Novel Insight into the Agonistic Mechanism of Alefacept In Vivo: Differentially Expressed Genes May Serve as Biomarkers of Response in Psoriasis Patients
| Autor: | Asifa Haider, Irma Cardinale, Kamruz Darabi, Raj Bandaru, Michelle A. Lowes, James G. Krueger, Inna Novitskaya, Francesca Chamian, Humphrey Gardner, Patricia Gilleaudeau, Mary S. Whalen, Toyoko Kikuchi |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Adult
Male Agonist medicine.drug_class Recombinant Fusion Proteins T cell CD3 Immunology CD2 Antigens Down-Regulation Alefacept Apoptosis CD8-Positive T-Lymphocytes Pharmacology Biology Lymphocyte Activation Resting Phase Cell Cycle Proinflammatory cytokine T-Lymphocyte Subsets Lymphopenia Psoriasis medicine Humans Immunology and Allergy Aged Skin CD28 Middle Aged medicine.disease Up-Regulation medicine.anatomical_structure Gene Expression Regulation biology.protein Female Immunologic Memory Biomarkers CD8 Protein Binding medicine.drug |
| Zdroj: | The Journal of Immunology. 178:7442-7449 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|