Myeloid cells in autoimmune diseases

Multiple Sclerosis (MS) and Type 1 Diabetes (T1D) are autoimmune diseases caused by dysregulation of the immune system. Monocytes/macrophages are myeloid cells that play a pivotal role in both induction and resolution of these diseases depending on the stage and microenvironment of disease course. Similar to monocytes/macrophages, microglia are CNS resident macrophages that during MS may also exhibit both pro‐inflammatory and anti‐inflammatory properties. The main purpose of my PhD project was to develop a method to induce a regulatory or suppressive phenotype of myeloid cells for use in adoptive transfer as a novel therapy in preclinical studies of autoimmunity.

In Paper I we tested the hypothesis whether there are any differences in activation states between mouse strains with different genetic backgrounds. We used congenic Nramp1 ‐susceptible and ‐resistant macrophages on BALB/c and C57BL/6 mouse backgrounds and determined fundamental differences in macrophage activation states between the two different strains as well as Nramp1‐specific effects.

In Paper II we tested the therapeutic effect of M2 macrophages in T1D. Our results reveal that after a single adoptive transfer of IL‐4/IL‐10/TGF‐β‐stimulated macrophages > 80% of the treated mice were protected from disease development. In Paper III we explored the same treatment in a MOG‐induced EAE model. We were able to demonstrate that intranasal administration of IL‐4/IL‐10/TGF‐β‐stimulated microglia can attenuate EAE development in DBA/1 mice. In Paper IV we translated the rodent M2 macrophage induction protocol to a human monocyte‐macrophage setting. Our findings indicate a robust stimulation protocol for generation of an optimal, specific, stable, and immunosuppressive human monocyte‐derived macrophage phenotype.

The results presented in this thesis collectively demonstrate induction of a regulatory phenotype IL‐4/IL‐10/TGF‐β in various myeloid cells including rodent macrophages, microglia and human monocytes. The IL‐4/IL‐10/TGF‐β‐induced M2 cells had a potent deactivating effect on pro‐inflammatory LPS/IFNγ‐activated macrophages (M1), significantly suppressed T cell proliferation and induced Tregs. Several modes of action are thus indicated to explain the therapeutic clinical effects, which were particularly apparent during chronic disease states. Based on these results, further clinical development of this therapy is thus warranted.

List of scientific papers

I. Mia S, Plantinga T, Andresen P., Holm, B. & Harris RA. Nramp1 and background gene effects determine distinct macrophage activation phenotypes. [Manuscript]

II. Parsa R, Andresen P, Gillett A, Mia S, Zhang XM, Mayans S, Holmberg D, Harris RA. Adoptive transfer of immunomodulatory M2 macrophages prevents Type 1 Diabetes in NOD mice. Diabetes. 2012 Nov; 61(11):2881‐92.
https://doi.org/10.2337/db11-1635

III. Zhang XM, Lund H, , Mia S, Parsa R, Harris RA. Adoptive transfer of cytokine‐induced immunomodulatory adult microglia attenuates experimental encephalomyelitis in DBA/1 mice. GLIA. 2014. [Accepted]
https://pubmed.ncbi.nlm.nih.gov/24677019

IV. Mia S, Warnecke A, Zhang XM, Malmström V, Harris RA. An optimized protocol for human M2 macrophages using M‐CSF and IL‐4/IL‐10/TGF‐β yields a dominant immunosuppressive phenotype. Scandinavian Journal of Immunology. 2014 Feb 12.
https://doi.org/10.1111/sji.12162