Dr. Matthias Von Herrath

recent publications

IL-4R Is Expressed on Alpha and Beta Cells of Human Pancreata (2020)

PROBLEM: CD8+ T cells and macrophages, driven by IFN-γ activation, have been shown to play a role in beta cell killing in T1D. This Th1 response is often coupled with a reduction in the Th2 response, driven by IL-4. The expression of this cytokine in NOD mice beta cells has been shown to prevent T1D. But the mechanism of this protective effect has not been entirely understood: does IL-4 suppress T cells or does IL-4R signaling in beta cells protect them from the immune assault?

NOVEL APPROACH: We reinvestigated the expression of IL-4R in the human pancreas and traced its cellular source using multiplex florescence imaging

FINDINGS: IL-4R is expressed in the islets of the human pancreas

Loss of IDO1 Expression From Human Pancreatic β-Cells Precedes Their Destruction During the Development of Type 1 Diabetes (2018)

PROBLEM: Indoleamine 2,3 dioxygenase-1 (IDO1) is a powerful immunoregulatory enzyme that is deficient in patients with type 1 diabetes (T1D)

NOVEL APPROACH: We present the first systematic evaluation of IDO1 expression and localization in human pancreatic tissue

FINDINGS: Although IDO1 was constitutively expressed in β-cells from donors without diabetes, less IDO1 was expressed in insulin-containing islets from double autoantibody-positive donors and patients with recent-onset T1D, although it was virtually absent in insulin-deficient islets from donors with T1D. Scatter plot analysis suggested that IDO1 decay occurred in individuals with multiple autoantibodies, prior to β-cell demise. IDO1 impairment might therefore contribute to β-cell demise and could potentially emerge as a promising therapeutic target.

Increase in Pancreatic Proinsulin and Preservation of β-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset (2017)

PROBLEM: In T1D, the hypothesis that β-cell loss occurs early during the prediabetic phase has recently been challenged. The objective of this study was to add refinement to the classic model of linear β-cell loss and to fill an important gap in our understanding of the prediabetic phase in human T1D

NOVEL APPROACH: We studied, for the first time in the human pancreas, the distribution of proinsulin in single- and double-Ab+ individuals preceding the onset of disease as well as in patients with recent-onset type 1 diabetes and correlated it with loss of insulin content, β-cell mass, and PI area–to–insulin (PI-to-INS) area ratio

FINDINGS: Here we show, for the first time in situ, that in pancreas sections from autoantibody-positive (Ab+) donors, insulin area and β-cell mass are maintained before disease onset and that production of proinsulin increases. This suggests that β-cell destruction occurs more precipitously than previously assumed. Indeed, the pancreatic proinsulin-to-insulin area ratio was also increased in these donors with prediabetes. Using high-resolution confocal microscopy, we found a high accumulation of vesicles containing proinsulin in β-cells from Ab+ donors, suggesting a defect in proinsulin conversion or an accumulation of immature vesicles caused by an increase in insulin demand and/or a dysfunction in vesicular trafficking. In addition, islets from Ab+ donors were larger and contained a higher number of β-cells per islet. Our data indicate that β-cell mass (and function) is maintained until shortly before diagnosis and declines rapidly at the time of clinical onset of disease. This suggests that secondary prevention before onset, when β-cell mass is still intact, could be a successful therapeutic strategy.

bio

Dr. Matthias Van Herrath’s lab aims to develop techniques to prevent or permanently reverse T1D. Some projects include:

  • Characterization of specificity and phenotype of pancreatic CD8 T cells in human Type 1 Diabetes
  • Exploring toxic effects of T1D patient’s serum in pancreatic β cells
  • Expression of HLA class II in human pancreatic tissue sections
  • Characterization of in-situ IL17 expression in human pancreas
  • Detailed in-situ characterization of cytokines, immune and endocrine cell in the human pancreas
  • Neuro-immune crosstalk in the pancreas during onset of type 1 diabetes
  • Modeling and detection of viral infections in human pancreas slices
  • Characterization of HLA class I expression in autoantibody positive and type 1 diabetic donors
  • Detailed in-situ characterization of cytokines, immune and endocrine cell in the human pancreas

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