Novel insight into the agonistic mechanism of alefacept in vivo: Differentially expressed genes may serve as biomarkers of response in psoriasis patients
Novel insight into the agonistic mechanism of alefacept in vivo: Differentially expressed genes may serve as biomarkers of response in psoriasis patients
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DOI：
10.4049/jimmunol.178.11.7442
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发表时间：
2007-06-01
影响因子：
4.4
通讯作者：
Krueger, James G.
中科院分区：
文献类型：
--
作者：
Haider, Asifa S.;Lowes, Michelle A.;Krueger, James G.
阿法塞是一种LFA 3-IG融合蛋白，可与CD 2结合，并被认为通过拮抗CD 2信号传导或裂解CD 2（+）细胞来抑制T细胞活化。Alefacept是器官移植受者或移植物抗宿主病的潜在未来治疗药物，并且是一种批准的治疗寻常型银屑病的药物，寻常型银屑病是一种T细胞介导的炎性疾病。然而，alefacept治疗12周后仅改善了50%的银屑病患者。我们研究了一组银屑病患者在治疗过程中阿法赛特的免疫学效应。我们发现T细胞，特别是CD 8（+）T细胞，在外周循环中迅速减少。循环T细胞的减少与诱导的细胞凋亡无关。出乎意料的是，除了抑制炎性基因外，我们发现在PBMC中治疗的第一天期间，IFN-γ诱导的STAT 1、IL-8和单核因子的mRNA的显著诱导。我们在体外证实了alefacept在PBMC中的激动作用，其类似于T细胞上的CD 3/CD 28连接。这些数据表明，alefacept激活白细胞中的基因表达程序，并表明其治疗作用可能是作为一种混合激动剂/拮抗剂。此外，对alefacept治疗有反应的患者显示出独特的基因调节模式。而alefacept下调TCR的CD 3D和CD 2的反应，无反应者揭示了更高的表达的T细胞活化基因，如CD 69在治疗前的PBMC。这些发现为在治疗早期或在治疗广泛的促炎性疾病之前将应答者与无应答者分类提供了潜在的基础。本研究1）确定alefacept是一种新型CD 2激动剂分子，用于诱导白细胞活化基因（先前的工作提出其机制为CD 2拮抗剂），2）基因的差异活化可能对该药物的临床应答者进行分类，这对于该药物的成本效益使用至关重要。
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 similar to 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.