Regenerative Therapies for Diabetes

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.

Website of current type 1 diabetes study "Pre-POINT".

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.

About

1987-1991: Research Fellow, Department of Immunology, University College Medical School, London 1991-1992: Lecturer, Department of Immunology, London Hospital Medical College 1992: PhD in Pathology, University of Western Australia 1993-1996: Assistente Ricercatore, Department of Medicine, San Raffaele Scientific Institute 1996-2007: Head of Unit, Immunology of Diabetes, San Raffaele Scientific Institute 2001-2007: Director, Telethon- JDRF Center for Beta Cell Replacement, San Raffaele Institute since 2007: Professor for Preclinical approaches to stem cell therapy / Diabetes, CRTD

Selected publications

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 (in press)

Mayr A, Schlosser M, Grober N, Kenk H, Ziegler AG, Bonifacio E, Achenbach P. (2007): GAD Autoantibody Affinity and Epitope Specificity Identify Distinct Immunization Profiles in Children at Risk for Type 1 Diabetes. Diabetes (in press).

Mercalli A, Sordi A, Ponzoni M, Maffi P, De Taddeo F, Gatti G, Servida P, Bernardi M, Bellio L, Bertuzzi F, Secchi A, Bonifacio E, Piemonti L. (2006): Rapamycin induces a caspase-independent cell death in human monocytes. Am J Transplantation 6:1331-1341.

Battaglia M, Stabilini A, Draghici E, Gregori S, Bonifacio E, Roncarolo MG. (2006): Induction of tolerance in type 1 diabetes via both CD4+CD25+ Tr and T regulatory type 1 cells. Diabetes 55: 1571-1580.

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.

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