title: Novel insight into the agonistic mechanism of alefacept in vivo: differentially expressed genes may serve as biomarkers of response in psoriasis patients.
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 approximately 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-gamma 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.
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY 10021, USA.
authors.forename: Asifa S
authors.initials: AS
authors.lastname: Haider
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lowes
authors.forename: Humphrey
authors.initials: H
authors.lastname: Gardner
authors.forename: Raj
authors.initials: R
authors.lastname: Bandaru
authors.forename: Kamruz
authors.initials: K
authors.lastname: Darabi
authors.forename: Francesca
authors.initials: F
authors.lastname: Chamian
authors.forename: Toyoko
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Patricia
authors.initials: P
authors.lastname: Gilleaudeau
authors.forename: Mary S
authors.initials: MS
authors.lastname: Whalen
authors.forename: Irma
authors.initials: I
authors.lastname: Cardinale
authors.forename: Inna
authors.initials: I
authors.lastname: Novitskaya
authors.forename: James G
authors.initials: JG
authors.lastname: Krueger
mesh_terms: D000328:Adult; D000368:Aged; D000077944:Alefacept; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D018801:CD2 Antigens / Q000096:biosynthesis / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011565:Psoriasis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000819:agonists* / Q000378:metabolism / Q000627:therapeutic use; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D015415:Biomarkers; D018801:CD2 Antigens; D011993:Recombinant Fusion Proteins; D000077944:Alefacept