Application of cytokine-induced myeloid-derived suppressor cells mitigates murine pancreatic insulitis through inhibition of activated T cells

Abstract Background Type 1 diabetes is an inflammatory state. Myeloid-derived suppressive cells (MDSCs) originate from immature myeloid cells and quickly expand to control host immunity during infection, inflammation, trauma, and cancer. Immunotherapy is a method of disease treatment that involves stimulating or suppressing an immune response. Although the spleens and blood of tumor-bearing mice are the most common MDSC source for immunotherapy, many safety precautions must be considered. Methods Cytokine-induced MDSCs were propagated from bone marrow cells cultured with mouse recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, and IL-1β. Arginase-1 and inducible NO synthase (iNOS) expressions of MDSCs were evaluated using quantitative reverse-transcriptase PCR. Diabetes was diagnosed as a sustained blood sugar level > 350 mg/dL. The immunized T cells harvested from the spleens of nonobese diabetic (NOD) mice cotransplanted with cMDSCs were injected intravenously to the NOD mice with severe combined immune deficiency (SCID), twice a week for 5 consecutive weeks. Diabetes-free survival of NOD–SCID mice was measured. Fibronectin expressions of the renal glomerulus and insulin production of the pancreas were analyzed using immunohistochemistry studies. Results This study presents an ex vivo procedure to develop MDSCs from bone marrow cells propagated from GM-CSF, IL-6, and IL-1β cytokines expressing less costimulatory and more inhibitory surface markers as well as considerably high levels of the iNOS enzyme through the signal transducer and activator of transcription 1 (STAT1) signaling pathway. In addition, the MDSCs also displayed immature morphology and strong immunosuppression of T cell proliferation. The adoptive transfer of cMDSCs improved the hyperglycemic state in and prolonged the diabetes-free survival of NOD-SCID mice induced by reactive splenic T cells harvested from NOD mice. In addition, cMDSC use reduced fibronectin production in the renal glomeruli and improved pancreatic insulitis in the NOD–SCID mice. Conclusions The administration of cMDSCs propagated from GM-CSF, IL-6, and IL-1β cytokines provides an alternative immunotherapy protocol for the treatment of diabetic pancreatic insulitis and renal nephropathy.