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

Shahnawaz Imam, R. Prathibha, Pervaiz Dar, Khalil Almotah, Ahmed Al-Khudhair, Syed Abdul Moiz Hasan, Nancy Salim, Talha Naser Jilani, Raghavendra G. Mirmira, Juan Carlos Jaume

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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.

Original languageEnglish (US)
Article number1533
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Imam, S., Prathibha, R., Dar, P., Almotah, K., Al-Khudhair, A., Hasan, S. A. M., Salim, N., Jilani, T. N., Mirmira, R. G., & Jaume, J. C. (2019). eIF5A inhibition influences T cell dynamics in the pancreatic microenvironment of the humanized mouse model of Type 1 Diabetes. Scientific reports, 9(1), [1533]. https://doi.org/10.1038/s41598-018-38341-5