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Diabetologie und Stoffwechsel 2011; 6(2): 98-103
DOI: 10.1055/s-0031-1271436
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© Georg Thieme Verlag KG Stuttgart ˙ New York

Therapie des Typ-1-Diabetes im Wandel – Neue Möglichkeiten durch Immunintervention?

Treatment of Type 1 Diabetes is Changing – Breakthrough in Immune Intervention?M. Wallner1 [1] , L. Thümer1 [1] , M. Hummel1 , A. G. Ziegler1
  • 1Forschergruppe Diabetes, Klinikum rechts der Isar der Technischen Universität München
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Publication Date:
06 April 2011 (online)

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Zusammenfassung

Hintergrund: Der Typ-1-Diabetes zählt zu den Autoimmunerkrankungen. Ein Zusammenspiel von genetischen, immunologischen und zelltoxischen Faktoren führt zur Zerstörung der insulinproduzierenden Betazellen des Pankreas bei Menschen mit Typ-1-Diabetes. Eine Reihe von Immuntherapeutika befinden sich in Erprobung, um den natürlichen Verlauf der Typ-1-Diabeteserkrankung günstig zu beeinflussen. Methoden: Selektive Literaturrecherche in mehreren Datenbanken (Pubmed und clinicaltrials.gov, Stand: November 2010). Ergebnisse: Die heute in klinischen Studien verwendeten Immuntherapeutika zielen auf unterschiedliche Mechanismen der Immunabwehr wie der Antigenpräsentation (antigenspezifische Therapie, Rituximab), der Expansion autoreaktiver T-Zellen (anti-CD3) und der Inflammation durch Zytokine (IL-1β-Antagonist). Immuntherapeutika werden nicht nur nach Manifestation eines Typ-1-Diabetes adjuvant zu einer intensivierten Insulintherapie, sondern auch als Primärprävention bei Kindern mit sehr hohem Diabetesrisiko oder als Sekundärprävention bei Kindern, Jugendlichen und Erwachsenen mit positiven Inselautoantikörpern eingesetzt. Schlussfolgerungen: Adjuvante Immuntherapeutika und Kombinationen unterschiedlicher Substanzklassen könnten zur Verbesserung des Therapieerfolgs bei Typ-1-Diabetes in Zukunft eine große Rolle spielen. Wichtig wird auch die Bewertung der Sicherheitsprofile der Therapien sein, damit sie im Kindesalter oder auch zur Prävention vermehrt zum Einsatz kommen können. 

Abstract

Background: Type 1 diabetes is an autoimmune disease. An interaction of genetic, immunologic and cell-toxic factors leads to the destruction of insulin producing beta cells in the pancreas of patients with type 1 diabetes. A number of immune therapeutics which are to improve the natural progress of the disease are currently evaluated in clinical trials. Methods: Selective research of the literature in databases (pubmed and clinicaltrials.gov, November 2010). Results: Immune therapeutics used in current clinical trials target different mechanisms of the immune system, like antigen presentation (antigen specific therapy, Rituximab), expansion of auto reactive t-cells (anti-CD3), and inflammation via cytokines (IL-1β-antagonist). Immune therapeutics are not only applied after diabetes onset adjuvant to intensive insulin therapy, but also as primary prevention in children with a high diabetes risk or as secondary prevention in children, adolescent and adults with positive islet autoantibodies. Conclusion: Adjuvant immune therapeutics and combinations of different therapeutic principles may play an important role for future treatment of type 1 diabetes. The evaluation of drug safety will be crucial, so that therapies can be applied in early childhood or as preventive treatment. 

