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: 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
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 178 Issue 11 Pg. 7442-9 (Jun 01 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17513795 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Validation Study)

Chemical References

• Biomarkers
• CD2 Antigens
• Recombinant Fusion Proteins
• Alefacept

Topics

• Adult
• Aged
• Alefacept
• Apoptosis (genetics, immunology)
• Biomarkers (blood)
• CD2 Antigens (biosynthesis, genetics)
• CD8-Positive T-Lymphocytes (immunology, metabolism, pathology)
• Down-Regulation (genetics, immunology)
• Female
• Gene Expression Regulation (immunology)
• Humans
• Immunologic Memory (genetics)
• Lymphocyte Activation (genetics)
• Lymphopenia (genetics, immunology, pathology)
• Male
• Middle Aged
• Protein Binding (genetics, immunology)
• Psoriasis (genetics, immunology, pathology, therapy)
• Recombinant Fusion Proteins (administration & dosage, agonists, metabolism, therapeutic use)
• Resting Phase, Cell Cycle (genetics, immunology)
• Skin (immunology, metabolism, pathology)
• T-Lymphocyte Subsets (immunology, metabolism, pathology)
• Up-Regulation (genetics, immunology)