Cytokine signatures in human (pre-)diabetic pancreas

• Applicant: Dr. Susanne Pfeiffer
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 409226100

Increased infiltration of immune cells in the human pancreas is a correlate of immune process in type 1 diabetes. CD8+T and B cells constitute the major components of such infiltrates; CD4+T cells, CD68+ macrophages and CD11c+ dendritic cells provide a more modest contribution, FoxP3+TREGs and CD138+ plasma cells are apparently quite rare. A more detailed in situ characterization of these cells is necessary to arrive at a better definition of type 1 diabetes pathogenesis determinants. To further investigate the functional properties and the complex interplay of immune cells infiltrating the pancreas, a functional immune cell characterization at the level of interferon/cytokine production is planned in this project. Inflammatory cytokines such as type 1 interferons (IFN-I), IFNγ, TNFα and IL-1β have long been implicated in the pathogenesis of T1D. The aim of the proposed project is to define precise expression patterns of cytokines and interferons, their cellular sources, their in situ actions on immune and endocrine cells, and the topographical relation to MHC-I hyperexpression in the pre/diabetic pancreas. Pancreatic tissue sections comprising samples from pre-diabetic (autoantibody-positive (aab+)) donors, donors with recent onset T1D and healthy control samples will be obtained through the nPOD consortium. Adjusted immunohistochemistry/immunofluorescent multiplexing strategies will be employed for the visualization of cytokines and cytokine signaling components and correlate expression patterns with the presence/absence of MHC-I hyperexpression and major cell subsets (CD8+T cells, APCs, endocrine cells). A reconstruction of the highly dynamic autoimmune processes operative in type 1 diabetes disease will help construct a time-line for type 1 diabetes pathogenesis and progression, possibly revealing new therapeutic options.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Matthias von Herrath