Scientific American

m e d i c i n e Surprises from Celiac Disease Study of a potentially fatal food-triggered disease has uncovered a process that may contribute to many autoimmune disorders • By Alessio Fasano

y vote for the most important scientif- growth of stable communities, the proteins un- Key Concepts ic revolution of all time would trace doubtedly began killing people (often children) ■ ■ Celiac disease (CD) is Mback 10,000 years ago to the Middle whose bodies reacted abnormally to them. Eat- an autoimmune disorder East, when people first noticed that new plants ing such proteins repeatedly would have eventu- triggered by ingestion of arise from seeds falling to the ground from oth- ally rendered sensitive individuals unable to gluten, a major protein er plants—a realization that led to the birth of properly absorb nutrients from food. Victims in wheat, or of related agriculture. Before that observation, the human would also have come to suffer from recurrent proteins in other grains. race had based its diet on fruits, nuts, tubers and abdominal pain and diarrhea and to display the ■ ■ Research into the root occasional meats. People had to move to where emaciated bodies and swollen bellies of starving causes indicates that their food happened to be, putting them at the people. Impaired nutrition and a spectrum of the disorder develops mercy of events and making long-term settle- other complications would have made their lives when a person exposed to ments impossible. relatively short and miserable. gluten also has a genetic Once humans uncovered the secret of seeds, If these deaths were noticed at the time, the susceptibility to CD and they quickly learned to domesticate crops, ulti- cause would have been a mystery. Over the past an unusually permeable mately crossbreeding different grass plants to 20 years, however, scientists have pieced togeth- intestinal wall. create such staple grains as wheat, rye and bar- er a detailed understanding of CD. They now ■ ■ Surprisingly, essentially ley, which were nutritious, versatile, storable, and know that it is an autoimmune disorder, in the same trio—an environ- valuable for trade. For the first time, people were which the immune system attacks the body’s mental trigger, a genetic able to abandon the nomadic life and build cities. own tissues. And they know that the disease susceptibility and a “leaky It is no coincidence that the first agricultural ar- arises not only from exposure to gluten and its gut”—seems to underlie eas also became “cradles of civilization.” ilk but from a combination of factors, including other autoimmune disorders as well. This finding This advancement, however, came at a dear predisposing genes and abnormalities in the raises the possibility that price: the emergence of an illness now known as structure of the small intestine. new treatments for CD celiac disease (CD), which is triggered by ingest- What is more, CD provides an illuminating may also ameliorate ing a protein in wheat called gluten or eating example of the way such a triad—an environ- other conditions. similar proteins in rye and barley. Gluten and its mental trigger, susceptibility genes and a gut ab- —The Editors relatives had previously been absent from the hu- normality—may play a role in many autoim- man diet. But once grains began fueling the mune disorders. Research into CD has thus sug-

32 Scientific American August 2009 gested new types of treatment not only for the be a cause.” As clever as Gee obviously was, the Foods containing wheat, rye or disease itself but also for various other autoim- true nature of the disease escaped even him, as barley trigger an autoimmune mune conditions, such as type 1 diabetes, mul- was clear from his dietary prescription: he sug- reaction (against the body’s own tiple sclerosis and rheumatoid arthritis. gested feeding these children thinly sliced bread, tissues) in people afflicted with toasted on both sides. celiac disease. The response harms the intestinal lining and Early Insights Identification of gluten as the trigger occurred impairs the body’s absorption of After the advent of agriculture, thousands of after World War II, when Dutch pediatrician nutrients. Chronic exposure to years passed before instances of seemingly well- Willem-Karel Dicke noticed that a war-related those foods can also lead to ) fed but undernourished children were docu- shortage of bread in the Netherlands led to a sig- cancer and other ill effects in mented. CD acquired a name in the first century nificant drop in the death rate among children such individuals. A.D., when Aretaeus of Cappadocia, a Greek affected by CD—from greater than 35 percent photoillustration physician, reported the first scientific descrip- to essentially zero. He also reported that once tion, calling it koiliakos, after the Greek word wheat was again available after the conflict, the for “abdomen,” koelia. British physician Samuel mortality rate soared to previous levels. Follow- Gee is credited as the modern father of CD. In a ing up on Dicke’s observation, other scientists

); jen christiansen ( 1887 lecture he described it as “a kind of chron- looked at the different components of wheat, ic indigestion which is met with in persons of all discovering that the major protein in that grain, photograph ages, yet is especially apt to affect children gluten, was the culprit. between one and five years old.” He even cor- Turning to the biological effects of gluten, in-

credit tk ( rectly surmised that “errors in diet may perhaps vestigators learned that repeated exposure in

