nPOD. Immunology

Innate immunity and diabetes

Although T1D is considered to be mainly a T-cell mediated and a beta-cell specific disease we have generated over the years the hypothesis (and some supporting data) that innate immunity is also key in disease initiation and that T1D might be a disease of the whole pancreas that manifests in autoimmunity to beta cells.

Our published data indicate that neutrophils infiltrate the pancreas of patients with T1D [1] and our still unpublished results suggest that peripheral markers of Neutrophil Extracellular Traps (NETs: a networks of extracellular fibers composed of DNA extruded from neutrophils, which can bind pathogens but can also lead to tissue damage and dangerous exposure of self antigens) are found increased patients with T1D. In addition, we have evidence that neutrophils infiltrate the whole pancreas and not only the islets [1] (a phenomenon also reported for CD8+T cells [2]). Neutrophils can also exert interesting functions when invade tissues (e.g.,production of neutrophil extracellular traps -NETs, interaction with other innate immune cells, and source of post-translationally modified self antigens) –functions that overall we call the “innate network”.

Thus, the objective of this project is to test the hypothesis that neutrophils and NETs are increased in AAb pos and T1D nPOD donors. We propose to use the POD cohort to identify innate immune cells and their markers of activity. These important samples will allow us to test our hypothesis and –if confirmed–to design new therapeutic approaches.

ADDENDUM: Although T1D is considered to be mainly a T-cell mediated and a beta-cell specific disease we have generated over the years supporting data that innate immunity is also key in disease initiation and that T1D might be a disease of the whole pancreas that manifests in autoimmunity to beta cells.

Our published data indicate that neutrophils infiltrate the pancreas of patients with T1D [1] and peripheral markers of Neutrophil Extracellular Traps (NETs: a networks of extracellular fibers composed of DNA extruded from neutrophils, which can bind pathogens but can also lead to tissue damage and dangerous exposure of self antigens) are found increased in patients with T1D. In addition, we have evidence that neutrophils infiltrate the whole pancreas and not only the islets(a phenomenon also reported for CD8+T cells2). Neutrophils can also exert interesting functions when they invade tissues (e.g.,production of neutrophil extracellular traps -NETs, interaction with other innate immune cells, and source of post-translationally modified self antigens) –functions that overall we call the “innate network”.

We recently generated new data3demonstrating that: (i) purified circulating neutrophils have a specific gene-signature in pre-symptomatic subjects and in patients with T1D. This signature is already present at very early stages of the disease (i.e., in autoAb negative subjects); (ii) NETting neutrophils (cells that have protruded Neutrophil Extracellular Traps) are present in the pancreas of subjects with recent onset T1D and autoAb positive donors but not in non-diabetic controls.

Thus, the objective of this “addendum” is to isolate pancreas infiltrating neutrophils for transcriptomic characterization and validate the peripheral correlate through the DepArray™ technology.We propose to use the nPOD cohort to delineate the transcriptomic signature of neutrophils attracted into the pancreas of pre-symptomatic and symptomatic T1D subjects that would differ from that of non-diabetic donors.

These important samples will allow us to test our hypothesis and –if confirmed –to design new therapeutic approaches.

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