Ezio Bonifacio Group
Regenerative Therapies for Diabetes
Type I diabetes is characterized by insulin deficiency primarily caused by the autoimmune-mediated destruction of insulin secreting pancreatic islet beta cells. 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.
Our overall goal is to prevent the autoimmune mediated destruction of islet beta cells. We are therefore continuing our research in search of new markers to identify persons with an increased risk for the development of type 1 diabetes. These include genetic markers, autoantibodies against islet beta cells, T cells responses to beta cell antigens and distinct immune cell profiles. Since the autoreactive immune cells are rare, we developed 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.
Since 2016 we screen newborns for their type 1 diabetes genetic risk using a genetic risk score in the Freder1k study in Saxony. Families of high-risk children are offered participation in follow-up and prevention trials. These include the Primary Oral Insulin Trial (POInT) that is conducted through the GPPAD consortium and which is based on our earlier findings in the Pre-POInT study. POInT includes over 1,000 babies as a 1:1 randomized control trial assessing the ability of high daily doses of oral insulin to induce immune tolerance and reduce the risk of developing pre-symptomatic type 1 diabetes (identified as multiple islet autoantibody positive).
Future Projects and Goals
- 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.
- Define new markers of autoimmunity for the early identification of infants and children who will develop type 1 diabetes.
- Clinical primary prevention trials in genetically susceptible infants
- Establish a screening program in Saxony for children with a presymptomatic type 1 diabetes (Fr1da-study)
Methodological and Technical Expertise
- FACS analysis and cell sorting
- Single cell RNAseq for human immune cells
- Immunoassay and antibodies
- T and B lymphocyte receptor sequencing