Tuesday, March 19, 2013

How Do Food Allergy Treatments Work?

I've been thinking a lot lately about whether our experience with the FAHF-2 food allergy trial was worth all the time and hassle. In a sense, the jury is still out because we don't know yet what effect the medication may have had on my son's milk allergy. (The near impossibility of getting an almost 18-year-old to stay still in one place while consuming baked milk is a topic for another blog post.) However, I also grapple with what exactly the medication did.

So why is there a creepy Orc over there, you ask? Because it seems to me that, up until this point, food allergy treatments have used a Lord of the Rings strategy. Think of the cast of characters this way:

The allergen is the Orc. Maybe he's completely misunderstood, but bad things seem to occur as soon as he hits the kingdom so, as soon as they see even one Orc, the  mast cells go all nutty and light the signal fires. This starts a cascade of chemical messages throughout the body.

Histamines and other chemical messengers play the part of the Riders of Rohan. They see the fires and go forth to every cell in the body and say "rally the troops!"  Antihistamines work by coating cell receptors so the Riders of Rohan simply can't get inside the cell to deliver the message. That's why there's a lot of debate about whether putting out some of those signal fires can help to lessen reactions.

However, doctors don't recommend antihistamine only to treat reactions for an important reason: neither the number of Orcs or the number of Riders of Rohan determine the allergic response. It's what happens next that determines just hives...or full-out anaphylaxis...or something in-between.

Whether a few riders make it through or a lot of them do, at some point, the body decides how forcefully it's going to respond. For most people, the response seems to be dose-dependent: the more Orcs in the body, the more Riders of Rohan, the more forceful the response.

However, for a sub-segment of allergic individuals, the response is way out of proportion to the threat. If the right few Orcs show up...or the right Riders reach the king...a severe response/reaction can occur. There are a couple of theories as to why. One theory is that some people have a genetic variant that causes their body to over-respond to perceived threats. Another theory is that children who are allergic to more than one hot spot on a protein are likely to have a more robust response.


Once the King and all his troops are called to the body's battlefield, it's hard to stop the war. Epinephrine is the best way. Like the Ents in the river scene in "The Two Towers", epinephrine opens up closed airways and sweeps away chemical messengers that have caused so much trouble. It also gets fluids to return to the river bed instead of running rampant through the body once all the fun is over.

So how does all this relate to the food allergy clinical trials currently underway? In almost all of these trials (oral immunotherapy, SLIT, skin patch), the idea is to just keep slipping Orcs into the body until the Riders of Rohan get used to them. After all, there are only so many times you can pelt into the hall of the king and shout "Rally the troops!" before the king stops listening.

However, these studies all seem to have an upper limit. While the Riders will ignore a few Orcs, eventually a tipping point is reached where the body can no longer ignore the incursions. That's the difference between desensitization (getting used to a few Orcs) and tolerance (no longer seeing Orcs as a threat at all). Plus, most of these studies seem to depend on having those Orcs constantly milling about. If you take the Orcs away for a few weeks and then reintroduce them, the signal fires get lit and the riders ride, just as if they were never there at all. That's why kids who miss a day of oral therapy can suddenly find themselves having a bad reaction. Is living with Orcs really the best option?

The newest therapy on the horizon is OIT combined with omalizumab (Xolair®), a drug that works at the very beginning of the process by inserting itself into the receptors in mast cells so IgE can't bind. If you think of the Orc and the signal fire, omalizumab acts like rain on the fire wood. The signal fire never gets started, so the Riders of Rohan never ride and...well, you get the idea.

The problem with this is that omalizumab also seems to get in the way of the immune system recognizing and fighting cancer cells. It can also work in the complete opposite way and cause anaphylaxis for some people. That's why it comes with what's known as a "black box" warning -- a strong caution that only people who really don't have another choice should consider using the drug. However, the people conducting these food-allergy studies believe that the very small amount of time the drug will be used will not cause any long-term immune effects.

The theory is that one day, the body will wake up after therapy and see Orcs everywhere. Since there were no signal fires and no Riders of Rohan, the armies of Middle Earth will (in theory) just shrug and go "hey, guess those Orcs weren't so bad after all."

Yeah, doesn't seem like it would work to me either. But that's the theory. Some kids just seemed destined to learn to live with Orcs, so this may just be accelerating the process for those kids. For others, it may just be a faster way to learn that they're not good candidates for OIT. Only time will tell if it's all just a fantasy.

So what happens with FAHF-2?

That seems to be a different story altogether. Rather than training the body to ignore an allergen through desensitization, the medication seems to cause a general snooziness in the immune system. Poppies...poppies.

How does it work? No one knows. Somewhere along the Yellow Brick Road, something changes. FAHF-2 works for all allergens and it works whether those allergens are in the body or not, so it's a very different model than OIT. Perhaps it reduces overall inflammation. Perhaps it promotes an environment where something missing (gut bacteria?) can get re-established. Whatever the mechanism, it does not seem to have the same overall suppressive effect on the immune system that omalizumab does.

The truth with all this is that, despite long flowcharts of chemical mediators attached to most research studies, no one really knows the answer to the important question: what causes an allergy in the first place? Why does the Wicked Witch of the Allergic West tell some children "I'll get you, my pretty" and ignore other kids altogether? What bucket of water will destroy all that beautiful wickedness?

Somewhere out there is the magic formula that will cause these allergies to just melt away. Maybe we all just need to click our ruby slippers together a little harder.


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