Antigen presenting cells in autoimmune diabetes: phenotype, function and modulation by Linomide

Abstract: The aim of this thesis was to better understand the role of antigen presenting cells (APC) in the development of diabetes in the nonobese diabetic (NOD) mouse. We have shown that DC and Mphi that infiltrate the islets of Langerhans produce tumour necrosis factor-a (TNF-a), a cytokine known to contribute to the pathogenesis in the early stages of diabetes development. TNF-a is produced from the early stages of insulitis development and occurs independently of T cells. Furthermore, we have found that NOD APC express relatively low levels of the costimulatory molecule CD86 (B7-2) and therefore have a poor T cell stimulatory capacity. This gives rise to a reduced T cell activation as well as an impaired upregulation of the negative T cell regulator CTLA-4, suggesting that APC defects contribute to disease development. The immunomodulator Linomide inhibits diabetes in NOD mice. We found that this is accompanied by a reduced lymphocyte and dendritic cell infiltration into the islets of Langerhans. In addition, Linomide treatment results in a reduced production of TNF-a whereas instantly, following the initiation of Linomide treatment the production of IL-12 p40 and IFN-g is increased. IFN-g is known to upregulate MHC class II as well as adhesion and costimulatory molecules that are important in antigen presentation. In analogy, we found that Linomide treatment of SJL/J mice results in the upregulation of MHC class II, CD11a, CD54 and CD80 on Mphi, indicating an improved T cell stimulatory capacity. In addition, the ability of several Linomide analogues to inhibit experimental autoimmune encephalomyelitis correlates with their ability to upregulate MHC class II on Mphi, suggesting that APC activation may indeed inhibit autoimmune disease. In summary, APC are required for the induction of T cell activation and therefore also for the induction of autoimmunity. However, given that the development of regulatory T cell responses could be dependent on optimal antigen presentation, autoimmune disease may be due to ineffective APC function. Therefore, improving APC capacity, e.g. by Linomide treatment, may indeed inhibit autoimmune disease.