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.
Highlights
The hallmark of type 1 diabetes (T1D) is immune-mediated destruction of insulin secreting β-cells of the pancreatic islets of Langerhans, resulting in hyperglycemia and lifelong dependency on exogenous insulin
Note that CTLs cells were reduced in treated groups and that the difference only becomes apparent at peri-pancreatic lymph node (PPLN) and PN but no overall effect was observed
The analysis revealed that the T-regulatory cell (Treg)/Th17 ratios were increased significantly in the pancreas, inguinal lymph node (IGLN) and PPLN of males, whereas the effect on the ratio in these tissues was non-significant in females (Fig. 5A)
Summary
The hallmark of type 1 diabetes (T1D) is immune-mediated destruction of insulin secreting β-cells of the pancreatic islets of Langerhans, resulting in hyperglycemia and lifelong dependency on exogenous insulin. Th17 cells are reported to be elevated in the peripheral blood and pancreatic lymph nodes of T1D patients as compared to healthy humans[3,12,13] Both Th1 and Th17 cells seem to cooperate in the mediation of T1D. Marwaha et al (2010) reported that Treg cells acquire a Th17 like phenotype in human T1D patients[12] It is not yet clear if this reprogramming is required for T1D induction or if it is instead a consequence of the immune/ inflammatory response. T helper cells cannot directly interact with the β-cells due to their lack of MHC class II expression and are unable to cause direct cytotoxicity They contribute to β-cell death through soluble mediators like cytokine and other death signals (eg IL1, TNFa, IFNγ, FASL). Β-cell antigen-specific CD8 T cell expansions have been identified in the peripheral blood of T1D patients[35,36] and CD8 T cells predominate the cellular infiltrate of the spleen from cadaveric T1D donors[37,38]
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