Schlüsselwörter

Typ-1-Diabetes - Immunintervention - Prävention

Key words

type 1 diabetes - immune intervention - prevention

Literatur

  • 1 Patterson C C, Dahlquist G G, Gyürüs E et al. Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–2020: a multicentre prospective registration study.  Lancet. 2009;  373 2027-2033
    CrossrefGoogle Scholar
  • 2 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
    CrossrefGoogle Scholar
  • 3 A Phase III Study to Investigate the Impact of Diamyd in Patients Newly Diagnosed With Type 1 Diabetes (EU). http://www.clinicaltrials.gov/ct2/show/NCT00723411
    Google Scholar
  • 4 Elias D, Meilin A, Ablamunits V et al. Hsp60 peptide therapy of NOD mouse diabetes induces a Th2 cytokine burst and downregulates autoimmunity to various beta-cell antigens.  Diabetes. 1997;  46 758-764
    CrossrefGoogle Scholar
  • 5 Efficacy and Safety Study of DiaPep277 in Newly Diagnosed Type 1 Diabetes Adults. http://www.clinicaltrials.gov/ct2/show/NCT01103284
    Google Scholar
  • 6 Chatenoud L. Immune therapy for type 1 diabetes mellitus – what is unique about anti-CD3 antibodies?.  Nat Rev Endocrinol. 2010;  6 149-157
    CrossrefGoogle Scholar
  • 7 Chatenoud L, Primo J, Bach J F. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice.  J Immunol. 1997;  158 2947-2954
    Google Scholar
  • 8 Keymeulen B, Walter M, Mathieu C et al. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass.  Diabetologia. 2010;  53 614-623
    CrossrefGoogle Scholar
  • 9 Herold K C, Gitelman S E, Masharani U et al. A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes.  Diabetes. 2005;  54 1763-1769
    CrossrefGoogle Scholar
  • 10 Pescovitz M D, Greenbaum C J, Krause-Steinrauf H et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function.  N Engl J Med. 2009;  361 2143-2152
    CrossrefGoogle Scholar
  • 11 Baumgartl H J, Standl E, Schmidt-Gayk H et al. Changes of vitamin D3 serum concentrations at the onset of immune-mediated type 1 (insulin-dependent) diabetes mellitus.  Diabetes Res. 1991;  16 145-148
    Google Scholar
  • 12 Mathieu C, Gysemans C, Giulietti A et al. Vitamin D and diabetes.  Diabetologia. 2005;  48 1247-1257
    CrossrefPubMedGoogle Scholar
  • 13 Walter M, Kaupper T, Adler K et al. No effect of the 1alpha,25-dihydroxyvitamin D3 on beta-cell residual function and insulin requirement in adults with new-onset type 1 diabetes.  Diabetes Care. 2010;  33 1443-1448
    CrossrefGoogle Scholar
  • 14 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
    Google Scholar
  • 15 Pickersgill L MS, Mandrup-Poulsen T R. The anti-interleukin-1 in type 1 diabetes action trial – background and rationale.  Diabetes Metab Res Rev. 2009;  25 321-324
    CrossrefGoogle Scholar
  • 16 Mastrandrea L, Yu J, Behrens T et al. Etanercept treatment in children with new-onset type 1 diabetes: pilot randomized, placebo-controlled, double-blind study.  Diabetes Care. 2009;  32 1244-1249
    CrossrefGoogle Scholar
  • 17 Gottlieb P A, Quinlan S, Krause-Steinrauf H et al. Failure to preserve beta-cell function with mycophenolate mofetil and daclizumab combined therapy in patients with new- onset type 1 diabetes.  Diabetes Care. 2010;  33 826-832
    CrossrefGoogle Scholar
  • 18 Haller M J, Wasserfall C H, McGrail K M et al. Autologous umbilical cord blood transfusion in very young children with type 1 diabetes.  Diabetes Care. 2009;  32 2041-2046
    CrossrefGoogle Scholar
  • 19 Haller M J, Viener H, Wasserfall C et al. Autologous umbilical cord blood infusion for type 1 diabetes.  Exp Hematol. 2008;  36 710-715
    CrossrefGoogle Scholar
  • 20 Gillespie K M, Gale E AM, Bingley P J. High familial risk and genetic susceptibility in early onset childhood diabetes.  Diabetes. 2002;  51 210-214
    CrossrefGoogle Scholar
  • 21 Achenbach P, Pan L, Ziegler A G. Frühdiagnostik bei Typ-1-Diabetes.  Der Diabetologe. 2008;  4 47-58
    CrossrefGoogle Scholar
  • 22 Harrison L C. Vaccination against self to prevent autoimmune disease: the type 1 diabetes model.  Immunol Cell Biol. 2008;  86 139-145
    CrossrefGoogle Scholar
  • 23 Ziegler A G, Hummel M, Schenker M et al. Autoantibody 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
    CrossrefPubMedGoogle Scholar
  • 24 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
    CrossrefGoogle Scholar
  • 25 Diabetes Prevention Trial – Type 1 Diabetes Study Group . Effects of insulin in relatives of patients with type 1 diabetes mellitus.  N Engl J Med. 2002;  346 1685-1691
    CrossrefGoogle Scholar
  • 26 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
    CrossrefGoogle Scholar
  • 27 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 – Type 1.  Diabetes Care. 2005;  28 1068-1076
    CrossrefGoogle Scholar
  • 28 Oral Insulin for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes. http://www.clinicaltrials.gov/ct2/show/NCT00419562
    Google Scholar
  • 29 Trial of Intranasal Insulin in Children and Young Adults at Risk of Type 1 Diabetes. http://www.clinicaltrials.gov/ct2/show/NCT00336674
    Google Scholar
  • 30 Steffes M W, Sibley S, Jackson M et al. Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial.  Diabetes Care. 2003;  26 832-836
    CrossrefGoogle Scholar
  • 31 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
    CrossrefGoogle Scholar
  • 32 Aly T A, Ide A, Jahromi M M et al. Extreme genetic risk for type 1 A diabetes.  Proc Natl Acad Sci USA. 2006;  103 14074-14079
    CrossrefGoogle Scholar
  • 33 TEDDY study group . The Environmental Determinants of Diabetes in the Young (TEDDY) study: study design.  Pediatr Diabetes. 2007;  8 286-298
    CrossrefGoogle Scholar
  • 34 TRIGR study group . Study design of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR).  Pediatr Diabetes. 2007;  8 117-137
    CrossrefGoogle Scholar
  • 35 Knip M, Virtanen S M, Seppä K et al. Dietary intervention in infancy and later signs of beta-cell autoimmunity.  N Engl J Med. 2010;  363 1900-1908
    CrossrefGoogle Scholar
  • 36 Schmid S, Buuck D, Knopff A et al. BABYDIET, a feasibility study to prevent the appearance of islet autoantibodies in relatives of patients with Type 1 diabetes by delaying exposure to gluten.  Diabetologia. 2004;  47 1130-1131
    Google Scholar
  • 37 Stene L C, Joner G. Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study.  Am J Clin Nutr. 2003;  78 1128-1134
    Google Scholar
  • 38 Ludvigsson J. Immune intervention in children with type 1 diabetes.  Curr Diab Rep. 2010;  10 370-379
    CrossrefGoogle Scholar

1 gemeinsame Erstautorenschaft

Univ.-Prof. Dr. med. A.-G. Ziegler

Forschergruppe Diabetes · Lehrstuhl Diabetes und Gestationsdiabetes · Klinikum rechts der Isar der Technischen Universität München

Kölner Platz 1

80804 München

Phone: 00 49 / 89 / 30 68 33 80

Email: anziegler@lrz.uni-muenchen.de

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