction in the number of memory-effector T lymphocytes was correlated with the improvement in psoriasis. CONCLUSIONS Treatment with alefacept for 12 weeks is associated with improvement in chronic plaque psoriasis; some patients have a sustained clinical response after the cessation of treatment. Alefacept selectively targets CD45RO+ memory effector T lymphocytes, suggesting that they have a role in the pathogenesis of psoriasis.

[1]  T Fredriksson,et al.  Severe psoriasis--oral therapy with a new retinoid. , 1978, Dermatologica.

[2]  P. Brottier,et al.  T cell activation via CD2 [T, gp50] molecules: accessory cells are required to trigger T cell activation via CD2-D66 plus CD2-9.6/T11(1) epitopes. , 1985, Journal of immunology.

[3]  C. June,et al.  Increases in tyrosine phosphorylation are detectable before phospholipase C activation after T cell receptor stimulation. , 1990, Journal of immunology.

[4]  Annette J. Dobson,et al.  An introduction to generalized linear models , 1991 .

[5]  J. Voorhees,et al.  Proliferating cells in psoriatic dermis are comprised primarily of T cells, endothelial cells, and factor XIIIa+ perivascular dendritic cells. , 1991, The Journal of investigative dermatology.

[6]  A. Alcover,et al.  The tyrosine kinase activity of p56lck is increased in human T cells activated via CD2 , 1991, European journal of immunology.

[7]  T. Annesley,et al.  Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial. , 1991, The New England journal of medicine.

[8]  S. Bixler,et al.  Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses , 1993, The Journal of experimental medicine.

[9]  D. Kioussis,et al.  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. , 1994, Journal of immunology.

[10]  A. Gottlieb,et al.  PUVA bath therapy strongly suppresses immunological and epidermal activation in psoriasis: a possible cellular basis for remittive therapy , 1994, The Journal of experimental medicine.

[11]  P. Hochman,et al.  The effects of an immunomodulatory LFA3-IgG1 fusion protein on nonhuman primates. , 1994, Therapeutic immunology.

[12]  T. Hamilton,et al.  Duration of remission during maintenance cyclosporine therapy for psoriasis. Relationship to maintenance dose and degree of improvement during initial therapy. , 1995, Archives of dermatology.

[13]  G. Weinstein,et al.  Treatment of psoriasis. , 1976, The New England journal of medicine.

[14]  J. Voorhees,et al.  Intralesional T-lymphocyte activation as a mediator of psoriatic epidermal hyperplasia. , 1995, The Journal of investigative dermatology.

[15]  M. Rogge,et al.  Immunomodulation by LFA3TIP, an LFA-3/IgG1 fusion protein: cell line dependent glycosylation effects on pharmacokinetics and pharmacodynamic markers. , 1995, Therapeutic immunology.

[16]  A. Gottlieb,et al.  Successful ultraviolet B treatment of psoriasis is accompanied by a reversal of keratinocyte pathology and by selective depletion of intraepidermal T cells , 1995, The Journal of experimental medicine.

[17]  James G. Krueger,et al.  Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis , 1995, Nature Genetics.

[18]  C. Marboe,et al.  Short course single agent therapy with an LFA-3-IgG1 fusion protein prolongs primate cardiac allograft survival. , 1996, Transplantation.

[19]  M. Lebwohl,et al.  Duration of remission of psoriasis therapies. , 1999, Journal of the American Academy of Dermatology.

[20]  T. Kupper,et al.  Inflammatory skin diseases, T cells, and immune surveillance. , 1999, The New England journal of medicine.