Leukocyte attraction and transmigration in type 1 diabetes [Elektronische Ressource] : neutralization of CXCR3 and JAM-C reduces the severity of disease / von Selina Christen

Sujets

• Gesundheit

Informations

• Publié par: goethe_universitat_frankfurt_am_main
• Publié le: 01 janvier 2010
• Nombre de lectures: 30
• Langue: English
• Poids de l'ouvrage: 83 Mo

Extrait

Leukocyte attraction and
transmigration in type 1 diabetes:
Neutralization of CXCR3 and JA M -C
reduces the severity of disease
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3 1 Table of C ontents
1 TABLE OF C ONTENTS .....................................................................4
2 SUMMARY ......................................................................................7
3 ZUSAMMENFASSUNG.......................................................................9
3.1 BLCKIENG N CC3 HEND 1D.................................... ....................10
3.2 DER EINFLSUS VON JAM-C AFU T1D.................................. .................................11
4 LIST OF ABBREVIATIONS...............................................................14
5 LIST OF FIGURES ..........................................................................16
6 INTRODUC TION.............................................................................19
6.1 EIE OF HE IMMNE EM...................................... .............................19
6.1.1 Innaet immune syestm............................................................ ..................19
6.1.2 Adapitev immune ssyetm............................................................ ..............20
6.1.3 T L .......................................................................................... 20
6.2 AUIOT MMNU ITY................................................. ....................................................22
6.2.1 Genetic susceptibility factors................................................................... 23
6.2.2 Enivronmenatl facorts............................................................. ..................24
6.2.3 Virus-induecd autoimmunity............................................................. ........24
6.3 DIABEET S OVERVIEW............................................. ..............................................26
6.3.1 Anaomt y and ufnitonc o f het panrecas ...................................................27
6.3.2 1 ......................................................................................... 28
6.4 MOE MDEL F 1D.................................................................................... 31
6.4.1 Classifiatcon and morpholog y of he t mplyhocityc horciomeninitgis ivrus
.................................................................................................................... 32
6.4.2 IP-LCMV Mo 1D.................................................................... 33
6.5 CHEMOKINES................................................ .........................................................35
6.5.1 Chemoiknes eovrivew............................................................. ...................35
6.5.2 The role of cytokines in T1D...................................... ...............................36
6.5.3 The role of CXCL10 and CXCR3 in T1D............................ ........................37
6.6 ADHESION MLO ECLU ES........................................... .............................................39
6.6.1 Rolling, adhesion and transmigraiton - the afmilies of adhesion molecules
.................................................................................................................... 39
4
T rfo led R The
T OR S O US
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TSYS U T W VR OV
T R ÄW RX OV UR O6.7 A A ..................................................... .............42
6.7.1 Ju ..................................42
6.7.2 Strutcure and ibohecmialc properites......................................................43
6.7.3 Ti ...............................................43
6.7.4 Propeirtes, inetraciton and liagnds...........................................................44
6.7.5 The role of JAM-C in various diseases and pancreatitis.......................... 44
7 AIMS OF THE STUDY.....................................................................47
7.1 RAST EGTY....................................................... ......................................................47
7.2 AI M 1: INIIBHIT NO FO CCXR3 DURIGN T1D............................................... ...........48
7.3 AI M 2: AJ -M C ADN IS T IFNELUCNE O N 1T D............................................ ............51
8 RESULTS .....................................................................................55
8.1 PROEJ CT 1: CCXR3 ADN IS T RLEO I N T1D.............................................. ............55
8.1.1 Implaaintton of osmiot c pumps uagranetes a ocnastn t delievr y of
suifiec nt NIBR2130...................................................................................55
8.1.2 Inhibition of CXCR3 significantly delays the outcome of disease in RIP-
LCMV-NP miec............................................................................................56
8.1.3 Inhibition of CXCR3 has no effect on ß cell function......................... ......58
8.1.4 Inhibition of CXCR3 has no influence on islet infiltration in virus-induced
T1D ............................................................................................................. 59
8.1.5 Neuratlizaiton of CXCR3 has no signifianc t influeenc on het funitocnal
itacivt oy Lf CMV-speiifc lc ymphocyets....................................................60
8.2 PROEJ CT 2: AJ -M C ADN IS T RLEO I N T1D............................................. .............64
8.2.1 LCMV-infeitocn resuls t in an upregulaiton of JAM-C around het isles t of
Langerhans.................................................................................................64
8.2.2 JAM-C : N JAM-C T1D
inidcenec.....................................................................................................66
8.2.3 JAM-C : Th y LCMV- T t
afetr nerualtization o f JAM-C....................................................................70
+8.2.4 JAM-C : I t CD8 T cel exratvsion and ß
- / ......................................7 3
8.2.5 JAM-C : C JAM-C
panrecati c endohetlial eclls o f rantsegni c pHHNS-JAM-C miec...............81
8.2.6 JAM-C overexpression: Virus-induced diabetes is not accelerated........82
5
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SELUCELMO NOISHED L NTOINCJU8.2.7 JAM-C : N t ,
or het presene c of LCMV-spiefic c T elcls.................................................83
9 DISCUSSION.................................................................................88
9.1 ATRACT IT NO ADN RAT SNIGMRAIT NO I N T1D....................................................8 8
9.2 IINHIBIOT N FO CXCR3 RECEPRO T WIT H A N CXCR3 ATNAGOINS T AND IST
INFLECNUE NO T1D.............................................................. ................................88
9.3 JA- A 1....................................................... ........................94
10 MATERIAL AND METHODS .........................................................102
10.1 SORCUE OF MAERTIALS........................................................... ........................102
10.1.1 Pla istc awre........................................................................................... ...102
10.1.2 Chemialcs............................................................................................. .....102
10.1.3 Composiiton of bufers, soluitons and ulcurte med.ia ...........................104
10.1.4 Enmzesy and proeitns.............................................................................106
10.1.5 Nu .................................................................106
10.1.6 Anitobdies............................................................................................. ...107
10.1.7 Ki.............................................................................................. ..............108
10.1.8 Cell inles............................................................................................ ........108
10.1.9 Virus............................................................................................... ...........109
10.1.10 Mo .......................................................................................... 109
10.2 .......................................................................................................... 110
10.2.1 Cell biologialc mehotds............................................................................110
10.2.2 Mo ....................