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Cytokine
production in blood leukocytes of prediabetic children
and effect of intranasal insulin
Principal Investigator: Jorma Ilonen, University
of Turku, Finland
Abstract | Investigators
| Background
| Resources
Abstract
Objectives: The aim of the study is to
create assays able to detect the beginning of islet cell
specific cellular immune response, the destructive capacity
of this response, and its natural development as well
as the possible effect of intranasal insulin treatment
on the direction of this response.
Basis: The proposal
is based on the ongoing Finnish Diabetes Prediction
and Prevention project identifying large number of study
subjects who are in various stages of prediabetes and
will in part be recruited to a secondary prevention
trial testing the effect of intranasal insulin treatment.
Rationale: It is known
that a long prediabetic period exists during which antibodies
to several diabetes associated autoantigens can be detected.
Insulin is the only well characterised antigens which
is beta-cell specific and autoantibodies to insulin
are usually the first to appear. In addition there are
several other autoantigens, GAD65 and IA-2 being the
best characterised. Autoimmunity as such does not necessarily
lead to beta-cell destruction and clinical disease,
but the balance of immune response between cytotoxic/destructive
Th1 and protective/tolerance promoting Th2/Th3 type
of responsiveness is important as supported also by
animal models. It is thus conceivable that assays able
to discern the type of ongoing autoimmunity could be
developed, and one might by tolerazing treatment affect
the direction of the response.
Significance: Reliable
assays able in early phase to show the ongoing beta-cell
destruction would allow the targeting of preventive
treatment to subjects who without treatment would in
most cases develop the clinical disease. The developed
assays might most probably also be able to monitor the
efficiency of tolerization treatment and this will be
tested in associated intranasal treatment trial.
Protocol Summary: The
protocol to be tested will include stimulation of peripheral
blood lymphocytes with insulin and insulin peptide recognised
as a major epitope in destructive beta-cell response
and detection of T-cell responses using a classic proliferative
response and repeated proliferation test with primed
cells. The production of intracellular and secreted
cytokines representing Th1, Th2 and Th3 type of responsiveness
will be also measured using flow cytometry and ELISPOT
methods and expression of cytokine mRNA in native and
stimulated cells measured using quantitative RT-PCR
methodology. The precursor frequency of cells recognising
dominant insulin and GAD65 epitopes will be also measured
using tetramer technology.
 Participating
Investigators
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Jorma Ilonen, University
of Turku, Finland |
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Outi Vaarala, National
Public Health Institute, Finland |
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Olli Simell, University
of Turku, Finland |
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Mikael Knip, University
of Helsinki, Finland |
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William Kwok, Virginia
Mason Research Center, Seattle, WA |
Background
Articles
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Natural
history of beta-cell autoimmunity in young children
with increased genetic susceptibility to type 1
diabetes recruited from the general population -
J Clin Endocrinol Metab [go ] |
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Natural course of preclinical
type 1 diabetes - Hormone Res[go]
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Resources
& Interesting Links
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Type 1
Diabetes Predication and Prevention Project - University
of Turku [go] |
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