Circulating concentrations of cytokines as markers for pathogenic processes in type 1 diabetes and their association with {β-cell [beta-cell] function, {β-cell [beta-cell] stress and metabolic status [Elektronische Ressource] / vorgelegt von Christian Pfleger

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Informations

• Publié par: heinrich-heine-universitat_dusseldorf
• Publié le: 01 janvier 2008
• Nombre de lectures: 10
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Circulating concentrations of cytokines as markers for
pathogenic processes in type 1 diabetes and their association
with ß-cell function, ß-cell stress and metabolic status





Inaugural-Dissertation

zur
Erlangung des Doktorgrades der
Mathematisch-Naturwissenschaftlichen Fakultät
der Heinrich-Heine-Universität Düsseldorf


vorgelegt von
Christian Pfleger
aus Düsseldorf


Mai 2008




















Gedruckt mit der Genehmigung der
Mathematisch-Naturwissenschaftlichen Fakultät der
Heinrich-Heine-Universität Düsseldorf

Referent: PD. Dr. N.C. Schloot
Korreferent: Prof. Dr. M. Kassack












to
Leonie, Maya and Lilu
Contents

List of abbreviations II

Chapter 1 1
Introduction

Chapter 2 29
Effect of serum content and diluent selection on assay sensitivity and signal
intensity in multiplex bead-based immunoassays
J Immunol Methods. 2008 Jan 1;329(1-2):214-8

Chapter 3 39
Relation of circulating concentrations of chemokine receptor CCR5 ligands to
C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes
Clin Immunol. 2008 Apr 21. (Epub ahead of print)

Chapter 4 61
Association of IL-1ra and adiponectin with C-peptide and remission in patients
with type 1 diabetes
Diabetes. 2008 Apr;57(4):929-37

Chapter 5 87
Association of ß-cell function with T-cell reactivity to islet antigens in recent
onset type 1 diabetes
Manuscript in preparation

Chapter 6 111
Summary and General discussion

Summary/ Zusammenfassung 127
Curiculm vitae 133
List of scientific publications/ oral presentations and posters/ awards and price 137
Danksagung 141
I List of abbreviations

BBDR biobreeding diabetes-resistant
BMI body mass index
CCL CC-chemokine ligand
CCR okine receptor
CTLA cytotoxic T-lymphocyte associated
DZB daclizumab
ELISA enzyme-linked immunosorbent
ELISPOT enzymunosorbent spot
Foxp forkhead family transcription factor
GAD glutamicacid decarboxylase
HbA1c haemoglobin A1c
Hsp heat shock protein
HLA human leucocyte antigen
ICA islet cell antibody
IAA insulin antibody
IA-2 insulinoma associated antigen-2
IDDM insulin dependent diabetes mellitus type 1
IFN interferon
IL interleukin
MHC major histocompatibility complex
MCP macrophage chemoattractant protein
MFI mean fluorescence intensity
MIP macrophage inflammatory protein
MMF mycophenolate mofeteil
NOD non-obese diabetic
PBMC peripheral mononuclear cell
PHA mitogen phytohemagglutinin
PI phorbol-myristate-acetate and ionomycin
PL parameter logistic
PMA phorbol-myristate-acetate
II RANTES regulated upon activation, normal T-cell expressed and secreted
ROR retinoic acid-related orphan nuclear receptor
SI stimulation index
STAT transducer and activator of transcription
SOCS suppressor of cytokine signaling
T-bet T-box expressed in T-cells
TC tissue culture medium
TGF transforming growth factor
TLR Toll like receptor
TNF tumor necrosis factor
Treg regulatory T-cells
TT tetanus toxoid
VNTR variable number of tandem repeats
ZnT zinc transporter
III

IV

1

Introduction Chapter 1
Type 1 diabetes

Type 1 diabetes is an immune mediated disease characterized by the selective destruction of
insulin producing ß-cells in the pancreas, leading to insulin deficiency and hyperglycemia.
Patients require lifelong administration of exogenous insulin for their survival (1).
Interactions between genetic and yet unknown environmental factors are thought to be the
origin of type 1 diabetes. This is illustrated by the highly variable incidence of type 1 diabetes
among different ethnic populations: from 0.1/100.000 per year in China to more than
40/100.000 per year in Finland. In addition, a north-south gradient with lowest incidence
rates in the south has been described, but high incidence rates have been also reported in
Kuwait and Puerto Rico. Of concern is the rapidly rising incidence of type 1 diabetes
worldwide and the trend towards an earlier disease onset. Most striking is this development in
regions with traditionally low incidence (2,3). The incidence of type 1 diabetes is estimated to
be about 40% higher in 2010 than in 1997 (4).
The onset of clinically overt type 1 diabetes occurs when remaining ß-cells are not able to
maintain sufficient metabolic control. However, after clinical onset and initiation of insulin
therapy around 30-60% of children and adolescents develop a temporary and partial
remission phase that is called "honeymoon phase". This phase develops during the first 1-6
months after starting insulin treatment and may last up to 1-2 years (5). Adults and
adolescents are more likely to enter remission than very young children which probably
reflects a more aggressive disease progression at younger age (6). However, the underlying
mechanisms of remission are not clear and may not only be attributable to improved ß-cell
function, but also to a decline of insulin resistance as result of better glycemic control (7,8).

Pathogenesis of type 1 diabetes
Autoantibodies that are directed against islet antigens such as islet cells (ICA), insulin (IAA),
glutamic acid decarboxylase (GADA) and protein tyrosine phosphatase (IA-2/IA-2ß) can be
detected years before the onset of clinical type 1 diabetes and identify individuals at risk to
develop type 1 diabetes (9-11). Recently, a new autoantigen has been found, the zinc
transporter T8 (ZnT8), and the combined measurement of ZnT8A, GADA, IA2A, and IAA
raised autoimmunity detection rates to 98% at disease onset, a level that approaches the need
to detect prediabetes in a general pediatric population (12). However, not all of these so
2