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DOI: 10.1055/s-0030-1249169
© Georg Thieme Verlag KG Stuttgart · New York
Übersicht über aktuelle Studien zur Prävention und Immunintervention des Diabetes mellitus Typ 1
Survey of recent clinical trials of the prevention and immunointervention of type 1 diabetes mellitusPublikationsverlauf
eingereicht: 8.4.2009
akzeptiert: 17.12.2009
Publikationsdatum:
17. Februar 2010 (online)

Zusammenfassung
Immunmodulatorische Therapieansätze bei Diabetes mellitus Typ 1 (T1DM) zielen auf die Verhinderung der Entstehung (Primär-) und Progression (Sekundär-) von Inselautoimmunität bei nicht-diabetischen Personen mit hohem Erkrankungsrisiko bzw. den Erhalt der β-Zell-Restfunktion bei Patienten mit neu-manifestiertem Diabetes (Tertiärprävention). Diese Arbeit soll einen Überblick über aktuelle Immuninterventionsstudien bei T1DM geben. 1.) Die Pre-POINT-Studie prüft eine Intervention mit oralem/nasalem Insulin, im Sinne einer Schutzimpfung, bei Autoantikörper-negativen Kindern mit hohem genetischem Diabetesrisiko. 2.) Die „Cord Blood Study” untersucht die Wirksamkeit einer Transfusion von autologem Nabelschnurblut bei Kindern mit T1DM im Hinblick auf die β-Zell-Regeneration und Verbesserung der Blutglukose-Kontrolle. 3.) In der „GAD Vaccination Study” soll die kürzlich in einer Phase-II-Studie nachgewiesene Wirkung einer rhGAD65-Impfung, die zum Erhalt der β-Zell-Restfunktion bei Patienten mit T1DM führte, in einer Phase-III-Studie mit 320 neu-erkrankten Kindern verifiziert werden. 4.) Die AIDA-Studie prüft die anti-inflammatorische/β-Zell-protektive Wirkung des Interleukin-1-Rezeptor-Antagonisten Anakinra bei 80 Patienten mit T1DM.
Abstract
Immunomodulatory strategies in the management of type 1 diabetes mellitus (T1DM) have as their primary target the prevention of initiating islet autoimmunity (primary-), the secondary one is the progression to diabetes (secondary-) in non-diabetic persons at risk, and the decline of β-cell function in new-onset patients (tertiary-prevention). This article reviews four recent immunointervention trials in patients with T1DM. (1) The Pre-POINT study is a primary prevention trial that will test whether vaccination with oral or nasal insulin can prevent the progression of islet autoimmunity and of T1DM in autoantibody-negative children who are genetically at high diabetes risk. (2) The Cord Blood study is a tertiary immunointervention trial that will test whether administration of autologous umbilical cord blood to children with T1DM can lead to regeneration of pancreatic islet insulin-producing β-cells and improved blood glucose control. (3) The GAD Vaccination study will test whether vaccination with alum-formulated rhGAD65 (recombinant human glutamic acid decarboxylate) can preserve β-cell function in 320 children with newly diagnosed T1DM, as has been suggested in a recent phase II study. (4) The AIDA study will test the β-cell protective effect of interleukin-1-receptor antagonist Anakinra in 80 patients with T1DM, which has recently been shown to improve β-cell function in patients with type 2 diabetes.
Schlüsselwörter
Diabetes mellitus Typ 1 - Immunprävention - Immunintervention - Interventionsstudie
Keywords
type 1 diabetes mellitus - immunoprevention - immunointervention - intervention trial
Literatur
- 1
Achenbach P, Barker J, Bonifacio E.
Modulating the natural history of type 1 diabetes in children
at high genetic risk by mucosal insulin immunization.
Curr
Diab Rep.
2008;
8
87-93
MissingFormLabel
- 2
Achenbach P, Bonifacio E, Koczwara K, Ziegler A G.
Natural History
of Type 1 Diabetes.
Diabetes.
2005;
54
(Suppl. 2)
S25-S31
MissingFormLabel
- 3
Aly T A, Ide A, Barker J M. et al .
HLA genotype and haplotype sharing determine
extremely high risk of early childhood type 1 diabetes.
Proc
Natl Acad Sci USA.
2006;
103
14 074-14 079
MissingFormLabel
- 4
Atkinson M A, Eisenbarth G S.
Type 1
diabetes: new perspectives on disease pathogenesis and treatment.
Lancet.
2001;
358
221-229
MissingFormLabel
- 5
Bach J -F.
Insulin-dependent diabetes mellitus is an autoimmune disease.
Endocrine Rev.
1994;
15
516-542
MissingFormLabel
- 6
Barker J M, Barriga K J, Yu L. et al .
Prediction of autoantibody positivity and
progression to type 1 diabetes: Diabetes Autoimmunity Study in the
Young (DAISY).
J Clin Endocrinol Metab.
2004;
89
3896-3902
MissingFormLabel
- 7
Bendtzen K, Mandrup-Poulsen T, Nerup J, Nielsen J H, Dinarello C A, Svenson M.
