Novel insight into the agonistic mechanism of alefacept in vivo: Differentially expressed genes may serve as biomarkers of response in psoriasis patients

Asifa S. Haider, Michelle A. Lowes, Humphrey Gardner, Raj Bandaru, Kamruz Darabi, Francesca Chamian, Toyoko Kikuchi, Patricia Gilleaudeau, Mary S. Whalen, Irma Cardinale, Inna Novitskaya, James G. Krueger

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Alefacept is an LFA3-Ig fusion protein that binds to CD2 and is thought to inhibit T cell activation by antagonism of CD2 signaling or by lysis of CD2 + cells. Alefacept is potential future therapeutic for organ transplant recipients or graft-vs-host disease and is an approved therapeutic for psoriasis vulgaris, which is a T cell-mediated inflammatory disease. However, alefacept improves psoriasis in only ∼50% of patients treated for 12 wk. We studied the immunologic effects of alefacept in a group of psoriasis patients during treatment. We found that T cells, especially CD8+ T cells, were rapidly decreased in the peripheral circulation. Decreases in circulating T cells were not associated with induced apoptosis. Unexpectedly, in addition to suppression of inflammatory genes, we found a marked induction of mRNAs for STAT1, IL-8, and monokine induced by IFN-γ during the first day of treatment in PBMC. We confirmed the agonistic effects of alefacept in PBMC in vitro, which were similar to CD3/CD28 ligation on T cells. These data establish that alefacept activates gene expression programs in leukocytes and suggest that its therapeutic action may be as a mixed agonist/antagonist. Furthermore, responding patients to alefacept treatment show unique patterns of gene modulation. Whereas alefacept down-regulated TCRs CD3D and CD2 in responders, nonresponders reveal a higher expression of T cell activation genes such as CD69 in pretreatment PBMC. These finding suggest a potential basis for categorizing responders vs nonresponders at an early time point in treatment or before treatment of a broad range of proinflammatory diseases. This study 1) establishes alefacept as a novel CD2 agonist molecule for induction of leukocyte activation genes (prior work proposed its mechanism as a CD2 antagonist) and 2) that differential activation of genes may categorize clinical responders to this agent, critical for cost-effective use of this drug.

Original languageEnglish (US)
Pages (from-to)7442-7449
Number of pages8
JournalJournal of Immunology
Volume178
Issue number11
DOIs
Publication statusPublished - Jun 1 2007

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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