ESPE Abstracts (2014) 82 PL2

Learning from Histopathology to Design Novel Immune-Therapies for Type 1 and 2 Diabetes

M von Herrath

Center for T1D Research, LJI, La Jolla, California, USA

Study of the histopathology of human type 1 and 2 diabetes through the national pancreatic organ donor (nPOD) consortium has yielded interesting new insights that should also aid us in developing improved therapeutic approaches.

1. When insulitis is observed, it usually shows a predominance of CD8 T cells, some of which are autoantigen specific (see also Coppieters et al. JEM 2012). It will be therapeutically challenging to remove/prevent CD8 memory effector cells from attacking islets, especially in more advanced disease. Autoreactive CD8 cells are also present in the blood of type 1 patients.

2. Islets exhibit a characteristic overexpression of MHC class I in T1D, the cause of which is unknown and could be viral (entero or herpes virus for example). It is thus possible that islets in type 1 diabetes are selectively sensitized towards CD8 attacks. In contrast, autoreactive CD4 cells can be isolated and detected in blood from both, type 1 and 2 diabetes patients, possible caused by presentation of islet antigens through MHC class II following β-cell stress.

3. The exocrine pancreas might play a hence under-appreciated role in the pathogenesis of both, type 1 and 2 diabetes. We observe increased infiltration by CD8 lymphocytes, in type 1 diabetes also in autoantibody positive individuals.

4. Destruction of β-cells in type 1 diabetes occurs in a lobular fashion, indicating that there might be events that render whole pancreatic lobes susceptible to attack and loss of β-cells. Localized bacterial and viral infections are potential candidates.

An optimal immunotherapeutic strategy would in our opinion involve a combination of a systemic induction phase, which should ideally eliminate some of the autoreactive CD8 cells without causing excessive immunosuppression followed by a maintenance phase that re-instates islet specific immune regulation and metabolic control. Biomarkers will be required to identify those individuals most likely to respond.

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