The Pancreatic Macrophage Compartment in Health and autoimmune Diabetes: a study on Maturation, Mobility and Matrix interactions

Type 1 diabetes is a disease that results from a disturbed glucose metabolism due to a deficiency in insulin production. This deficiency is the consequence of immune- mediated damage to the insulin-producing ß-cells. The cause of type 1 diabetes is presently unknown and probably multifactorial. The initiation and progression of the inflammatory process that destroys the ß-cells involves the interplay of environmental factors with an autoimmune-prone genetic background. Abnormal immune regulation explains the autoimmune phenomena observed in diabetic patients and in spontaneous animal models for the disease to a limited extent only. The precise reason for the immune system to target the pancreatic islets of Langerhans is still unclear. The pathogenic process in the pancreas is characterized by the pathology- related intra-islet infiltration of T and B-lymphocytes that mediate islet destruction. This T and B-cell infiltration is preceded by an accumulation of macrophages and dendritic cells at the islet periphery. The early peri-islet accumulation of these antigen presenting cells probably reflects the first response of the immune system that is progressively heading for islet destruction. Macrophages are involved in every step of the diabetogenic process. In the non- obese diabetic (NOD) mouse that spontaneously develops diabetes, various macrophage-abnormalities like defective maturation, reduced phagocytosis and increased production of IL-12, have been described previously. Moreover, macrophages are present in higher numbers in the pancreas of the NOD mouse from birth onwards, randomly distributed in the connective tissue and exocrine parenchyma. In this thesis we present the results of our studies on the murine pancreatic macrophage compartment. We have questioned in particular the possible underlying causes for the abnormal early peri-islet accumulation of macrophages. Therefore, the studies were performed with an emphasis on the interactions of macrophages with the extracellular matrix of the pancreatic connective tissue.