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

• Published in: Scientific reports 2019-02, Vol.9 (1), p.1533, Article 1533
• Main Authors: Imam, Shahnawaz, Prathibha, R., Dar, Pervaiz, Almotah, Khalil, Al-Khudhair, Ahmed, Hasan, Syed Abdul-Moiz, Salim, Nancy, Jilani, Talha Naser, Mirmira, Raghavendra G., Jaume, Juan Carlos
• Format: Article
• Language: English
• Subjects: 13/1; 13/21; 13/31; 13/51; 14/63; 38/1; 38/77; 38/90; 42; 42/70; 631/250/38; 692/163/2743/137/1418; Animals; Antigen presentation; Antigen-presenting cells; Antigens; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cytotoxicity; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); 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; Helper cells; Heptanes - chemistry; Heptanes - metabolism; Heptanes - pharmacology; Humanities and Social Sciences; Humans; Immunomodulation; Initiation factor eIF-5A; Insulin-Secreting Cells - metabolism; Interleukin 1; Interleukin 17; Interleukin 21; Interleukins - blood; Lymphocytes T; Major histocompatibility complex; Male; Mammalian cells; Mice; Mice, Transgenic; multidisciplinary; Oxidoreductases Acting on CH-NH Group Donors - antagonists & inhibitors; Oxidoreductases Acting on CH-NH Group Donors - metabolism; Pancreas; 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; Rodents; Science; Science (multidisciplinary); T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Transgenic mice
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-38341-5

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.