Research Associate University of British Columbia Vancouver, British Columbia, Canada
Abstract Text: In Type 1 diabetes, islet β cells are destroyed by diabetogenic CD8 T cells. Macrophages also participate in diabetogenic CD8 T cell activation. Phosphodiesterase inhibitors Pentoxifylline and Rolipram prevent diabetes in non-obese diabetic (NOD) mice through the inhibition of inflammatory cytokine production. Our aim was to investigate effects of phosphodiesterase inhibitors (apremilast and roflumilast) on diabetogenic immune responses in NOD mice.
Young pre-diabetic female NOD mice were treated with oral apremilast or vehicle for 3 weeks. Dendritic cell (DC) priming, IGRP V7+CD8+ diabetogenic T cell numbers and Foxp3+CD73+ CD4 T regular cells (Tregs) were then assessed by flow cytometry. The effects of apremilast and roflumilast on bone marrow (BM) cell differentiation and peritoneal macrophage activation were evaluated.
Treatment of 5-week old NOD mice with apremilast reduced the priming of adoptively transferred 8.3 CD8 T cells. There was a decrease in IGRP V7+CD8+ T cells in the pancreatic lymph nodes (PLN) and increase in Tregs in apremilast-treated compared to control mice. The addition of apremilast or roflumilast to the culture of BM cells decreased numbers of CD11c+ BMDCs. Apremilast and roflumilast also decreased CD86 expression on peritoneal macrophages stimulated by LPS. There was no demonstrable effect on peptide-induced diabetogenic T cell activation and function.
Our data demonstrate that apremilast and roflumilast have inhibitory effects on BMDC differentiation, macrophage activation and diabetogenic immune responses. Treatment of NOD mice with apremilast or roflumilast at an early stage of diabetes may effectively prevent diabetes development through the inhibition of innate immune responses.
.jpg "Yiqun Zhang, N/A, n/a photo")
