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Allergic asthma is a chronic inflammatory disease that affects the larger, conducting, airways. In the last decades the incidence of allergic asthma has dramatically increased. The pathology of allergic asthma is characterized by a T helper 2 cell inflammation against an allergen, the inflammation leads to IgE production. The produced IgE antibodies will prime the mast cells, with will lead to airway hyper responsiveness. Other characteristics of allergic asthma are extensive mucus production, airway remodelling, eosinophill and lymphoid influx. The current thought is that allergic asthma has an environmental and a genetic factor, which affects the immune system.
Normally the immune system is able to discriminate between harmful antigens and harmless allergens. The discrimination between harmless and harmful leads respectively to an inflammatory response or to tolerance. Individuals with a susceptible genetic background can be stimulated by environmental allergens, such as house dust mite. The allergens recognized by the immune system, leading to a Th2 cell mediated inflammatory response.
Important in the suppression of an inflammatory response and the induction of tolerance are the regulatory T cells (Tregs). Tregs are a subset of T cells that can inhibit inflammatory responses either by the production of anti-inflammatory cytokines or by cell-cell interactions. A recent paper showed that allergic asthma patients have lower numbers of Tregs and that those Tregs are not able to expand properly (Karlsson et al. 2004). Therefore, the immune system of allergic asthma patients is not able to suppress the inflammation.
The current treatment of allergic asthma is based on a symptomatic treatment, either against mast cells that produce histamines or steroids against Th2 cells. But the steroids are not specifically against Th2 cells, they block the entire immune system in the lungs. A new idea is that patients could benefit more from specific treatment against Th2 cells. One idea is to stimulate (allergen specific) Tregs, that in theory could suppress the harmful Th2 cell inflammation. And therefore the Tregs are widely under investigation for their suppressive role in inflammation.
A recent paper showed that treated sensitized mouse with adoptive transfer of in vitro expanded allergen specific Tregs (Kearly et al. 2008). The first results that this group showed were very promising; the allergic reaction is at least partially blocked by the admission of in vitro expanded Tregs. This treatment with in vitro expanded Tregs is very expensive way suppressing the Th2 cells, because patients should receive chronic treatment. To improve the in vitro stimulated Treg treatment, the novel idea is to stimulate and expand Tregs in vivo to prevent allergic asthma.
Schreiber et al. focused on the in vivo expansion of Tregs by using an agonist for the TNFRSF25 receptor, a member of the TNF receptor super family. The authors show that TNFRSF25 is highly expressed on Tregs but not on conventional T cells. In a mouse model, stimulation of the TNFRSF25 receptor by an agonist, 4C12, gives Tregs expansion in vitro and in vivo. And the expanded Tregs are able to suppress conventional T cells in vitro.
To test if the 4C12 expanded Tregs are able to suppress the Th2 cell inflammation in vivo and therefore prevent allergic asthma. In this experiment they used OVA/Alum sensitized mice, with were treated with 4C12, 4 days before allergen challenge.
After challenge, the mice that received treatment show a decrease in allergic asthma features. The Th2 cytokines, such as IL-4, IL-5 and IL-13 were suppressed. And the number of lung infiltrating cells, lymphocytes and neutrophills, did also decrease.
The authors did investigate the mechanism behind Treg expansion. They showed that MHC 2 and the T cell receptor (TcR) are crucial for Treg expansion in vivo. Indicating that antigen presentation in the context of MHC 2 and TcR recognition is important. The antigen that is presented by the MHC 2 is still unknown, but the authors suggested that it is an auto-antigen. Therefore the suppressive reaction of the generated Tregs is not allergen specific, but the suppression of the Tregs suppresses the entire immune system.
The article of Schreiber et al. showed that it is possible to in vivo stimulate and expand Tregs, without stimulating and expanding conventional T cells. Therefore the authors found a novel mechanism in Tregs control. This is the first report that showed that in vivo stimulated Tregs are able to properly suppress a Th2 cell mediated inflammation in allergic asthma by down regulating Th2 cytokines and cell infiltration. The authors state that this treatment could possibly be used in auto-immune diseases that lack the proper Treg suppression.
Despite the positive results of this paper, there are some important points missing. The authors used a set time point for challenge after treatment. The authors chose to challenge the mice 4 days after treatment, because the Tregs are maximally expanded on day 4 after treatment. By taking a perfect time point, the authors did not investigate if challenged Tregs on another time point can suppress the Th2 cell inflammation as well. So, the question remains if the expanded Tregs after a shorter or longer time are still able to properly suppress the Th2 cell inflammation after challenge.
This point is very important in for application in patients, it means that patients should receive a treatment at 4 days before allergic asthma attack. Because this is not possible the patients should receive chronic or seasonally treatment, to prevent a relapse in Treg levels.
Another important point is that the authors did chose for a mouse model that mainly resembles Th2 inflammation after challenge. A recent report showed that allergic asthma in humans is not only Th2 mediated (Woodruff et al. 2009). There are rather two major sub-phenotypes of allergic asthma in humans. These sub-phenotypes are divined by the degree of Th2 cell mediated inflammation. And therefore the authors concluded that the current used mouse model for allergic asthma do not explain adequately the non-Th2 driven allergic asthma. It is therefore questionable if the results found in the paper of Schreiber et al. are applicable on all allergic asthma patients.
The treatment with TNFRSF25 does give positive results in the Th2 driven allergic asthma in mice, could possibly be used as treatment for Th2 allergic asthma patients. But, in my opinion, the usage of TNFRSF25 does give positive results in healthy, sensitized mice. These mice do not resemble allergic asthma patients, and is therefore not directly applicable for humans. There are at least two major problems that need further attention.
First, there is an important role for genetic susceptibility in allergic asthma. It is known that the susceptible genes in allergic asthma are mainly involved in immune-regulation, in Tregs. One of the susceptible genes is the FoxP3 gene, important in the development and expansion of Tregs. FoxP3 mutations that knock out the gene can cause auto-immune diseases with an allergic phenotype. In asthma patients the FoxP3 gene is not knocked-out but altered (Bottema et al. 2010).
In the experiment of Schreiber et al. they used genetically healthy mice, with Tregs that could properly expand. Changes in the FoxP3 gene in allergic asthma patients could cause impaired Treg expansion. Even after stimulation with TNFRSF25.
Secondly, the chances of side effects of this treatment are very high. The expanded Tregs are not allergen specific, meaning that they not only suppress allergen specific Th2 cells but the entire immune system. By suppressing the entire immune system, not only the harmful Th2 inflammation is suppressed, but for example the immune reaction against infections and the tumorimmunosurveillance too. In addition, the treatment with TNFRSF25 is a chronic treatment. The Tregs should be stimulated with 4C12 the rest of the patients lives, because the optimum of Treg expansion was measured at day 4 after treatment. Stopping treatment means that the levels of Tregs decline, and that the level of conventional T cells will increase again. A chronic treatment increases the chance of getting the side effects that are mentioned above.
All in all, Schreiber et al. did show a novel and interesting mechanism for Treg control in a mouse model. The treatment of TNFRSF25 did give Treg expansion in vivo, and suppression of allergic features. But TNFRSF25 treatment in allergic asthma patients is, in my opinion, not applicable for the reasons mentioned above. The focus should be more on stimulating and generating allergen specific Tregs that are able to selectively suppress Th2 cells in allergic asthma and develop memory.
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