Research Groups

Portrait Ezio Bonifacio

Ezio Bonifacio

Regenerative Therapies for Diabetes

Previous and Current Research

Type I diabetes is characterized by insulin deficiency primarily caused by the autoimmune-mediated destruction of insulin secreting beta cells located in the pancreas. Understanding how the autoimmunity initiates and is perpetuated is relevant to introducing therapies that will prevent beta cell destructive immunity.

The pathogenesis of diabetes mellitus hinges on the loss of pancreatic islet beta cells which in type 1 diabetes is mediated by autoimmunity. We have studied how autoimmunity develops in the course of the disease in children, the target beta cell antigens and epitopes, and the factors that predispose to autoimmunity. We discovered that autoimmunity develops most frequently around 1 to 2 years of age and that the proinsulin prohormone is the primary target antigen. We have also demonstrated that maternal diabetes protects against the development of beta cell autoimmunity. The findings have led to the first primary vaccine study that we are conducting as a multi-center international trial. This Pre-POINT trial identified doing of oral insulin that could engage the immune system and which now forms the basis for further primary and secondary prevention trials. These include Pre-POINT Early, which will test oral insulin versus placebo treatment at age 6 months.

Our overall goal is to prevent the autoimmune mediated destruction of islet beta cells. Therefore we are also interested in the development of markers that identify persons with high risk for developing type 1 diabetes. These include genetic markers, autoantibodies against islet beta cells, and T cells responses to beta cell antigens. Since the autoreactive immune cells are rare, we develop high end methods and analyses on single cell gene and protein expression that we use to identify response to therapy in our clinical trials, and to understand the transition from naïve to memory autoreactive responses in genetically susceptible children.

Future Projects and Goals
  1. Identify the mechanisms of autoreactive T effector and T regulatory expansion in man that can be harnessed to maintain or re-instate self-immune tolerance.
  2. Markers of autoimmunity for the early identification of infants and children who will develop type 1 diabetes.
  3. Clinical primary antigen-specific prevention trials in genetically susceptible infants.
  4. Establish a newborn testing and primary prevention program.
Methodological and Technical Expertise
  • FACS analysis and cell sorting
  • Multiplex gene expression on single T lymphocytes
  • Immunoassay
  • Deep sequencing of T cell receptors
  • Transplantation of cells in mice
Selected Publications

Bonifacio E, Ziegler A-G, Klingensmith G, Schober E, Bingley PJ, Rottenkolber M, Theil A, Eugster A, Puff R, Peplow C, Buettner F, Lange K, Eisenbarth G, Hasford J, Achenbach P.
Effects of high dose oral insulin on immune responses in children at high risk for type 1 diabetes: the Pre-POINT randomized clinical trial.
JAMA 2015; 313(15):1541–9

Bonifacio E.
Predicting type 1 diabetes using biomarkers.
Diabetes Care 2015;38(6):989–96

Eugster A, Lindner A, Catani M, Heninger AK, Dahl A, Klemroth S, Kühn D, Dietz S, Bickle M, Ziegler AG, Bonifacio E.
High Diversity in the TCR Repertoire of GAD65 Autoantigen-Specific Human CD4+ T Cells.
J Immunol. 2015; 194(6):2531–8

Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J, Steck A, Winkler C, Ilonen J, Veijola R, Knip M, Bonifacio E, Eisenbarth GS.
Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children.
JAMA. 2013;309(23):2473–9

Heninger AK, Monti P, Wilhelm C, Schwaiger P, Kuehn D, Ziegler AG, Bonifacio E.
Activation of islet autoreactive naïve T cells in infants is influenced by homeostatic mechanisms and antigen presenting capacity.
Diabetes 2013; 62(6):2059–66

CV

Since 2007
Professor for Preclinical approaches to stem cell therapy / Diabetes, CRTD

2001–2007
Director, Telethon-JDRF Center for Beta Cell Replacement, San Raffaele Institute

1996–2007
Head of Unit, Immunology of Diabetes, San Raffaele Scientific Institute

1993–1996
Assistente Ricercatore, Department of Medicine, San Raffaele Scientific Institute

1992
PhD in Pathology, University of Western Australia

1991–1992
Lecturer, Department of Immunology, London Hospital Medical College

1987–1991
Research Fellow, Department of Immunology, University College Medical School, London

Contact

Center for Regenerative Therapies Dresden (CRTD)
TU Dresden
Fetscherstraße 105
01307 Dresden

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