Previous and current research

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.

As we showed in patients who receive new islet beta cells through transplantation, diabetes-associated autoimmunity has memory and is activated upon re-exposure to antigen. Therefore, attempts to regenerate or replace lost islet beta cells are thwarted unless there is suppression of the response. While this can be achieved by classic immuno-suppression, strategies that lead to antigen-specific immune tolerance are favoured. In this context, we have investigated T regulatory inducing therapies that can lead to tolerance to self antigen and to allo-antigen in pre-clinical animal models.

Our overall goal is to prevent the autoimmune mediated destruction of islet beta cells. Therefore we are also interested in the identification of markers identifying persons with high risk for developing diabetes. These markers are autoantibodies against islet beta cells. Recently, a novel autoantibody was identified and we have shown that screening children for this novel autoantibody stratifies the risk for type 1 diabetes.

Website of current type 1 diabetes study "Pre-POINT". We are also coordinating an EU FP7 consortium with 12 other partners, on type 1 diabetes, „DIAPREPP“.

Future prospects and goals

1. Identify the mechanisms of autoreactive T effector and T regulatory expansion in man that can be harnessed to re-instate self immune tolerance through autologous regenerative therapies that include cord blood cells.
2. Develop beta cell therapeutics using precursors beta cells.
3. Establish a clinical type 1 diabetes prevention translational centre.
   
   

Figure legend: A mouse pancreatic islet, stained for insulin (red) produced by beta cells, glucagon (green) produced by alpha cells and nucleus (blue). 

Group Members

List of group members

Selected Publications

Sordi V, Melzi R, Mercalli A, Formicola R, Doglioni C, Tiboni F, Ferrari G, Nano R, Chwalek K, Borg D, Lammert E, Bonifacio E, Piemonti L. Mesenchymal Cells Appearing in Pancreatic Tissue Culture are Bone Marrow-Derived Stem Cells With the Capacity to Improve Transplanted Islet Function. Stem Cells. 2009 Nov 18. [Epub ahead of print]PMID: 19924826

Monti P, Brigatti C, Heninger AK, Scirpoli M, Bonifacio E. Disengaging the IL-2 receptor with DACLIZUMAB enhances IL-7 mediated proliferation of CD4+ and CD8+ T cell. Am J Transplant Sep 25. [Epub ahead of print]PMID: 19788505

P. Achenbach, V. Lampasona, U. Landherr, K. Koczwara, S. Krause, H. Grallert, C. Winkler, M. Pflüger, T. Illig, E. Bonifacio, A. G. Ziegler (2009): Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk. Diabetologia 52:1881–188

Monti P, Scirpoli M, Maffi P, Ghidoli N, De Taddeo F, Bertuzzi F, Piemonti L, Falcone M, Secchi A, Bonifacio E. (2008) Islet transplantation in autoimmune diabetes patients induces homeostatic cytokines that expand autoreactive memory T cells. J Clin Invest 118 (5):1806-14

Monti P, Scirpoli M, Rigamonti A, Mayr A, Jaeger A, Bonfanti R, Chiumello G, Ziegler AG, Bonifacio E (2007): Evidence for in vivo primed and expanded autoreactive T cells as a specific feature of patients with type 1 diabetes. J. Immunol; 179: 5785-92.

Achenbach P, Koczwara K, Knopff A, Naserke H, Ziegler AG, Bonifacio E (2004): Mature high affinity immune responses to (pro)insulin anticipate the autoimmune cascade leading to type 1 diabetes. J Clin Invest 114: 589-597.