Allergic asthma is a chronic inflammatory disease that affects the larger, conducting, air passages. In the last decades the incidence of allergic asthma has dramatically increased. The pathology of allergic asthma is characterized by a T assistant 2 cell redness against an allergen, the redness leads to IgE production. The produced IgE antibodies will prime the mast cells, with will take to airway hyper reactivity. Other features of allergic asthma are extended mucous secretion production, airway remodelling, eosinophill and lymphoid inflow. The current idea is that allergic asthma has an environmental and a familial factor, which affects the immune system.
Normally the immune system is able to know apart between harmful antigens and harmless allergens. The favoritism between harmless and harmful leads severally to an inflammatory response or to tolerance. Persons with a susceptible familial background can be stimulated by environmental allergens, such as house dust touch. The allergens recognized by the immune system, taking to a Th2 cell mediated inflammatory response.
Important in the suppression of an inflammatory response and the initiation of tolerance are the regulative T cells ( Tregs ) . Tregs are a subset of T cells that can suppress 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 Numberss of Tregs and that those Tregs are non able to spread out decently ( Karlsson et al. 2004 ) . Therefore, the immune system of allergic asthma patients is non able to stamp down the redness.
The current intervention of allergic asthma is based on a diagnostic intervention, either against mast cells that produce histamines or steroids against Th2 cells. But the steroids are non specifically against Th2 cells, they block the full immune system in the lungs. A new thought is that patients could profit more from specific intervention against Th2 cells. One thought is to excite ( allergen particular ) Tregs, that in theory could stamp down the harmful Th2 cell redness. And hence the Tregs are widely under probe for their suppressive function in redness.
A recent paper showed that treated sensitized mouse with adoptive transportation of in vitro expanded allergen specific Tregs ( Kearly et al. 2008 ) . The first consequences that this group showed were really promising ; the allergic reaction is at least partly blocked by the admittance of in vitro expanded Tregs. This intervention with in vitro expanded Tregs is really expensive manner stamp downing the Th2 cells, because patients should have chronic intervention. To better the in vitro stimulated Treg intervention, the fresh thought is to excite and spread out Tregs in vivo to forestall allergic asthma.
Schreiber et Al. focused on the in vivo enlargement of Tregs by utilizing an agonist for the TNFRSF25 receptor, a member of the TNF receptor super household. The writers show that TNFRSF25 is extremely expressed on Tregs but non on conventional T cells. In a mouse theoretical account, stimulation of the TNFRSF25 receptor by an agonist, 4C12, gives Tregs enlargement in vitro and in vivo. And the expanded Tregs are able to stamp down conventional T cells in vitro.
To prove if the 4C12 expanded Tregs are able to stamp down the Th2 cell redness in vivo and hence prevent allergic asthma. In this experiment they used OVA/Alum sensitized mice, with were treated with 4C12, 4 yearss before allergen challenge.
After challenge, the mice that received intervention show a lessening in allergic asthma characteristics. The Th2 cytokines, such as IL-4, IL-5 and IL-13 were suppressed. And the figure of lung infiltrating cells, lymph cells and neutrophills, did besides lessening.
The writers did look into the mechanism behind Treg enlargement. They showed that MHC 2 and the T cell receptor ( TcR ) are important for Treg enlargement in vivo. Bespeaking that antigen presentation in the context of MHC 2 and TcR acknowledgment is of import. The antigen that is presented by the MHC 2 is still unknown, but the writers suggested that it is an auto-antigen. Therefore the suppressive reaction of the generated Tregs is non allergen specific, but the suppression of the Tregs suppresses the full immune system.
The article of Schreiber et Al. showed that it is possible to in vivo stimulate and expand Tregs, without exciting and spread outing conventional T cells. Therefore the writers found a fresh mechanism in Tregs control. This is the first study that showed that in vivo stimulated Tregs are able to decently stamp down a Th2 cell mediated redness in allergic asthma by down modulating Th2 cytokines and cell infiltration. The writers province that this intervention could perchance be used in auto-immune diseases that lack the proper Treg suppression.
Despite the positive consequences of this paper, there are some of import points losing. The writers used a set clip point for challenge after intervention. The writers chose to dispute the mice 4 yearss after intervention, because the Tregs are maximally expanded on twenty-four hours 4 after intervention. By taking a perfect clip point, the writers did non look into if challenged Tregs on another clip point can stamp down the Th2 cell redness as good. So, the inquiry remains if the expanded Tregs after a shorter or longer clip are still able to decently stamp down the Th2 cell redness after challenge.
