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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 mellitusPublication History
eingereicht: 8.4.2009
akzeptiert: 17.12.2009
Publication Date:
17 February 2010 (online)
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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
- 2 Achenbach P, Bonifacio E, Koczwara K, Ziegler A G. Natural History of Type 1 Diabetes. Diabetes. 2005; 54 (Suppl. 2) S25-S31
- 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
- 4 Atkinson M A, Eisenbarth G S. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet. 2001; 358 221-229
- 5 Bach J -F. Insulin-dependent diabetes mellitus is an autoimmune disease. Endocrine Rev. 1994; 15 516-542
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 13 DPT-1. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med. 2002; 346 1685-1691
- 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
- 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
- 16 Faria A MC, Weiner H L. Oral tolerance. Immunol Rev. 2005; 206 232-259
- 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
- 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
- 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
- 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
- 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
- 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
- 23 Hess D. et al . Bone marrow-derived stem cells initiate pancreatic regeneration. Nat Biotechnol. 2003; 21 763-770
- 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
- 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
- 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
- 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
- 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
- 29 Lechner A. et al . Bone marrow stem cells find a path to the pancreas. Nat Biotechnol. 2003; 21 755-756
- 30 Lennard A L, Jackson G H. Stem cell transplantation. BMJ. 2000; 321 433-437
- 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
- 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
- 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
- 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
- 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
- 36 Mandrup-Poulsen T. The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia. 1996; 39 1005-1029
- 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
- 38 Mathis D, Vence L, Benoist C. β-Cell death during progression to diabetes. Nature. 2001; 414 792-798
- 39 Mayer L, Shao L. Therapeutic potential of oral tolerance. Nat Rev Immunol. 2004; 4 407-419
- 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
- 41 Notkins A L, Lernmark A. Autoimmune type 1 diabetes: resolved and unresolved issues. J Clin Invest. 2001; 108 1247-1252
- 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
- 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
- 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
- 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
- 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
- 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
- 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
Prof. Dr. med. Anette-G. Ziegler
Forschergruppe Diabetes der TU München
Kölner
Platz 1
80804 München
Phone: 089/30683380
Fax: 089/30687509
Email: anziegler@lrz.uni-muenchen.de