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

Schweingruber, Nils

dc.contributor.advisor	Reichardt, Holger Prof. Dr.
dc.contributor.author	Schweingruber, Nils
dc.date.accessioned	2014-06-24T09:06:54Z
dc.date.available	2014-07-02T22:50:05Z
dc.date.issued	2014-06-24
dc.identifier.uri	http://hdl.handle.net/11858/00-1735-0000-0022-5EF5-7
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-4562
dc.language.iso	deu	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/
dc.subject.ddc	610	de
dc.title	Neuartige Wirkmechanismen und Therapiestrategien von Glukokortikoiden in der Behandlung von Multipler Sklerose im Tiermodell	de
dc.type	doctoralThesis	de
dc.title.translated	Novel mechanisms and therapeutic strategies of glucocorticoids in the treatment in an animal model of multiple sclerosis	de
dc.contributor.referee	Reichardt, Holger Prof. Dr.
dc.date.examination	2014-06-25
dc.description.abstracteng	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.	de
dc.contributor.coReferee	Flügel, Alexander Prof. Dr.
dc.subject.ger	Glukokortikoide	de
dc.subject.ger	GC	de
dc.subject.ger	Dexamethason	de
dc.subject.ger	Multiple Sklerose	de
dc.subject.ger	MS	de
dc.subject.ger	EAE	de
dc.subject.ger	Tiermodelle	de
dc.subject.ger	Liposomen	de
dc.subject.ger	Prednisolon	de
dc.subject.ger	Makrophagen	de
dc.subject.ger	T-Zellen	de
dc.subject.ger	Migration	de
dc.subject.ger	Transmigration	de
dc.subject.ger	CXCR4	de
dc.subject.ger	CCR7	de
dc.subject.ger	CXCL12	de
dc.subject.ger	CCL19	de
dc.subject.ger	MIP	de
dc.subject.ger	SDF	de
dc.subject.ger	Apoptose	de
dc.subject.ger	Plerixafor	de
dc.subject.ger	AMD-3100	de
dc.subject.ger	M1	de
dc.subject.ger	M2	de
dc.subject.ger	Polarisierung	de
dc.subject.ger	Immunsystem	de
dc.subject.ger	Therapie	de
dc.subject.eng	GC	de
dc.subject.eng	glucocorticoids	de
dc.subject.eng	dexamethason	de
dc.subject.eng	multiple sclerosis	de
dc.subject.eng	MS	de
dc.subject.eng	EAE	de
dc.subject.eng	animal model	de
dc.subject.eng	migration	de
dc.subject.eng	transmigration	de
dc.subject.eng	macrophages	de
dc.subject.eng	t cell	de
dc.subject.eng	CXCR4	de
dc.subject.eng	CCR7	de
dc.subject.eng	CXCL12	de
dc.subject.eng	CCL19	de
dc.subject.eng	MIP	de
dc.subject.eng	SDF	de
dc.subject.eng	apoptosis	de
dc.subject.eng	AMD-3100	de
dc.subject.eng	M1	de
dc.subject.eng	M2	de
dc.subject.eng	polarization	de
dc.subject.eng	immune system	de
dc.subject.eng	therapy	de
dc.identifier.urn	urn:nbn:de:gbv:7-11858/00-1735-0000-0022-5EF5-7-9
dc.affiliation.institute	Medizinische Fakultät	de
dc.subject.gokfull	Medizin (PPN619874732)	de
dc.description.embargoed	2014-07-02
dc.identifier.ppn	78871631X

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