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Ein Peptidkonjugatvakzin gegen Masern [Elektronische Ressource] = A peptide-conjugate vaccine against measles / vorgelegt von Mike M. Pütz

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188 pages
Ein Peptidkonjugatvakzin gegen Masern A Peptide-Conjugate Vaccine against Measles DISSERTATION der Fakultät für Chemie und Pharmazie der Eberhard-Karls-Universität Tübingen zur Erlangung des Grades eines Doktors der Naturwissenschaften vorgelegt von Mike M. Pütz 2004 Tag der mündlichen Prüfung: 9. Februar 2004 Dekan: Prof. Dr. Hansgeorg Probst 1. Berichterstatter: Prof. Dr. Günther Jung 2. Berichterstatter: Prof. Dr. Claude P. Muller ii This doctoral thesis has been performed in the Department of Immunology, Laboratoire National de Santé, Luxembourg under the guidance of Prof. Dr. Günther Jung, Institut für Organische Chemie, Universität Tübingen, Germany and Prof. Dr. Claude P. Muller, Department of Immunology, Laboratoire National de Santé, Luxembourg. iii Acknowledgments Iwould like to thank my promoter Prof. Dr. Claude P. Muller for offering me to join his team at the Department of Immunology, Laboratoire National de Santé, Luxembourg (LNS-DI), for his persistent and genuine scientific guidance and for his continuous confidence. I also wish to thank Ulla Muller for the professional and cheerful assistance in many non-scientific purposes. I want to thank my promoter Prof. Dr.
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Ein Peptidkonjugatvakzin gegen Masern


A Peptide-Conjugate Vaccine against Measles





DISSERTATION




der Fakultät für Chemie und Pharmazie
der Eberhard-Karls-Universität Tübingen

zur Erlangung des Grades eines Doktors der Naturwissenschaften





vorgelegt von



Mike M. Pütz



2004










Tag der mündlichen Prüfung: 9. Februar 2004
Dekan: Prof. Dr. Hansgeorg Probst

1. Berichterstatter: Prof. Dr. Günther Jung
2. Berichterstatter: Prof. Dr. Claude P. Muller




ii



This doctoral thesis has been performed in the
Department of Immunology, Laboratoire National de Santé, Luxembourg

under the guidance of

Prof. Dr. Günther Jung,
Institut für Organische Chemie, Universität Tübingen, Germany

and
Prof. Dr. Claude P. Muller,
Department of Immunology, Laboratoire National de Santé, Luxembourg.






iii

Acknowledgments
Iwould like to thank my promoter Prof. Dr. Claude P. Muller for offering me to join
his team at the Department of Immunology, Laboratoire National de Santé,
Luxembourg (LNS-DI), for his persistent and genuine scientific guidance and for his
continuous confidence. I also wish to thank Ulla Muller for the professional and
cheerful assistance in many non-scientific purposes.

I want to thank my promoter Prof. Dr. Günther Jung, Institut für Organische Chemie,
Universität Tübingen, Germany, for his sincere interest and enthusiasm for the project
and for his precious inputs and critics, despite the distance between Tübingen and
Luxembourg. I would like to thank PD Dr. Karl-Heinz Wiesmüller for his valuable
advices and help and for the exciting scientific and non-scientific activities during the
annual Oberjoch seminars.

I would like to thank Dr. Johan Hoebeke, Institut de Biologie Moléculaire et
Cellulaire, Strasbourg, France for his invaluable expertise and extensive teaching
during the BIACORE and molecular modeling experiments.

I want to thank Dr. Isabelle Kolber and Dr. Serge Schneider, Division de Toxicologie,
Laboratoire National de Santé, Luxembourg for their unconditioned support with
mass spectrometry facilities.

I would like to thank the director of the Laboratoire National de Santé, Dr. François
Schneider for giving me the opportunity to use the facilities at the LNS-DI. Financial
support from the Centre de Recherche Public-Santé, the Fonds National de Recherche,
the European Union project BIO4-CT98-0242, the Ministère de la Culture, de
l’Enseignement Supérieur et de la Recherche is also gratefully acknowledged.

iv

Iwish to thank Caroline Calmes, Francine Closener and Alain Steffen for their
friendship and reliable support during all these years.
Iwould like to thank present and former colleagues of the Department, Wim, Sabrina,
Jacques, Stefan, Fred, René, Fabienne, Corinne, Mick, Benjamin, Sophie, Marie-
France, Stéphanie, Carole, Claudine, Jonathan, Bart, Géraldine, Brice, Tom, Nathalie,
Anna, Jessica, Chantal for their definite and devoted support, thus creating a cheerful
and stimulating atmosphere in the team. Special thanks to Fred for his commendable
encyclopedic skills and to Sabrina for the critical reading of this manuscript. Most
special thanks to Wim for his infallible and friendly assistance throughout these years.

