Identification of interleukin-13 related biomarkers using peripheral blood mononuclear cells

Abstract

Asthma is a chronic disorder characterized by airway inflammation, reversible bronchial obstruction, hyper-responsiveness and remodelling. Data from human in vitro studies and experimental in vivo models of asthma has implicated interleukin (IL)-13 in the asthma phenotype suggesting that a therapeutic agent against it could be effective in treating asthma. The role of biomarkers is becoming increasingly important in the clinical development of therapeutics. Here we describe the use of the GeneChip((R)) DNA microarray technology platform to explore and identify potential response to therapy biomarkers that are associated with the biology of IL-13. Peripheral blood mononuclear cells (PBMCs) from eight healthy donors were cultured in the presence of IL-13, IL-4, an anti-IL-13 monoclonal antibody (mAb) or an isotype control mAb, and RNA from the treated cells was subjected to microarray analysis. The results revealed a number of genes, such as CCL17 (TARC), CCL22 (MDC), CCL23 (MPIF-1), CCL26 (eotaxin 3) and WNT5A (human wingless-type MMTV integration site family member 5A), that showed increased expression in the IL-13 and IL-4 treatment groups. Real-time polymerase chain reaction (PCR) subsequently confirmed these results. A follow-up study in PBMCs from five additional healthy donors showed that the neutralization of IL-13 completely blocked IL-13-induced TARC, MDC and eotaxin 3 production at the protein level. These data suggest that TARC, MDC, eotaxin 3, CCL23 and WNT5A if validated could serve as potential biomarkers for anti-IL-13 therapeutics.

New asthma biomarkers: lessons from murine models of acute and chronic asthma

“…In the IT, however, activated biological processes correspond to organ development, morphogenesis, angiogenesis, and so forth, suggesting that active remodeling of lung or bronchi is occurring at this stage. ␤-Catenin/Wnt pathway has been suggested to be a reliable biomarker of asthma and proposed to be a therapeutic target (33,37). However, in our microarray experiments, this pathway is upregulated only at IT.…”

Novel eosinophilic gene expression networks associated with IgE in two distinct asthma populations

“…Other genes from our eosinophil-related gene sets have known associations with allergic asthma and may also have therapeutic or diagnostic potential, including CCL23, CLC, CEBPE, CAMK1, IDO1, SIGLEC8, SMPD3 and SPNS3. [44][45][46][47][48][49][50][51] Potential therapeutic targets include cell surface receptors, such as Siglec8, an inhibitory receptor on eosinophils with polymorphisms associated with asthma. [45][46][47] CCL23 is an eosinophilic chemokine that has been identified as a possible biomarker for anti-IL13-targeted therapies.…”

Alternative Activation of Macrophages: Mechanism and Functions

“…Microarrays have made it possible to investigate effects of IL-4 in macrophages of both species; however, given the limited number of published studies in human or mouse macrophages, a consensus of markers is hard to establish, particularly for humans (Syed et al, 2007;Martinez et al, 2006;Scotton et al, 2005). Genes that appear to be modulated in common by IL-4 in macrophages, monocytes, and perhaps circulating precursors include ALOX15, FN1, CD23a, MAO-A, GAS6, FXIIIA1, CCL26, CCL22, and IL-17RB.…”