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

AS Haider, MA Lowes, H Gardner… - The Journal of …, 2007 - journals.aai.org
AS Haider, MA Lowes, H Gardner, R Bandaru, K Darabi, F Chamian, T Kikuchi…
The Journal of Immunology, 2007journals.aai.org
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 …
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.
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