Infect Me With Parasites? TGIT(GFbeta)

The use of helminthic therapy (the intentional infection of a patient with parasitic worms) to treat autoimmune diseases has enjoyed recent popularity for treatment of conditions as diverse as Crohn’s disease (1) and multiple sclerosis (2) . The jury is still out on its efficacy, however, and the thought of intentionally infecting patients with parasites for therapeutic purposes seems counterintuitive if not downright crazy. Part of the controversy stems from the conflicting reports as to exactly how helminthic therapy works. Some researchers suggest that helminthic therapy works by an evasive maneuver on the part of the parasitic worms to trick the immune system into producing the wrong kind of response, a type 2 cytokine response. (3) The authors of a recent study used helminthic therapy in a mouse model of non-obese diabetes (an autoimmune disorder) in order to attempt an answer to this question, which will be the focus of this blog post. (4)

The authors first demonstrated, by immunostaining, that mice deficient in IL-4 (a immune signaling molecule critical to the development of a type 2 response) fail to develop a type 2 response when infected with a parasitic worm in contrast to control mice that had normal levels of IL-4 which then developed a type 2 response. Given the role of IL-4 in promoting a type 2 response, this result seems fairly obvious and unnecessary to report. This is vital piece of data, however for the next experiment that these scientists performed.

The scientists then measured the onset of diabetes in the mice they were experimenting upon (remember they are specially designed to be genetically pre-disposed to develop diabetes) by measuring glucose levels in their blood. Surprisingly, mice infected with the parasite, regardless of competency in producing IL-4, did not develop diabetes. This suggests that a shift to a type 2 response is not the critical factor in the protection afforded by helminthic therapy in this model. What then, one might ask, are those wriggly worms doing to fend off diabetes?

The scientists who authored this study thought that it might have to do with regulatory T cells at first, but flow cytometry experiments they performed showed no difference in the numbers of regulatory T cells in any condition, infected/uninfected or IL-4 competent or not. They then hypothesized that either IL-10 or TGFβ, which have been implicated in regulating diabetes in mice could play a role. (5) Further flow cytometry experiments showed that TGFβ production was the critical factor in infected mice that correlated with the resistance to diabetes.

The results of this study suggest that the protection against diabetes afforded by helminthic therapy is not a result of a shift to a type 2 cytokine response, nor by regulatory T cells, but by an increase in the production of TGFβ, which is an immune signaling molecule that serves to tamp down the immune response. This opens up questions as to whether or not infection with parasitic worms is actually needed in order to convey the same protection that administration of TGFβ may be able to provide. This alternative to helminthic therapy must be explored further.

References

1) Summers, R. W., Elliott, D. E., Urban, J. F., Thompson, R., & Weinstock, J. V. (2005). Trichuris suis therapy in Crohn’s disease. Gut, 54(1), 87-90.

2) Benzel, F., Erdur, H., Kohler, S., Frentsch, M., Thiel, A., Harms, L., Wandinger, K.-P., et al. (2011). Immune monitoring of Trichuris suis egg therapy in multiple sclerosis patients. Journal of helminthology, 1-9.

3) Hübner, M. P., Stocker, J. T., & Mitre, E. (2009). Inhibition of type 1 diabetes in filaria-infected non-obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells. Immunology, 127(4), 512-22.

4) Hubner, M. P., Shi, Y., Torrero, M. N., Mueller, E., Larson, D., Soloviova, K., Gondorf, F., et al. (2011). Helminth Protection against Autoimmune Diabetes in Nonobese Diabetic Mice Is Independent of a Type 2 Immune Shift and Requires TGF- . The Journal of Immunology.

5) Hancock, W. W., Polanski, M., Zhang, J., Blogg, N., & Weiner, H. L. (1995). Suppression of insulitis in non-obese diabetic (NOD) mice by oral insulin administration is associated with selective expression of interleukin-4 and -10, transforming growth factor-beta, and prostaglandin-E. The American journal of pathology, 147(5), 1193-9.