Myeloid derived suppressor cells (MDSC) may represent a therapeutic tool for inducing tolerance in transplantation and autoimmune disorders. MDSC propagated from bone marrow (BM) can protect islet allografts from rejection. However, it is not practical nor feasible to generate large numbers of bone marrow derived MDSC from patients for the purposes of cellular therapy. We have previously shown that large numbers of MDSC can be propagated when iPS cell derived myeloid precursors are cultured in the presence hepatic stellate cells (HpSC). The resulting cells show typical features of MDSC i.e. phenotype – CD11b⁺, CD11c^–, MHC Class IIlo and low co-stimulatory molecule expression (CD80/86), expression of high levels of arginase-1 and iNOS and in-vitro immunosuppressive function. We hypothesized that iPS-derived (i) MDSC may be used to attenuate the T cell response in vivo for the treatment of autoimmune disease or allorejection. iPS derived myeloid precursors were cultured in the presence of HpSC (plus GM-CSF/IL-4) for a total of 5 days. BM derived dendritic cells (BM-DC) served as controls. The cells were characterized by flow cytometry and qPCR for Arg-1 and iNOS. We then tested the inhibitory effect of the iMDSC in vivo using the OVA-HEP transgenic mice in which membrane bound OVA is specifically expressed on hepatocytes. Adoptive transfer of OVA specific CFSE labelled CD4⁺ (2×10⁶) and CD8⁺ T cells (5×10⁶) led to elevation of serum ALT. This was increased even further with the administration of OVA pulsed DC, whereas the administration of OVA-pulsed iMDSC maintained ALT levels comparable to the controls. Immunohistochemical staining demonstrated that administration of DC increased OVA-specific CD8⁺ infiltration in the portal areas, while limited infiltration of specific CD8⁺ cells was seen following iMDSC administration. The absolute number of dividing CFSE positive CD8⁺ cells was analysed by isolating the liver non-parenchymal cells and performing flow cytometry. The mice treated with iMDSC had a reduction in the absolute number of OVA specific CD8⁺ infiltrating T cells. We have demonstrated that iMDSC attenuate the antigen specific cytotoxic response in the in vivo setting in the mouse. This may prove an attractive source of immune suppressive MDSC for clinical therapeutics.

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