Histopathological studies of human diabetes using pancreata available through the nPOD consortium reveal interesting features of the disease that were less well understand previously. Prior to diagnosis the frequency of insulitic lesions is low. This might be indicative of a relapsing remitting disease course. The most frequent cell found in islets is the CD8 lymphocyte, but a generalized mild elevation of CD8 infiltration is also seen in the exocrine pancreas of autoantibody positive donors, T1D patients as well as T2D patients, but not healthy controls. Most islets in type 1 diabetes also exhibit an upregulation of MHC class I, a feature never seen in type 2 diabetes. Along with the probably deleterious combination of MHC class 1 upregulation and CD8 infiltration, autoreactive CD8 cells (as detectable by Q-dots) are only present in blood of type 1 patients, while CD4 autoreactive cells are detected by Elispot in type 1 but sometimes also type 2 diabetes. Therefore general beta-cell stress might lead to CD4 sensitization, while upregulation of MHC class I leads to additional CD8 sensitization and a more rapid decline in beta-cell mass.
Controlling autoreactive CD8 memory T cells will remain a significant challenge therapeutically. Their complete elimination could possible occur in an antigen specific way, but not through generalized immunosuppression, since side effects will be unacceptable, as some trials have shown historically, albeit possible to reverse the disease even after diagnosis immunologically. Antigen specific therapies together with suitable biomarkers will therefore need to take a prominent role for this disease, especially if induction of regulatory cells occurs as well. Ultimately one should envision a combination therapy, where a short course induction treatment with a systemic immune modulator is followed by a maintenance therapy using an antigens-specific platform. Strategic aspects how to prioritize existing therapies and biomarkers will be discussed.