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The Use of Myeloid Suppressor Cells to Inhibit Experimental Autoimmune Encephalomyelitis: a Potential Immunotherapy for Multiple Sclerosis

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Version 2 2023-03-13, 22:53
Version 1 2021-11-10, 01:41
posted on 2023-03-13, 22:53 authored by Slaney, Clare Yan

The ideal treatments for multiple sclerosis (MS) are ones that specifically target the disease causing autoreactive T cells without compromising the immune system's ability to respond to pathogens and infections. However, the current treatments for MS are antigen non-specific and there is a need for the development of antigen-specific therapies that do not induce global immunosuppression. Thus, this thesis aims to investigate the potential of using the body's own suppressor cells to develop an antigen-specific immunotherapy to inhibit experimental autoimmune encephalomyelitis (EAE), the murine model for MS. In our laboratory, there are two versions of mutated superantigens, SMEZ-2-M1 (SM) and double mutant SMEZ-2 (DM). SM is defective at its TCR binding site, but retains its ability to bind to MHCII molecules. Based on previous findings from our laboratory that administration of a SM conjugate with myelin oligodendrocyte glycoprotein (MOG35-55) peptide in incomplete Freund's adjuvant (IFA) suppressed EAE in a CD25+ regulatory T cell (Treg)-dependent manner, it was hypothesised that the administration of SM-MOG35-55/IFA expanded and/or activated MOG35-55 specific Tregs in vivo. In the first part of this thesis, I tested this hypothesis. The experimental results showed that neither the Foxp3+ nor CD25+ Tregs primed in vivo by SM-MOG35-55/IFA could inhibit EAE and surprisingly, treating mice with SM-MOG35-55/IFA did not significantly suppress EAE as previously described. Nevertheless, the administration of SM-MOG35-55 into mice using various methods repeatedly showed minor suppression of EAE, suggesting an in vivo suppressive capability of SM-MOG35-55. Interestingly, after being injected into mice intravenously, SM was captured by a blood MHCII-CD11b+F4/80+Gr-1+ cell population in an MHCII-independent manner. Cells expressing the same surface markers have been reported in the literature to be myeloid derived suppressor cells (MDSCs), suggesting that the SM+MHCII-CD11b+F4/80+Gr-1+ cells may be suppressor cells, i.e. a subpopulation of MDSCs, and play a role in SM-MOG35-55 mediated EAE suppression. In the second part of this thesis, I went on to test the blood MHCII-CD11b+F4/80+Gr-1+ cells' suppressive potential using DM. Unlike SM, DM is defective at both MHCII and TCR binding sites, and possessed an enhanced binding capability to the blood MHCIICD11b+ F4/80+Gr-1+ cells. The experimental results demonstrated that the blood MHCII-CD11b+F4/80+Gr-1+cells are potent suppressors of T cell responses, and were subsequently named as blood MDSCs (bMDSCs). bMDSCs suppressed T cell proliferation in vitro in a cell contact-dependant manner, and nitric oxide played an important role in this suppression. In the third part of this thesis, I investigated the potential of using DM for EAE suppression via bMDSCs. When DM was conjugated to MOG35-55 and administered subcutaneously into mice, EAE was suppressed in a MOG35-55-specific manner. Moreover, the adoptive transfer of bMDSCs from the DM-MOG35-55 treated mice transferred EAE suppression, confirming that bMDSCs play an important role in this suppression. Taken together, these results reveal a previously unknown role of bMDSCs in limiting immune responses. Moreover, the use of DM to direct the activity of bMDSC may prove to be a unique antigen-specific immunotherapy for EAE, which has great potential to be developed into a treatment of MS and other autoimmune diseases.


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Date of Award



Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Biomedical Science

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level


Degree Name

Doctor of Philosophy

Victoria University of Wellington Item Type

Awarded Doctoral Thesis



Victoria University of Wellington School

Malaghan Institute for Medical Research


Backstrom, Thomas