I want to thank my girlfriend Michèle for her love, care and tenderness…

I wish to thank my parents for giving me a home and much more than this…








v Index




List of Abbreviations




Abu amino butyric acid (also ‘B’)
AFUarbitrary fluorescence units
Alum aluminium hydroxide gel (also ‘alhydrogel’)
APCantigen presenting cell
ATCC American type culture collection
B amino butyric acid (also ‘Abu’)
BCEB-cell epitope
BCG Bacille Calmette-Guerin
BSAbovine serum albumin
Boc tert-butoxycarbonyl
BTC bis-(trichloromethyl)carbonate (also ‘triphosgene’)
CDCCenters for Disease Control and Prevention
CDV canine distemper virus
CFAcomplete Freund’s adjuvant
CFF consistent forcefield
95%CI95% confidence intervals
CPV canine parvovirus
CRM197‘crossreactive material’, nontoxic mutant of diphtheria toxin
ct cholera toxin
ctbnontoxic cholera toxin B subunit
CTL cytotoxic T-lymphocyte
CVFFconsistent valence forcefield
DCM dichloromethane
DIC1,3-diisopropylcarbodiimide
DIPEA N,N-diisopropylethylamine
DMEM Dulbecco’s modified Eagle’s medium
vi Index
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
DNAdesoxyribonucleicacid
dt diphtheria toxoid
DTHNE-peptide-diphtheria-toxoid conjugate
DTP diphtheria-tetanus-pertussis vaccine
DTT1,4-dithiothreitol
EBV Epstein-Barr virus
EDC N-ethyl-N’-[(3-dimethyl-amino)propyl] carbodiimide hydrochlorid
EDT 1,2-ethanedithiol
EDTAethylenediaminetetraacetic acid
ELISA enzyme linked immunosorbent assay
EPIExpanded Programme of Immunization
EPT end point titer
ESIelectron spray ionization
F fusion protein
FACSfluorescence-activated cell sorter
FBS-HI heat-inactivated fetal bovine serum
FCS fetal calf serum
FITCfluorescein isothiocyanate
Fmoc 9-fluorenylmethoxycarbonyl
FMDVfoot and mouth disease virus
H hemagglutinin protein
HBSSHEPES buffered salt solution
HIV human immunodeficiency virus
HEPES N-(2-hydroxyethyl) piperazine-N’-(2-ethanesulfonic acid)
HNE hemagglutinin noose epitope
HOBt1-hydroxybenzotriazole
HPLC high performance liquid chromatography
IC50%50%-inhibiting concentration
IFA incomplete Freund’s adjuvant
IFNinterferon
IgG immunoglobulin G
IgG-APIgG-alkaline phosphatase
vii Index
IL interleukin
IgMimmunoglobulin M
i.d. intradermal
i.p.intraperitoneal
i.m. intramuscular
i.n.intranasal
ISCOM immune stimulating complex
L large protein
LAVlive-attenuated vaccine
LNS Laboratoire National de Santé
ltheat-labile enterotoxin
ltb nontoxic heat-labile enterotoxin B subunit
Mmatrix protein
mAb monoclonal antibody
MES2-(N-morpholino) ethanesulfonic acid
MHC major histocompatibility complex
mRNAmessenger RNA
MS mass spectrometry
MVmeasles virus
MVA modified vaccinia virus Ankara
MWmolecular weight
N nucleoprotein
NALTnasal-associated lymphoid tissue
NE neutralizing epitope
NHS N-hydroxy-succinimide
NK natural killer cell
NMP N-methylpyrrolidone
OD optical density
ovaovalbumin
OVA HNE-peptide-ovalbumin conjugate
Pphosphoprotein
PBMC peripheral blood mononuclear cell
PBSphosphate buffered saline
PSG penicillin-streptomycin-L-glutamin
viii

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