Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Knuplez, E.
Investigating novel treatment options to suppress eosinophil effector responses
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2021. pp. 151
[OPEN ACCESS]
FullText
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Marsche Gunther
- Sattler Wolfgang
- Altmetrics:
- Abstract:
- Allergic diseases are a major healthcare problem worldwide affecting up to one third of the global population. Due to their increasing prevalence, they have become one of the most common chronic conditions in childhood. One of the immune cells strongly linked to an aberrant allergic response are eosinophils, which induce tissue damage and remodelling upon their over-activation. Hence, eosinophils have long been considered as important drug targets for development of essential anti-allergic therapeutics. However, additional homeostatic functions of eosinophils have recently been discovered, which warrant the development of alternative treatment options aimed at their over-activation and not elimination. Accordingly, this PhD thesis investigates novel treatment options for targeting eosinophil effector responses as well as provides tools for studying their biology. In the first part of my thesis I discovered that endogenous bioactive mediators and cleavage products of inflammatory secretory phospholipases lysophosphatidylcholines (LPCs) inhibit human eosinophil over-activation. We could show that saturated LPCs disrupted lipid-raft mediated signalling on the surface of eosinophils and thereby dampened their effector responses upon activation. Similarly, LPCs suppressed the migration of mouse eosinophils in lungs of animals upon eotaxin stimulation. Thus, our data have uncovered LPCs as compounds with strong modulatory activity on eosinophils and as potential lead compounds used for drug development. A disadvantage of using LPCs is that LPCs are rapidly metabolised upon application. Therefore, we next tested a metabolically stable structural analogue (miltefosine) and its mode of action on eosinophils. Miltefosine is an orally bioavailable drug, registered for treatment of the parasitic disease leishmaniasis with proven immunomodulatory functions. Comparable to our findings with LPC, we could observe inhibition of human eosinophil activation upon miltefosine treatment. What is more, we have successfully used miltefosine in preclinical studies, where it significantly reduced the infiltration of eosinophils and other immune cells in models of allergy. Importantly, miltefosine application improved lung function parameters following methacholine challenge in mice proving its suitability as a drug candidate for treatment of eosinophil-associated diseases. Recent progress in the field of drug targeting of eosinophils has been made with the development of a specific monoclonal antibody that activates the human eosinophil receptor Siglec-8. Targeting Siglec-8 eliminates eosinophils through antibody-dependent cellular cytotoxicity. During my research stay in the USA at the Feinberg School of Medicine in Chicago (Lab of Prof. Bruce Bochner), I investigated a novel transgenic mouse strain in which eosinophils express human Siglec-8 and murine Siglec-F is absent. We were able to show that this mouse strain has great advantages for transient eosinophil depletion. By characterising a novel transgenic mouse model with human-like Siglec expression on eosinophils, we have given research laboratories an entirely new tool to completely deplete eosinophils. As part of my thesis I reviewed and evaluated the existing and often conflicting literature on the function of LPCs in the vasculature and summarised it in a review article. In the review article, we highlight LPCs as major endogenous mediators involved in all stages of vascular inflammation and associated diseases. In summary, during my thesis I was able to show that lipid raft modulators such as endogenous LPC or its synthetic analogue miltefosine could serve as alternative approaches to target eosinophil overactivation. Furthermore, by characterising a novel transgenic mouse model with human-like Siglec expression on eosinophils, we have provided researchers with a novel tool for superior eosinophil elimination and for further exploration of the Siglec-8 biology.