Studies towards targeting Thymic Stromal Lymhopoietin (TSLP) and STAT (Signal Transducers and Activators of Transcription) pathways for therapeutic amelioration of Asthma bronchiale

Asthma is a globally prevalent chronic, inflammatory immune hyper-responsiveness, foreseen as a major health concern by WHO. It is now known to be linked to a dysregulated Th2 repertoire of cytokines (IL-4, IL-5, IL-10, IL-13). The disease is characterized by variable airway obstruction, hyperresponsiveness, inflammation, remodeling. desquamation of the bronchial epithelial layer, goblet cell hyperplasia and thickening of submucosa.

Recent advances in deciphering the molecular mechanisms of Asthma have led us to exploit the potential of cytokine TSLP, the TSLP receptor and its signal transduction as prospective targets for the development of ameliorative therapeutics.

Thymic stromic Lymphopoietin (TSLP) is a vital ligand that bridges the signaling information flow from antigen-exposed epithelial cells, which release it, to T helper cells via dendritic cells. TSLP was identified as a central regulator of acute and chronic pathogenic processes in Asthma. In light of these studies, we established a cellular model system on the basis of the factor-dependent murine pro-B cell line Ba/F3. We could demonstrate by phosphotyrosine protein analysis and by STAT type-specific reporter gene assays that the ligand-stimulated human TSLPR triggers activation of STAT3, STAT5 and STAT1.

Signal Transducers and Activators of Transcription are latent cytoplasmic proteins that turn into transcriptional regulators upon activation by cytokine receptors such as the TSLPR and, thus, play a pivotal role in the immuno-regulation of cellular inflammatory responses. Employing a murine asthma model, we observed profound STAT3 activity in alveolar leukocyte populations of asthmatic mice. Moreover, elevated levels of IL-6, IL-4, IL-1β, TNF-α and antigen-specific IgE were observed in their bronchoalveolar fluid. Based on our findings and those of others, we hypothize that the signal transduction axis TSLP-TSLPR-STAT3 is of critical importance for the pathogenesis of Asthma in both mice and humans.

By generating specific antibodies and cytokine variants, we have developed novel tools to analyze and specifically inhibit TSLPR activation. These agents are currently studied with regard to their diagnostic and therapeutic potential in human and murine cell systems.