Pathogenic and therapeutic manipulation of the IL-7/IL-7R axis in pancreatic islet transplantation and autoimmunity

• Applicant: Dr. Angela Hommel
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 276098819

Cell replacement therapy in type 1 diabetes mellitus must consider strategies to control immune mediated loss of donor graft or host tissue. Islet graft rejection is caused by autoimmunity and alloimmunity. We have shown that the IL-7/IL-7R pathway is relevant to autoimmune T cell mediated islet beta cell loss as well as homeostatic proliferation of memory T cells following islet transplantation. We further showed that IL-7 can favour activation and expansion of T cells, including autoreactive T cells, and that IL-7 can abrogate T regulatory cell function in vitro. Therefore, we reason, that interfering with IL-7 signaling can improve the outcome of islet graft survival. A useful model to study effects of IL-7 hyper-expression is lacking. We recently generated an inducible mouse model of IL-7 hyper-expression and established autoimmune and alloimmune islet transplantation mouse models. Using this model together with samples from patients undergoing transplantation, we will examine in vivo and in vitro IL-7 mediated homeostatic expansion effects on T cells during the induction of autoimmunity and the re-exposure to pancreatic islets after diabetes onset. Specifically, we will: 1. determine if and how IL-7 hyper-expression exacerbates pancreatic islet graft loss and islet autoimmunity; 2. identify therapeutics that successfully hinder IL-7 mediated beta cell immunity; and 3. identify whether autoreactive T cells in man are prone to expand and undergo phenotypic changes under homeostatic proliferation. The successful completion of the project will determine if and how the IL-7/IL-7R pathway should be targeted in type 1 diabetes and will potentially lead to novel therapeutic combinations to be used in beta cell transplantation and type 1 diabetes immunotherapy.

• DFG Programme: Research Grants