Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We herein discuss the impact of biological agents based on the ability of monoclonal antibodies to target specific molecules. This approach has given to clinical immunologists a spectrum of drugs able to manipulate the immune system. In the first session, we discuss drugs targeting T-cell function by: (1) targeting CD28 mediated costimulation (Abatacept and Belatacept); (2) interfering with interleukin-2 receptor (Basiliximab and Daclizumab); (3) blocking cell adhesion and homing (Alefacept, Efalizumab, Natalizumab). The second session is dedicated to drugs targeting cytokines or their receptors. The best known and largely experimented case is represented by drugs targeting tumor necrosis factor (TNF) (Infliximab, Adalilumab, Certolizumab) or its p75 receptor (Etanercept). However, newer products are now available to target other inflammatory cytokines including IL-6, IL-8, IL-12, IL-15, IL-18, IL-23. These agents have the potential to become powerful tools in the control of several immune-mediated diseases, especially auto-immune and inflammatory ones. They traslate into reality the prediction that antibodies will eventually become "magic bullets which seek their own target" (P. Ehrich, 1906).
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PMID:The impact of biological agents interfering with receptor/ligand binding in the immune system. 1647 34

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.
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PMID:Novel insight into the agonistic mechanism of alefacept in vivo: differentially expressed genes may serve as biomarkers of response in psoriasis patients. 1751 95