MACROPHAGES IN T1D · Functional profiling and therapeutic tolerization of macrophages in type 1 diabetes

Type 1 diabetes (T1D) is a chronic condition that results from the specific destruction of pancreatic beta cells by the immune system. As a consequence, affected individuals can no longer regulate their blood sugar levels and become dependent on glucose monitoring and insulin injections. Despite careful disease management, serious neuronal and vascular long-term complications can often not be avoided. This debilitating disease is an important and growing public health concern in Europe: it is predicted that by 2020 approximately 24.400 individuals will be diagnosed with T1D annually.It is thought that T cells are the principal effector subset that drives beta cell decay within the islets of Langerhans. Inflammatory islet lesions (‘insulitis’) are predominantly populated by T cells and T cell species reactive against pancreatic islet antigens can be found in the blood around disease onset. The importance of innate immunity and in particular macrophages has historically attracted a minor degree of attention. Nevertheless, macrophages are abundantly represented within islet infiltrates from patients and are required for disease manifestation in animal models. Recent evidence from clinical trials has exposed the failure of strategies for inducing peripheral T cell tolerance, most recently with anti-CD3 antibody therapy. While genetically defined thymic escape and consequent T cell autoimmunity may be very important in type 1 diabetes, we hypothesize that T cell-mediated recruitment and activation of macrophages represents a secondary yet significant pathological pathway. The research outlined in this application is designed to determine the functional phenotype of islet-infiltrating macrophages around diagnosis, their role in antigen shuttling to the pancreatic lymph nodes and their capacity to adopt a tolerogenic role upon treatment.