Eukaryotic translation initiation factor 5A inhibition alters physiopathology and immune responses in a “humanized” transgenic mouse model of type 1 diabetes

Abstract

Imam S, Mirmira RG, Jaume JC. Eukaryotic translation initiation factor 5A inhibition alters physiopathology and immune responses in a "humanized" transgenic mouse model of type 1 diabetes. Am J Physiol Endocrinol Metab 306: E791-E798, 2014. First published February 4, 2014 doi:10.1152/ajpendo.00537.2013.-Therapeutic options for treatment of type 1 diabetes (T1D) are still missing. New avenues for immune modulation need to be developed. Here we attempted at altering the diabetes outcome of our humanized model of T1D by inhibiting translation-initiation factor eIF5A hypusination in vivo. Double-transgenic (DQ8-GAD65) mice were immunized with adenoviral vectors carrying GAD65 for diabetes induction. Animals were subsequently treated with deoxyhypusine synthase (DHS) inhibitor GC7 and monitored for diabetes development over time. On one hand, helper CD4 ϩ T cells were clearly affected by the downregulation of the eIF5A not just at the pancreas level but overall. On the other hand, the T regulatory cell component of CD4 responded with activation and proliferation significantly higher than in the non-GC7-treated controls. Female mice seemed to be more susceptible to these effects. All together, our results show for the first time that downregulation of eIF5A through inhibition of DHS altered the physiopathology and observed immune outcome of diabetes in an animal model that closely resembles human T1D. Although the development of diabetes could not be abrogated by DHS inhibition, the immunomodulatory capacity of this approach may supplement other interventions directed at increasing regulation of autoreactive T cells in T1D. mouse model; type 1 diabetes physiopathology; deoxyhypusine synthase IN TYPE 1 DIABETES (T1D) a complex interplay of immune cells makes pancreatic ␤-cells targets of destruction (9). T1D is a chronic autoimmune disease where autoantigen-activated CD4 ϩ T cells help CD8 ϩ T cells become mediators of selective ␤-cell destruction (16). Recent observations of human islets from diabetic patients have established a prominent role for CD8 ϩ T cells (3, 15). Therefore, facilitating CD4 ϩ T cell regulation of CD8ϩ T cells appears to be a promising therapeutic strategy.A T1D mouse model where antigen-specific diabetes after immunization with a clinically relevant human autoantigen, in the context of human MHC-class II diabetes-susceptibility transgenes occurs, was recently developed (5,6,8). In this transgenic model, human glutamic acid decarboxylase (GAD65) is expressed in pancreatic ␤-cells, and human MHC II (DQ8) is expressed in antigen-presenting cells (APCs). Upon a triggering event by which tolerance to GAD65 is broken in the periphery (1), APCs present antigen, activate T cells, and initiate the downstream events that lead to diabetes (5,6,8).Eukaryotic translation initiation factor 5A (eIF5A) is a small (17-kDa), highly conserved protein identified as a translation initiation/elongation factor (11). Studies in mammalian cells have showed that only 5% of protein translation in a quiescent cell is dep...

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

“…Hypusinated eIF5A has been shown to promote cytokine-mediated β-cell dysfunction through post-transcriptional regulation of iNOS 43 . Earlier studies by our group have indicated that eIF5A inhibition delays the onset of T1D in our humanized mouse model 44 as well as in NOD mice 45 . Here, we show that eIF5A inhibition alters T cell profiles, especially T helper subsets, in the pancreas and draining lymph nodes of the mouse model.…”

“…Humanized mouse model of T1D consisting of Murine MHC-class II deficient (mII _ ), HLA-DQA1*0301/DQB1*0302 (DQ8), and hGAD65 transgenic mice 48 in BTBR background 49 were used in this study 46,47 . DQ8 and hGAD65 homozygosity was determined as previously described 44,48–50 . The Institute Animals Care and Use Committee (IACUC), approved all animal protocols.…”

Insulin action on protein synthesis and its association with eIF5A expression and hypusination

“…The eIF5A protein is involved in the initiation and elongation of translation and is related to the processes of transcription, the transit of macromolecules through the nuclear pore complex, nonsense-mediated mRNA decay and cell proliferation and differentiation [32,[37][38][39][40][41][42][43][44][45][46]. The eIF5A protein has also been linked to inflammatory processes, diabetes, cancer, malaria and viral infections, such as HIV-1 and Ebola [47][48][49][50][51][52][53][54][55][56]. eIF5A is associated with ribosomes actively engaged in translation, strengthening the involvement of this protein in the protein synthesis process [57,58].…”

Hypusination of eIF5A as a Target for Antiviral Therapy

“…These findings suggest that inhibition of hypusination through substrate competition at DHPS is possible. GC7 has been extensively studied as an antitumor agent (reviewed by Nakanishi and Cleveland, 2016), as well as in vivo for several applications (Imam et al, 2014;Melis et al, 2016), so animal model testing of GC7 efficacy is a logical next step in investigating the importance of eIF5A for virus replication and pathogenesis.…”