TNFα Increases Myeloid-derived Suppressor Cells: How Does This Apply to IBD?

How TNFa affects myeloid derived suppressor cellsMyeloid-derived suppressor cells (MDSCs) are the new suppressive darlings of the immunology world. These suppressive cells are created as a result of prolonged inflammation and help limit T cell activities. No surprise that they are now being considered as a potential therapy for IBD and autoimmune disease. But, a recent study points its finger at TNFα as being one of the main culprits leading to MDSC development and treatment with anti-TNFα helps keep them in check. However, this would suggest that anti-TNFα treatment in IBD patients might also curb MDSC development. This doesn’t quite seem to line up.

Today it’s Easter and, given that I am bit backed up on work, I am working on a TIBDI post. It’s actually not that bad, it’s cold outside, and I’m looking at set of particularly interesting articles may lead you to rethink your ideas about IBD.

The main article that I looked at was published in Immunity. The article focuses on cells called myeloid-derived suppressor cells (MDSC). These cells are created from myeloid progenitors under conditions with high amounts of systemic pro-inflammatory cytokines, like IFNγ, IL-6 or TNFα. Under these conditions, myeloid progenitors do not mature to granulocytes, dendritic cells and macrophages. Instead, they become an immature progenitor that has suppressive features.

Their most noted suppressive features are the ability to produce reactive oxygen species and sequester of L-cysteine. This leads to T cell hypo-responsiveness through cell cycle arrest, the lowered expression of the TCR ζ chain, the alteration of the TCR binding site. They are also suspected to prime regulatory T cells.

As these cells come about from prolonged or chronic inflammation, the current studies looking at MDSC assumed that they would be useful for controlling inflammation. The unspoken reason that they do not succeed in their task of controlling chronic inflammation is that conditions causing chronic inflammation are too overwhelming. Indeed, studies looking at MDSC in colitis have suggested this.

One study published in 2008 in Gastroenterology by researchers in Germany showed that chronic enterocolitis caused by the repeated administration of antigen-specific CD8+ T cells to a host mouse led to a chronic form of mild inflammation with the development of MDSCs. In contrast, during acute disease when a single large dose of the antigen-specific CD8+ T cells were given, MDSCs were not developed. However, if the MDSCs were transferred from the chronically sick mice to mice being given acute disease, the MDSC were able to lower the severity. The group even showed that IBD patients had significantly higher amounts of MDSC in blood and that they suppressed T cell activities in vitro.

Another study published in the Journal of Digestive Diseases last year by a group in China also suggested the same thing for another colitis model. They collected MDSCs from mice with established TNBS colitis, which is caused by sensitization and re-challenge to the TNBS hapten. They then transferred these MDSCs to host mice and the TNBS colitis was again induced. These mice were partially protected from the disease. Both of these studies clearly suggest that under the right circumstances, MDSC are beneficial to regulating colitis.

Now getting back to the main article, things start to get confusing. The Israeli group found that TNFα, in particular, helped promote MDSC development in mice during a chronic inflammation model, where mice were repeatedly vaccinated with heat-killed Mycobacterim tuberculosis. In this model, the numbers of MDSCs were raised in the spleen and bone marrow and their production of reactive oxygen species was increased. T and NK cell function was compromised due to the loss of TCR ζ chains

Using a combination of in vitro and in vivo techniques with Tnf-/- mice; doses of Etanercept, which neutralizes TNFα; and MDSC depletion antibodies; they found that they could strikingly reduce the formation of MDSCs and normalize T and NK function. To sum it up, TNFα was responsible for large numbers of highly suppressive MDSCs and using Etanercept helped eliminate them.

This is where things get interesting and confusing. Etanercept is also used to treat a number of chronic conditions like IBD and rheumatoid arthritis. If MDSCs are supposed to be helpful in these conditions, why would their loss be helpful? This result calls into question the actual role of MDSCs in chronic disease.

I think that one of the first steps to find out what is really happening is to see if the numbers of MDSCs are actually lowered in IBD patients after anti-TNFα therapy. Additional steps would be to look at MDSC transfers in chronic models, and not just in acute models of inflammatory disease. All of the studies that I’ve mentioned here only look at the positive benefits of MDSC transfer in acute disease. These models are poor representatives of the inflammatory state in human patients, which have had their diseases for years. The question that needs to be addressed is, are these cells helping or hindering chronic autoimmune diseases?

What do you think? Do you think that the Immunity article should cause researchers to question the use of MDSC for treating chronic disease? Let me know in the comments below.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment.

Sources

Bronte, V., & gabrilovich, D. (2010). Myeloid-derived suppressor cells. (K. Minton & O. Leavy, Eds.) Nature Reviews Immunology.

Haile, L. A., Wasielewski, von, R., Gamrekelashvili, J., Krüger, C., Bachmann, O., Westendorf, A. M., et al. (2008). Myeloid-Derived Suppressor Cells in Inflammatory Bowel Disease: A New Immunoregulatory Pathway. Gastroenterology, 135(3), 871–881.e5. doi:10.1053/j.gastro.2008.06.032

Sade-Feldman, M., Kanterman, J., Ish-Shalom, E., Elnekave, M., Horwitz, E., & Baniyash, M. (2013). Tumor Necrosis Factor-α Blocks Differentiation and Enhances Suppressive Activity of Immature Myeloid Cells during Chronic Inflammation. Immunity, 38(3), 541–554. doi:10.1016/j.immuni.2013.02.007

Su, H., Cong, X., & Liu, Y. L. (2012). Transplantation of granulocytic myeloid derived suppressor cells (G-MDSCs) could reduce colitis in experimental murine models. Journal of Digestive Diseases, n/a–n/a. doi:10.1111/1751-2980.12029

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