Cytotoxicity
of human pI7 interleukin-1 for pancreatic islets of Langerhans.
Science.
1986;
232
1545-1547
MissingFormLabel
- 8
Beilhack G F, Scheffold Y C, Weissman I L. et al .
Purified allogeneic
hematopoietic stem cell transplantation blocks diabetes pathogenesis
in NOD mice.
Diabetes.
2003;
52
59-68
MissingFormLabel
- 9
Bonifacio E, Hummel M, Walter M, Schmid S, Ziegler A G.
IDDM1 and multiple family history of type 1 diabetes combine
to identify neonates at high riskfor type 1 diabetes.
Diabetes
Care.
2004;
27
2695-2700
MissingFormLabel
- 10
Blau H M, Brazelton T R, Weimann J M.
The evolving concept of a stem cell: entity
or function?.
Cell.
2001;
105
829-841
MissingFormLabel
- 11
Comi G, Kappos L, Clanet M. et
al .
Guidelines for autologous blood and marrow stem
cell transplantation in multiple sclerosis: a consensus report written
on behalf of the European Group for Blood and Marrow Transplantation
and the European Charcot Foundation. BMT-MS Study Group.
J
Neurol.
2000;
247
376-382
MissingFormLabel
- 12
Daniel D, Wegmann D R.
Protection of
nonobese diabetic mice from diabetes by intranasal or subcutaneous
administration of insulin peptide B-(9 – 23).
Proc Natl Acad Sci USA.
1996;
93
956-960
MissingFormLabel
- 13
DPT-1. Effects of insulin in relatives
of patients with type 1 diabetes mellitus.
N Engl J Med.
2002;
346
1685-1691
MissingFormLabel
- 14
Ende N, Chen R, Mack R.
NOD/LtJ
type I diabetes in mice and the effect of stem cells (Berashis)
derived from human umbilical cord blood.
J Med.
2002;
33
181-187
MissingFormLabel
- 15
Eizirik D L, Mandrup-Poulsen T.
A choice of
death – the signal-transduction of immune-mediated beta-cell
apoptosis.
Diabetologia.
2001;
44
2115-2133
MissingFormLabel
- 16
Faria A MC, Weiner H L.
Oral tolerance.
Immunol Rev.
2005;
206
232-259
MissingFormLabel
- 17
Fleischmann R M, Tesser J, Schiff M H. et al .
Safety of extended treatment with Anakinra
in patients with rheumatoid arthritis.
Ann Rheum Dis.
2006;
65
1006-1012
MissingFormLabel
- 18
Fraser C K, Diener K R, Brown M P, Hayball J D.
Improving
vaccines by incorporating immunological coadjuvants.
Expert
Rev Vaccines.
2007;
6
559-578
MissingFormLabel
- 19
Gale E A, Bingley P J, Emmett C L, Collier T.
European
Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled
trial of intervention before the onset of type 1 diabetes.
Lancet.
2004;
363
925-931
MissingFormLabel
- 20
Godfrey W R, Spoden D J, GE Y G. et al .
Cord blood CD4(+)CD25(+)-derived
T regulatory cell lines express FoxP3 protein and manifest potent suppressor
function.
Blood.
2005;
105
750-758
MissingFormLabel
- 21
Haller M J, Viener H L, Wasserfall C, Brusko T, Atkinson M A, Schatz D A.
Autologous
umbilical cord blood infusion for type 1 diabetes.
Exp Hematol.
2008;
36
710-715
MissingFormLabel
- 22
Harrison L C, Dempsey-Collier M, Kramer D R, Takahashi K.
Aerosol
insulin induces regulatory CD8 gamma delta T cells that prevent
murine insulin-dependent diabetes.
J Exp Med.
1996;
184
2167-2174
MissingFormLabel
- 23
Hess D. et
al .
Bone marrow-derived stem cells initiate pancreatic
regeneration.
Nat Biotechnol.
2003;
21
763-770
MissingFormLabel
- 24
Hummel M, Bonifacio E, Schmid S, Walter M, Knopff A, Ziegler A G.
Brief communication:
early appearance of islet autoantibodies predicts childhood type
1 diabetes in offspring of diabetic parents.
Ann Intern
Med.
2004;
140
882-886
MissingFormLabel
- 25
Jansen F K, Muntefering H, Schmidt W A.
Virus induced diabetes and the immune system.
I. Suggestion that appearance of diabetes depends on immune reactions.
Diabetologia.
1977;
13
545-549
MissingFormLabel
- 26
Kent S C, Chen Y, Bregoli L. et al .
Expanded T cells from pancreatic lymph
nodes of type 1 diabetic subjects recognize an insulin epitope.
Nature.
2005;
435
224-228
MissingFormLabel
- 27
Kimpimaki T, Kulmala P, Savola K. et al .
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.
2002;
87
4572-4579
MissingFormLabel
- 28
Larsen C M, Faulenbach M, Vaag A, Vølund A, Ehses J A, Seifert B, Mandrup-Poulsen T, Donath M Y.
Interleukin-1-Rezeptor
Antagonist in Type 2 Diabetes Mellitus.
N Engl J Med.
