eIF5A inhibition influences T cell dynamics in the pancreatic microenvironment of the humanized mouse model of Type 1 Diabetes

Sci Rep. 2019 Feb 7;9(1):1533. doi: 10.1038/s41598-018-38341-5.

Abstract

We have developed a transgenic mouse model of Type 1 Diabetes (T1D) in which human GAD65 is expressed in pancreatic β-cells, and human MHC-II is expressed on antigen presenting cells. Induced GAD65 antigen presentation activates T-cells, which initiates the downstream events leading to diabetes. In our humanized mice, we have shown downregulation of eukaryotic translation initiation factor 5 A (elF5A), expressed only in actively dividing mammalian cells. In-vivo inhibition of elF5A hypusination by deoxyhypusine synthase (DHS) inhibitor "GC7" was studied; DHS inhibitor alters the pathophysiology in our mouse model by catalyzing the crucial hypusination and the rate-limiting step of elF5A activation. In our mouse model, we have shown that inhibition of eIF5A resets the pro-inflammatory bias in the pancreatic microenvironment. There was: (a) reduction of Th1/Th17 response, (b) an increase in Treg numbers, (c) debase in IL17 and IL21 cytokines levels in serum, (d) lowering of anti-GAD65 antibodies, and (e) ablation of the ER stress that improved functionality of the β-cells, but minimal effect on the cytotoxic CD8 T-cell (CTL) mediated response. Conclusively, immune modulation, in the case of T1D, may help to manipulate inflammatory responses, decreasing disease severity, and may help manage T1D in early stages of disease. Our study also demonstrates that without manipulating the CTLs mediated response extensively, it is difficult to treat T1D.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology
  • Down-Regulation / drug effects
  • Endoplasmic Reticulum Stress / drug effects
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Eukaryotic Translation Initiation Factor 5A
  • Female
  • Gene Expression Regulation / drug effects
  • Glutamate Decarboxylase / genetics*
  • Glutamate Decarboxylase / metabolism
  • Heptanes / chemistry
  • Heptanes / metabolism
  • Heptanes / pharmacology
  • Humans
  • Insulin-Secreting Cells / metabolism
  • Interleukins / blood
  • Male
  • Mice
  • Mice, Transgenic
  • Oxidoreductases Acting on CH-NH Group Donors / antagonists & inhibitors
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism
  • Peptide Initiation Factors / antagonists & inhibitors
  • Peptide Initiation Factors / genetics
  • Peptide Initiation Factors / metabolism*
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • Enzyme Inhibitors
  • Heptanes
  • Interleukins
  • Peptide Initiation Factors
  • RNA-Binding Proteins
  • Oxidoreductases Acting on CH-NH Group Donors
  • deoxyhypusine synthase
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2
  • interleukin-21