Immunintervention bei neu diagnostiziertem Typ-1-Diabetes

 

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Zusammenfassung

Typ-1-Diabetes (T1D) ist die Folge eines T-Zell-vermittelten Autoimmunprozesses, der zur Zerstörung der pankreatischen Betazellen führt. Auch nach der klinischen Manifestation trägt eine körpereigene Restproduktion von Insulin wesentlich zu einer stabileren und besseren Blutzuckereinstellung bei und somit auch dazu, das Auftreten von diabetischen Folgeerkrankungen hinauszuzögern oder zu verhindern.

Diese Übersicht stellt die Studien zur Immunintervention bei neumanifestem T1D dar, die derzeit in deutschen Zentren auf nationaler oder internationaler Ebene durchgeführt werden. Primärer Endpunkt aller Studien ist der Erhalt der Betazell-Reserve, gemessen am basalen und stimulierten C-Peptid. Sekundäre Endpunkte umfassen HbA_1c, Insulinbedarf, Nüchternblutzucker sowie das zelluläre und humorale Immunmonitoring. 1) Die Wirksamkeit des synthetischen Peptids DiaPep277 soll in einer placebokontrollierten, doppelblinden Phase III Studie an 400 Teilnehmern in elf Ländern verifiziert werden. 2) In München und Mailand werden derzeit Mycophenolat mofetil und Daclizumab (MMF-DZB), zwei aus der Transplantationsmedizin bekannte Wirkstoffe, kombiniert. 3) In München läuft eine Studie zur Immunintervention mit 1,25-Dihydroxy-Vitamin D3 mit 40 Teilnehmern. 4) In Belgien, Paris und München werden 80 Teilnehmer einer Phase II-Studie mit dem aglykosylierten, nicht mitogenen monoklonalen CD3-Antikörper YTH 12.5 (ChAgly CD3) nach nur 6-tägiger Infusion bereits im 4. Jahr nachbeobachtet. Eine Zwischenauswertung nach 18 Monaten zeigte sich erfolgreich. 5) Eine Phase II Studie mit dem alterierten Peptidliganden APL-NBI-6024 zeigte keinen Effekt auf die Betazell-Restfunktion.

Summary

Type 1 diabetes (T1D) ist the result of a T-cell mediated autoimmune process leading to destruction of pancreatic beta cells. Even after clinical manifestation of the disease, a residual secretion of endogenous insulin essentially helps to maintain better metabolic control and also to delay or prevent the onset of complications.

This review describes intervention trials in newly diagnosed T1D which are currently performed in German diabetes centers on a national or international base. Primary endpoint in all these studies is the preservation of the beta cell reserve, indicated by basal and stimulated C-peptide. Secondary endpoints include HbA_1c levels, insulin requirements, fasting blood glucose levels, and monitoring of cellular and humoral immune responses. 1) The effectiveness of the synthetic peptide DiaPep277 will be verified in a double-blind placebo-controlled phase III study including 400 participants in 11 countries. 2) In Munich and Milan an ongoing study combines mycophenolate mofetil and daclizumab (MMF-DZB). Both drugs are known from transplant medicine. 3) In Munich, a trial tests the immunointervention with 1,25-dihydroxyvitamin D3 in 40 subjects. 4) In Belgium, Paris and Munich, 80 participants in a phase II study who were given the aglycosylated, non-mitogenic monoclonal anti-CD3 antibody YTH 12.5 (ChAgly CD3) intravenously over 6 days, have now been followed-up for nearly 4 years. A first analysis after 18 months showed a quite successful therapy. 5) A phase II trial with the altered peptide ligand APL-NBI-6024 did not show any effect on betacell residual function.

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Thomas Kaupper

Institut für Diabetesforschung

Kölner Platz 1

80804 München

Phone: 089/30793114

Fax: 089/3081733

Email: prevent.diabetes@lrz.uni-muenchen.de