Sunday, February 24, 2013
E-Selectin Tolerance Protects Against Stroke
E-Selectin is a cell surface glycoprotein cell adhesion molecule that is inducible by cytokines. It was used in this study because it is not constitutive and its expression is limited to the endothelium that becomes activated in response to an inflammatory stimuli. In this case, E-Selectin serves as a molecular target for regulatory T cells to activating blood vessels where they can release anti-inflammatory cytokines, suppressing vessel activation, and therefore preventing thrombosis and hemorrhage seen with strokes.
Previous studies have determined that mucosal tolerance to E- Selectin, meaning that the immune system does not see it as a foreign antigen, has the effect of preventing both hemorrhagic and ischemic strokes in spontaneously hypertensive, genetically stroke prone rats. This study was a continuation of that to determine whether tolerance to E-Selectin has protective effects in ischemic brain damage after permanent middle cerebral artery occlusion(MCAO) in SHR-SP rats, and whether those effects are regulated through the generation of regulatory T cells.
The study utilized a total of 35 male and female rats from SHR-SP breeders that were divided into 4 groups. These four groups were PBS(control) and E-Selectin tolerized groups that were each divided into single-tolerization and booster tolerization groups. The single tolerization groups received the PBS or E-Selectin nasally every other day for a total of 10 days and 5 administrations. The booster-tolerization received the intranasal installation on the same schedule, but was repeated once after 11 days. The tests for this study included Delayed Type Hypersensitivity(DTH) reaction, ELISA, assessment of infarct volume, as well as an adoptive transfer test. In the adoptive transfer test, the spleens were removed from rats 48 hours after their final dose of the tolerizing agent on the booster tolerization schedule. The spleens were used to make a suspension and culture cells to inject into SHR-SP rats before the MCAO.
The results of this study showed that E-Selectin mucosal booster tolerization had a significant decrease in infarct size in rats at both 6 and 48 hours after the onset of ischemia. Single tolerization experiments were not as significant and showed only a slight decrease in infarct size and minimal trend toward benefit in stroke outcome. The results from the DTH test showed that the responses to E-Selectin were repressed in rats that were tolerized to it, indicating that there were antigen specific regulatory T cells produced in tolerized rats, also implying a cell mediated response in protection against stroke. Additionally, the adoptive transfer of splenocytes from tolerized rats resulted in a similar level of protection in normal rats as seen in rats that were on the booster tolerization schedule, also supporting the finding that this reaction is cell mediated. Finally, the ELISA test showed an increase in IL-10 in tolerized splenocytes when compared to control splenocytes, showing again that there was a substantial involvement of regulatory T cells in the protection against the effects of stroke. Overall, the mechanism for this type of protection against the effects of a stroke still remains unknown and leaves room for future research in this area.
Does the utilization of E-Selectin seem like a reasonable option to prevent the effects associated with strokes?
Do you see any potential issues in using this type of therapy in humans?
Chen Y, Ruetzler C, Spatz S, et al. Mucosal Tolerance to E-Selectin provides cell-mediated protection against ischemic Brain Injury. Proceedings of the National Academy of Sciences. 2003:100(25);15107-15112
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I think that there would be a lot of issues if E-Selectin was were to be used on humans. Like we talked about in class, what would be the requirements for someone to get this therapy? It wouldn't seem make sense to give it to younger people who don't normally have the risk of stroke like older people might. However, not everyone ends up having a stroke so the risks of it may out way the benefits.
ReplyDeleteWhen researching this issue online, I found a website that tells you all of the clinical trials that are going on. In 2006, they received notice that a clinical trial was going to be started and that humans would be given E-Selectin. It isn't currently open for participation recruitment, but one of their requirements is that the person must have had some type of stroke or TIA 31-120 days prior to the study, must be 45 years old or older, and have a modified Rankin score of 0-2 at the time of enrollment.
I think it would be a good requirement that someone has had a stroke or TIA before receiving this treatment because they do have a higher chance of having another one.
http://clinicaltrials.gov/ct2/show/NCT00069069
Like we talked about in class I think this is a sort of good idea but it's definitely a work in progress. i don't think anybody should start hacking away at anyone else's E-Selectin before we do a lot more tests. I mean we know E-Selectin increases cell adhesion so lacking it can lead to more of a rolling process but who really know what the long term effects of this could be? No one can until a long term study is completed on a number of subjects. In addition to this what if we happen to stimulate E-Selectin and then it goes around recruiting skin specific t-lymphocytes like it does which could lead to major inflammation issues? And one more thing, like we talked about in class how would we know when to start giving someone this treatment and to kind of add a little caveat, these mice were getting treatments every other day, would it be necessary to have humans to participate in a similar way requiring every other day treatments? We have enough issues as it is just trying to get people to finish their prescribed twice a day for 10 days antibiotic treatments and such, imagine trying to get them to take something that we're not really sure will work every other day.
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