Neuartige Wirkmechanismen und Therapiestrategien von Glukokortikoiden in der Behandlung von Multipler Sklerose im Tiermodell

Novel mechanisms and therapeutic strategies of glucocorticoids in the treatment in an animal model of multiple sclerosis

by Nils Schweingruber
Doctoral thesis
Date of Examination:2014-06-25
Date of issue:2014-06-24
Advisor:Prof. Dr. Holger Reichardt
Referee:Prof. Dr. Holger Reichardt
Referee:Prof. Dr. Alexander Flügel
Persistent Address: http://dx.doi.org/10.53846/goediss-4562

 

 

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Abstract

English

Despite the enormous progress being made in the development of new therapies, such as monoclonal antibodies, GCs are still one of the best options available to treat inflammatory diseases. One of the main drawbacks of this class of compounds, however, are their some-times serious side-effects, that occur especially after prolonged and high-dose application. To solve this problem it is necessary to characterize in more detail the mode of action of GC therapy in the context of various inflammatory models. This can serve as a basis for the fu-ture development of improved drugs, but also contributes to the understanding of the patho-genesis of inflammatory diseases. The first part of the doctoral thesis deals with the possibility to therapeutically use an innova-tive application of GCs, namely prednisolone-loaded pegylated liposomes (PL). These allow, in principle, to achieve the same effect on inflammatory processes as free GCs, but in the presence of reduced systemic side-effects. While the clinical efficacy in models of rheuma-toid arthritis and experimental autoimmune encephalomyelitis (EAE) has already been estab-lished, new insights into the cellular and molecular mechanisms of PL should be obtained in the context of EAE in this work. By the use of conditional knock-out mice, it was in particular possible to distinguish between GR-dependent effects of PL on macrophages and T cells. Furthermore, the detailed characterization of macrophages in vitro and ex vivo has made it possible to determine the mechanism of action of PL as compared to free dexamethasone. The second part of the work focused on the role of apoptosis in the context of GC therapy of EAE and the influence of GCs on T cell migration. The role of GC-induced cell death (GICD) was evaluated in mouse models in which T cells were refractory to GICD. Furthermore, it should be tested whether the influence of GCs on chemokine-induced T cell migration plays a central role in the treatment of EAE. More precisely, the chemokine-chemokine receptor pair CXCL12/CXCR4 proved to be particularly promising in this regard. By in vitro analysis of T cells, pharmacological blockade of CXCR4 in EAE in vivo, as well as by testing primary T cells from healthy subjects and MS patients of different clinical disease courses, the importance of this novel mechanism of action of GCs in EAE and MS was analyzed.  In short, the aim of the present work was, to gain new and clinically relevant insights into the mechanism of GC therapy of MS, all the way from cell culture studies to human patients.
Keywords: GC; glucocorticoids; dexamethason; multiple sclerosis; MS; EAE; animal model; migration; transmigration; macrophages; t cell; CXCR4; CCR7; CXCL12; CCL19; MIP; SDF; apoptosis; AMD-3100; M1; M2; polarization; immune system; therapy
Schlagwörter: Glukokortikoide; GC; Dexamethason; Multiple Sklerose; MS; EAE; Tiermodelle; Liposomen; Prednisolon; Makrophagen; T-Zellen; Migration; Transmigration; CXCR4; CCR7; CXCL12; CCL19; MIP; SDF; Apoptose; Plerixafor; AMD-3100; M1; M2; Polarisierung; Immunsystem; Therapie
 
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