UC San Diego

As central regulators of asthma pathogenesis, allergen- specific CD4+ T cells are recruited to the lungs and secrete sustained levels of Th2 cytokines upon reencounter with inhaled allergen leading to the development of the hallmark indicators of asthma including airway hyperresponsiveness, mucus production and the recruitment of eosinophils to the affected lung tissue. Selectively upregulated in Th2 cells, Itk is a member of the Tec familiy of non-receptor tyrosine kinases and is required for Th2 cell development and effector function. Upon stimulation through the TCR, Itk associates with the adaptor protein SLP-76 and is recruited to the immunological synapse as part of a stable signaling complex leading to its subsequent enzymatic activation. As previously discovered using purified domain fragments, the Itk SH3 domain binds to its specific polyproline ligand represented by the amino acid sequence QQPPVPPQRPMA located on SLP-76 with a reported affinity of 0.77 mM (1). By modifying this sequence with the addition of a polyarginine cell penetration motif, Grasis et al. recently demonstrated that the engineered peptide designated R9-QQP was effective as a competitive inhibitor of Itk activation (2). In the current work, R9-QQP was translated to an OVA-inducible model of experimental asthma. Upon delivery in vivo, R9-QQP was demonstrated to specifically inhibit physiologically relevant parameters of airway inflammation and was further characterized as affecting the recruitment of eosinophils to the lung mucosa. Consistent with the role of Itk, Th2 cytokine secretion by lung draining lymph node cells was reduced upon restimulation with OVA in vitro. While current treatments are effective for most patients with clinical asthma, undesirable side effects as well as lack of effectiveness for some patients underscores the need to develop additional therapeutic strategies that target the immunological basis of allergic disease progression. By blocking an inducible and T cell-specific interaction, this study establishes the importance of the Itk-SLP-76 interaction in an allergic disease model as an attractive therapeutic target for the future development of biologically active small molecules inhibitors