2007;
356
1517-1526
MissingFormLabel
- 29
Lechner A. et al .
Bone marrow stem cells find a path to the
pancreas.
Nat Biotechnol.
2003;
21
755-756
MissingFormLabel
- 30
Lennard A L, Jackson G H.
Stem cell
transplantation.
BMJ.
2000;
321
433-437
MissingFormLabel
- 31
Leslie R D, Atkinson M A, Notkins A L.
Autoantigens IA-2 and GAD in Type I (insulin-dependent)
diabetes.
Diabetologia.
1999;
42
3-14
MissingFormLabel
- 32
Ludvigsson J, Faresjö M, Hjorth M. et al .
GAD treatment and Insulin secretion in
recent-onset type 1 diabetes.
N Engl J Med.
2008;
359
1909-1920
MissingFormLabel
- 33
Maedler K, Sergeev P, Ris F. et
al .
Glucose-induced beta-cell-production of IL-1beta
contributes to glucotoxicity in human pancreatic islets.
J
Clin Invest.
2002;
110
851-860
MissingFormLabel
- 34
Maedler K, Sergeev P, Ehses J A. et al .
Leptin modulates beta cell expression of
IL-1 receptor antagonist and release of IL-1beta in human islets.
Proc Natl Acad Sci USA.
2004;
101
8138-8143
MissingFormLabel
- 35
Mandrup-Poulsen T, Bendtzen K, Nerup J, Dinarello C A, Svenson M, Nielsen J H.
Affinity-purified
human interleukin I is cytotoxic to isolated islets of Langerhans.
Diabetologia.
1986;
29
63-67
MissingFormLabel
- 36
Mandrup-Poulsen T.
The role of interleukin-1 in the pathogenesis of IDDM.
Diabetologia.
1996;
39
1005-1029
MissingFormLabel
- 37
Maron R, Guerau-de-Arellano M, Zhang X, Weiner H L.
Oral administration
of insulin to neonates suppresses spontaneous and cyclophosphamide
induced diabetes in the NOD mouse.
J Autoimmun.
2001;
16
21-28
MissingFormLabel
- 38
Mathis D, Vence L, Benoist C.
β-Cell death during progression to diabetes.
Nature.
2001;
414
792-798
MissingFormLabel
- 39
Mayer L, Shao L.
Therapeutic potential of oral
tolerance.
Nat Rev Immunol.
2004;
4
407-419
MissingFormLabel
- 40
Näntö-Salonen K, Kupila A, Simell S. et al .
Nasal insulin to prevent
type 1 diabetes in children with HLA genotypes and autoantibodies
conferring increased risk of disease: a double-blind, randomised
controlled trial.
Lancet.
2008;
372
1746-1755
MissingFormLabel
- 41
Notkins A L, Lernmark A.
Autoimmune type 1 diabetes:
resolved and unresolved issues.
J Clin Invest.
2001;
108
1247-1252
MissingFormLabel
- 42
Palmers J P, Fleming G A, Greenbaum C J. et al .
C-Peptide is the appropriate
outcome measure for type 1 diabetes clinical trials to preserve β-cell
function: report of an ADA workshop, 21 – 22
October 2001.
Diabetes.
2004;
53
250-264
MissingFormLabel
- 43
Pleau. et
al .
Prevention of autoimmune disease in nonobese diabetic female
mice by treatment with recombinant glutamic acid decarboxylase (GAD65).
Clin Immunol Pathol.
1995;
76
90-95
MissingFormLabel
- 44
Schiff M H, Divittorio G, Fleischmann R M. et al .
The safety of Anakinra in
high-risk patients with active rheumatoid Arthritis – six-month observations
of patients with comorbid conditions.
Arthritis & Rheumatism.
2004;
50
1752-1760
MissingFormLabel
- 45
Skyler J S, Krischer J P, Wolfsdorf J. et al .
Effects of oral insulin
in relatives of patients with type 1 diabetes: The Diabetes Prevention
Trial-Typ 1.
Diabetes Care.
2005;
28
1068-1076
MissingFormLabel
- 46
Vardi P, Ziegler A G, Mathews J H. et al .
Concentration of insulin
autoantibodies at onset of type 1 diabetes. Inverse log-linear correlation with
age.
Diabetes Care.
1988;
11
736-739
MissingFormLabel
- 47
Zhang Z J, Davidson L, Eisenbarth G, Weiner H L.
Suppression
of diabetes in nonobese diabetic mice by oral administration of
porcine insulin.
Proc Natl Acad Sci USA.
1991;
88
10252-10256
MissingFormLabel
- 48
Ziegler A G, Hummel M, Schenker M, Bonifacio E.
Antibody appearance and
risk for development of childhood diabetes in offspring of parents
with type 1 diabetes: the 2-year analysis of the German BABYDIAB
Study.
Diabetes.
1999;
48
460-468
MissingFormLabel
Prof. Dr. med. Anette-G. Ziegler
Forschergruppe Diabetes der TU München
Kölner
Platz 1
80804 München
Telefon: 089/30683380
Fax: 089/30687509
eMail: anziegler@lrz.uni-muenchen.de