This point is really of import in for application in patients, it means that patients should have a intervention at 4 yearss before allergic asthma onslaught. Because this is non possible the patients should have chronic or seasonally intervention, to forestall a backsliding in Treg degrees.
Another of import point is that the writers did take for a mouse theoretical account that chiefly resembles Th2 redness after challenge. A recent study showed that allergic asthma in worlds is non merely Th2 mediated ( Woodruff et al. 2009 ) . There are instead two major sub-phenotypes of allergic asthma in worlds. These sub-phenotypes are divined by the grade of Th2 cell mediated redness. And hence the writers concluded that the current used mouse theoretical account for allergic asthma do non explicate adequately the non-Th2 driven allergic asthma. It is hence questionable if the consequences found in the paper of Schreiber et Al. are applicable on all allergic asthma patients.
The intervention with TNFRSF25 does give positive consequences in the Th2 driven allergic asthma in mice, could perchance be used as intervention for Th2 allergic asthma patients. But, in my sentiment, the use of TNFRSF25 does give positive consequences in healthy, allergic mice. These mice do non resemble allergic asthma patients, and is hence non straight applicable for worlds. There are at least two major jobs that need farther attending.
First, there is an of import function for familial susceptibleness in allergic asthma. It is known that the susceptible cistrons in allergic asthma are chiefly involved in immune-regulation, in Tregs. One of the susceptible cistrons is the FoxP3 cistron, of import in the development and enlargement of Tregs. FoxP3 mutants that knock out the cistron can do auto-immune diseases with an allergic phenotype. In asthma patients the FoxP3 cistron is non knocked-out but altered ( Bottema et al. 2010 ) .
In the experiment of Schreiber et Al. they used genetically healthy mice, with Tregs that could decently spread out. Changes in the FoxP3 cistron in allergic asthma patients could do impaired Treg enlargement. Even after stimulation with TNFRSF25.
Second, the opportunities of side effects of this intervention are really high. The expanded Tregs are non allergen specific, intending that they non merely suppress allergen specific Th2 cells but the full immune system. By stamp downing the full immune system, non merely the harmful Th2 redness is suppressed, but for illustration the immune reaction against infections and the tumorimmunosurveillance excessively. In add-on, the intervention with TNFRSF25 is a chronic intervention. The Tregs should be stimulated with 4C12 the remainder of the patients lives, because the optimum of Treg enlargement was measured at twenty-four hours 4 after intervention. Stoping intervention means that the degrees of Tregs diminution, and that the degree of conventional T cells will increase once more. A chronic intervention increases the opportunity of acquiring the side effects that are mentioned above.
All in all, Schreiber et Al. did demo a novel and interesting mechanism for Treg control in a mouse theoretical account. The intervention of TNFRSF25 did give Treg enlargement in vivo, and suppression of allergic characteristics. But TNFRSF25 intervention in allergic asthma patients is, in my sentiment, non applicable for the grounds mentioned above. The focal point should be more on stimulating and bring forthing allergen specific Tregs that are able to selectively stamp down Th2 cells in allergic asthma and develop memory.
1. Schreiber TH, Wolf D, Tsai MS, Chirinos J, Deyev VV, Gonzalez L, Malek TR, Levy RB, Podack ER. Therapeutic Treg enlargement in mice by TNFRSF25 prevents allergic lung redness. The Journal of Clinical Investigation Volume 120 ; 10, 2010 3629:3640.
2. Karlsson MR, Rugtveit J, Brandtzaeg P. Allergen-responsive CD4+CD25+ regulative T cells in kids who have outgrown cowHYPERLINK “ hypertext transfer protocol: //www.ncbi.nlm.nih.gov/pubmed/15197226 ” ‘HYPERLINK “ hypertext transfer protocol: //www.ncbi.nlm.nih.gov/pubmed/15197226 ” s milk allergic reaction. J Exp Med. 2004 21 ; 199 ( 12 ) :1679-88.
3. Kearly J. , Robinson DS, Lloyd CM. CD41CD251 regulative T cells change by reversal established allergic air passage redness and prevent airway remodelling. J Allergy Clin Immunol. 2008 Sep ; 122 ( 3 ) :617-24
4. Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, Koth LL, Arron JR, Fahy JV. T-helper type 2-driven redness defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009 ; 180 ( 5 ) :388-95
5. Bottema RW, Kerkhof M, Reijmerink NE, Thijs C, Smit HA, new wave Schayck CP, Brunekreef B, new wave Oosterhout AJ, Postma DS, Koppelman GH. Gene-gene interaction in regulative T-cell map in immediate allergy and asthma development in childhood. J Allergy Clin Immunol. 2010 126 ( 2 ) :338-46