Stephen Galli, MD, Department Chair, Pathology
Dr. Stephen Galli had been lecturing for many years on allergy and asthma, but it wasn’t until he came across his nut-allergic colleague vomiting and subsequently collapsing in the hall of Stanford’s Pathology Department, that he had his first personal experience with anaphylaxis and the “magic,” as he puts it, of epinephrine.
“Remember Uma Thurman in Pulp Fiction when she got right up after getting epinephrine injected into her heart?” says Galli. “It was just like that (except you always give epinephrine in the outer thigh in cases of anaphylaxis). Within less than a minute of being given an epinephrine injection, he was talking, knew where he was, who he was.”
Not only did this experience influence Galli’s research interests, but it also impacted his lectures, prompting him to compose this limerick to help his students recognize the signs of anaphylaxis and to remember how to treat it:
With organ systems involved, at least two
Or blood pressure drops, or no air’s getting through
If the setting is right, then you have the green light
Give epi and fluids, that’s what you should do.*
As Galli tells his students, “These lectures are much more important than any other lectures in immunology. No matter what you end up doing in medicine, whether you’re a radiologist or a pathologist or a psychiatrist, you may be called on to diagnose and treat anaphylaxis. And it isn’t something you have time to get a consult about. Because the delay between the time of onset of symptoms and the time of getting the epinephrine is one of the factors that determines life or death.”
Unless you’re a cannibal, everything you eat is foreign to you.
Galli explains that on a fundamental level, the immune system must learn to distinguish between self and non-self. Or, more specifically, between non-self and harmless as opposed to non-self and harmful. “It’s quite mysterious, isn’t it, that unless you’re a cannibal, everything you eat is foreign to you?” he comments.
In non-allergic individuals, the development of oral tolerance to foods happens naturally, as if the immune system learns that what is eaten every day is probably not harmful. But for people with allergies, this tolerance does not get properly activated. Although it may seem counterintuitive, oral immunotherapy (OIT) can help people to lose their reactivity to the offending allergen. And as Galli puts it, “There is a saying in medicine: one can’t argue with success. So if it’s working, then it’s our challenge to figure out why it’s working, and maybe to get it to work better."
Through steadfast research at the Sean N. Parker Center for Allergy Research at Stanford University and other sites, treatments like OIT will evolve and become better understood. Moreover, the Center aims to develop new therapies for allergies that go beyond oral immunotherapy. Dr. Kari Nadeau, Director of the Sean N. Parker Center for Allergy Research at Stanford University, adds, “One size does not fit all in the allergy context. We have to create different lines of therapeutic regimens that don’t have to be taken orally. The field of allergy should offer safe, and effective therapy choices that meet patient’s individual needs.”
Human Immune Monitoring
By studying immune cells like mast cells, basophils, B cells and T cells, Galli’s laboratory, in partnership with the Center, is deepening our understanding of the mechanisms underlying allergic response on a cellular and molecular level.
For example, under the support of a U19 Asthma and Allergic Diseases Cooperative Research Center grant from NIAID/NIH, Galli’s Laboratory, the Nadeau Laboratory, and the laboratory of Scott Boyd, MD, PhD, are collecting and studying a large quantity of blood samples from Stanford allergy patients undergoing oral immunotherapy (OIT). As OIT patients’ allergic response to a given food is reduced, basophils and other immune cells from their blood samples are being examined for signs of immunological change.
This research has already yielded some interesting findings. A study conducted last year revealed that patients who achieved tolerance after undergoing peanut OIT at Stanford showed an increased expression of the FOXP3 gene in the regulatory T cells present in their peripheral blood, as compared to patients who had not achieved tolerance. FOXP3 is a key player in regulatory T cell activity to suppress allergic reaction. This finding, if confirmed and extended in the group’s larger ongoing NIH-supported studies, may lead to the development of a blood test to monitor the development and persistence of clinical tolerance.
Galli explains that through “human immune monitoring” research such as this, Stanford aims to develop tests that are simple to do, and provide reliable information about the severity of the allergy, propensity of getting a severe reaction, likelihood that treatment has been successful, and/or the duration of treatment success. The standard IgE blood test currently available to the public provides none of these important pieces of information.
