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.

The Joy of Pregnancy: Relief of Rheumatoid arthritis symptoms during pregnancy

AIDS, multiple sclerosis, type 1 diabetes, Rheumatoid Arthritis (RA). You might be wondering where this seemingly depressing list is heading, and that’s a fairly reasonable question. Each of these diseases is an autoimmune disease, meaning that the ones immune system is attacking its own body as if it were foreign. You might be familiar with some more than others, perhaps through the media, or through family and friends. What you might not know, is what kind of therapeutic agents are being employed in combating these diseases. One disease in particular, Rheumatoid Arthritis, affects ones joints, and causes a very painful inflammation as your body attacks its own joint tissues.¹ While this doesn’t typically onset until later in one’s life, women in childbearing age can be affected. One phenomenon which has been observed is an actual regression of RA symptoms and potentially remission². Unfortunately, the symptoms are reported to return post pregnancy.³ This then leads to the question what is happening during pregnancy that alleviates the symptoms and in some cases causes remission.

Many studies have been conducted to answer such a question, and the results are highly variable. Some studies point out that a certain type of immune cells, Th1, and its reduction during pregnancy may be responsible for the alleviation and remission of rheumatoid arthritis and symptoms.⁴ One particular study seeks to investigate the effects of regulatory T cells (Tregs) and how they might be interrupting the deleterious effects exhibited in RA. Whatever it may be that these studies are attempting to credit with the beneficial effects of pregnancy, they all work towards understanding the disease in order to understand how to better prevent it. If the immune system of pregnant women is able to “fight” off RA, perhaps understanding the mechanism will allow insight into how this can be converted into a publicly available treatment.

Learning Through Your Gut

What is all the hype about probiotic yogurt these days and why would a person want to have, let alone add, bacteria into their body? The fact is that not all bacteria are bad; some can even be beneficial to our health. The role of bacteria found in the gut include helping with the digestion of food, providing vitamin K, helping protect the colon from the invasion of harmful bacteria, and helping to educate the immune system to differentiate between harmless and harmful bacteria.¹ However, it is still not well understood exactly why the body fails to trigger an immune response against these bacteria.

Our bodies fight invasion through the lymphocytes. These white blood cells are varied and one type, the T cell, produces a response against invasion by activating other cells called regulatory T cells. Lathrop and his associates set out to determine how these cells are involved in regulating immune responses in the colon.