Re-direction of interferon gamma and its signaling moiety: new options for the therapy of chronic diseases

PhD ceremony: Ms. R. Bansal, 16.15 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: Re-direction of interferon gamma and its signaling moiety: new options for the therapy of chronic diseases

Promotor(s): prof. K. Poelstra

Faculty: Mathematics and Naturalal Sciences

The thesis of Ruchi Bansal aims at the development of potential therapeutic approaches through which potent drugs (or cytokines) can be selectively targeted to a key pathogenic cell type in the chronic diseases. Liver cirrhosis, induced by viral infections (e.g. hepatitis B and C), alcohol abuse, metabolic syndrome or genetic disorders, is the major cause of morbidity and mortality worldwide. Currently, there are no effective and clinically approved anti-fibrotic therapies available and the treatment is mainly based on the removal of the underlying cause of the disease. Hepatic stellate cells (HSC) are the key pathogenic cells involved in the progression of liver fibrosis.

Among the potent anti-fibrotic therapeutic cytokines, Interferon gamma (IFNγ) is shown to be highly efficacious in vitro and in vivo in liver fibrosis models, but it failed in clinical trials due to lack of efficacy and unwanted systemic effects. In her thesis, Bansal has moved step by step forward and designed a small cytokine-derived molecule that does not bind to its native receptor but to an ‘accessory’ receptor that was abundantly expressed on her target cells, the (myo-) fibroblast in fibrotic tissue and stromal cells in tumor. Despite its delivery to another receptor, IFNγ still is endowed with potent anti-fibrotic and antitumor activities. This new IFNγ molecule re-directed to the PDGFβ-receptor not only has an increased effectivity on PDGF receptor expressing cells compared to native IFNγ but also lacks all the adverse effects observed with IFNγ-based therapies. Bansals studies present new strategies to design highly effective cytokines and provide a new potential therapeutic compound for chronic diseases like liver fibrosis.