Unraveling the origins of allergies
While his personal experience in seeing the adverse effects of allergies on friends and colleagues, and his scientific and medical interests, drew Galli to the study of allergies, there was also an intriguing natural history component that compelled him. “The idea that evolution would permit the existence of mast cells in essentially all vertebrates—cells, that when excessively activated by exposure to an otherwise harmless substance, could kill the host—would appear to fly in the face of what evolution is supposed to do, right?” he asks.
“That you develop reactivity to innocuous substances – pollen, a food item like peanuts—and then you encounter a small amount of it and the reaction to it kills you even though the entity itself is not harmful is a tremendous imbalance, a grotesque imbalance, between the cost and benefit of an immune response.”
“There have been no people described yet who have no mast cells,” Galli continues. “There have been very few people described who don’t have IgE, so it’s maintained in the population, even though in our developed society we’re experiencing an increase in the prevalence of disorders affecting IgE in which the outcome could be very serious illness, in some cases even death.” In fact, mast cells and IgEs are implicated in a range of allergic disorders beyond anaphylaxis, including allergic asthma, hay fever, atopic dermatitis, and gastroesophageal eosinophil infiltration.
“So, what’s that good function? That was my scientific question.”
Galli and others in the scientific community have begun to crack the answer to this question. Research indicates that mast cells and IgE antibodies help to protect us from the venomous creatures that we’ve co-evolved with for hundreds of millions of years. Cells very much like the mast cells of people and other vertebrates are present in animal species at least as far back in evolution as tunicates (an ancient marine animal). And Galli and his colleagues found that enzymes released by mast cells can inactivate toxins in venoms, thereby enhancing the survival of the envenomated animal. Galli’s group also recently found that IgE antibodies, which evolved later than mast cells but which permit mast cells to be activated extremely rapidly by venoms to which the animal has previously been exposed, allow mice to survive when challenged with even larger amounts of venom than they can tolerate on a first exposure.
“If you are a mouse, as long as you survive the first encounter with that venom, developing an IgE response to the venom can permit you to tolerate larger amounts of the venom in subsequent exposures,” says Galli, adding, “While it of course would not be ethical to attempt the same sorts of experiments in people, my guess is that the same principle applies in humans: in most people, having anti-venom IgE may reduce the toxicity of the venom, as long as one is not among the unfortunate individuals who develop a serious anaphylactic reaction when envenomated. However, a critical problem in modern medicine is that, in the developed world, many individuals have immune systems which generate IgE against not venom components, but components of peanuts and cat dander and pollen, and other intrinsically harmless antigens. In such people, the reactions that may have first developed to protect us against venoms are being elicited to no good purpose. We need to know how to control that.”
Tackling the allergic epidemic with a multidisciplinary approach
The Sean N. Parker Center for Allergy Research at Stanford University is tackling the allergy epidemic with a multidisciplinary approach unique to the Stanford School of Medicine, bringing in researchers from various fields across Stanford and from around the world together to attack the problem. By partnering with renowned scientists like Dr. Stephen Galli, who chairs the Center’s Scientific Advisory Board, the Center aims to not only learn how to better control allergic response, but to discover the root cause of allergies, and develop long-lasting cures.
Through uniting the efforts of multiple programs at Stanford which are housed in departments such as pathology, genetics, statistics, chemical engineering, bioengineering and others, the Center will catalyze potentially transformative changes in the field of allergy and immunology—changes that will have implications for a wide array of immune dysfunctions including asthma, food allergies, eosinophilic disorders, gastroenterological diseases, eczema, and more.
* Consult FARE’s Food Allergy and Anaphylaxis Emergency Care Plan for recommended treatment plan in case of an allergic reaction.
Interview by Barrie Shapiro
Barrie received her PhD in Chemistry from the University of Wisconsin and has two daughters with severe food allergies— one of whom has completed multi-allergen oral immunotherapy at Stanford. In addition to volunteering with the Center, Barrie works with her local schools and Girl Scouts of Northern California to promote allergy awareness and safe practices.