www.ScientificAmerican.com SCIENTIFIC AMERICAN 33 [Basics] CD patients causes the villi, fingerlike structures in the small intestine, to become chroni- Normal Digestion cally inflamed and damaged, so that they are In the normal digestive tract, partly processed food from the stomach enters the small intestine, unable to carry out their normal function of which is lined with fingerlike projections called villi (below left). Enzymes from the pancreas and breaking food down and shunting nutrients on the surface of the villi’s constituent epithelial cells (enterocytes) break down most of the food across the intestinal wall to the bloodstream to its smallest components—such as glucose and amino acids (below right). Then these nutrients (for delivery throughout the body). Fortunately, pass into the bloodstream to fuel tissues throughout the body. Celiac disease disrupts the absorp- if the disease is diagnosed early enough and pa- tion of nutrients by damaging enterocytes and by flattening the villi, which reduces the surface tients stay on a gluten-free diet, the architecture area available to interact with food (micrographs). of the small intestine almost always returns to normal, or close to it, and gastrointestinal symptoms disappear. Villi In a susceptible person, gluten causes this inflammation and intestinal damage by eliciting activity by various cells of the immune system. These cells in turn harm healthy tissue in an attempt to destroy what they perceive to be an Small infectious agent. intestine

A Diagnostic Discovery Stomach Fuller details of the many mechanisms through which gluten affects immune activity are still Large intestine Food from being studied, but one insight in particular has Small stomach already proved useful in the clinic: a hallmark intestine of the aberrant immune response to gluten is Microvilli production of antibody molecules targeted to an enzyme called tissue transglutaminase. This Enterocyte enzyme leaks out of damaged cells in inflamed areas of the small intestine and attempts to help heal the surrounding tissue. Discovery that these antibodies are so common in CD added a new tool for diagnosing the ers has confirmed similar levels in many coun- disorder and also allowed my team and other re- tries, with no continent spared. searchers to assess the incidence of the disease in How did 99 percent of cases escape detection a new way—by screening people for the presence for so long? The classical outward signs—per- of this antibody in their blood. Before then, doc- sistent indigestion and chronic diarrhea—ap- tors had only nonspecific tests, and thus the most pear only when large and crucial sections of reliable way to diagnose the disease was to re- the intestine are damaged. If a small segment view the patient’s symptoms, confirm the intes- of the intestine is dysfunctional or if inflamma- tinal inflammation by taking a biopsy of the gut, tion is fairly mild, symptoms may be less dra- and assess whether a gluten-free diet relieved matic or atypical. symptoms. (Screening for antibodies against It is also now clear that CD often manifests );

gluten is not decisive, because they can also oc- in a previously unappreciated spectrum of ) cur in people who do not have CD.) symptoms driven by local disruptions of nutri- For years CD was considered a rare disease ent absorption from the intestine. Disruption of photoillustration outside of Europe. In North America, for exam- We found that iron absorption, for example, can cause anemia, intestinal illustrationintestinal ple, classic symptoms were recognized in fewer the disease and poor folate uptake can lead to a variety of ( than one in 10,000 people. In 2003 we pub- neurological problems. By robbing the body of lished the results of our study—the largest hunt was nearly particular nutrients, CD can thus produce such ); jen christiansen ( for people with CD ever conducted in North 100 times more symptoms as osteoporosis, joint pain, chronic America, involving more than 13,000 people. fatigue, short stature, skin lesions, epilepsy, de- Astoundingly, we found that one in 133 appar- common mentia, schizophrenia and seizure. system digestive ently healthy subjects was affected, meaning the than had Because CD often presents in an atypical ElectronicPublishing Services, Inc. disease was nearly 100 times more common fashion, many cases still go undiagnosed. This kimmoss than had been thought. Work by other research- been thought. new ability to recognize the disease in all its photo credit tk (

34 Scientific American August 2009 [Basics] and other substances is through eating, and im- Normal Digestion mune soldiers sit under the epithelial cells that FAST facts

line the intestine (enterocytes), ready to pounce ■■ Normal intestinal lining Lining in person with celiac disease Roughly 1 percent of and call in reinforcements. One reason our im- the global population has mune system typically is not incited by this celiac disease, although thrice-daily protein invasion is that before our most do not know it. defenses encounter anything that might trouble them, our gastrointestinal system usually breaks ■■ More than two million people in the U.S. are down most ingested proteins into standard ami- afflicted with the disease. no acids—the building blocks from which all proteins are constructed. ■■ Some common symptoms in Gluten, however, has a peculiar structure: it infants and children are is unusually rich in the amino acids glutamine abdominal pain, bloating, Indigestible food and proline. This property renders part of the constipation, diarrhea, flows to rectum weight loss and vomiting. Enzyme for excretion molecule impervious to our protein-chopping machinery, leaving small protein fragments, or ■■ About half of adults with the peptides, intact. Even so, in healthy people, condition do not suffer from most of these peptides are kept within the gas- diarrhea at diagnosis. trointestinal tract and are simply excreted before the immune system even notices them. And ■■ Other signs that may occur in any gluten that sneaks across the gastrointesti- adults are anemia, arthritis, bone loss, depression, nal lining is usually too minimal to excite a sig- fatigue, infertility, joint pain, nificant response from a normally functioning seizures, and numbness in immune system. the hands and feet. CD patients, on the other hand, have inher- Nutrients ited a mix of genes that contribute to a heightened immune sensitivity to gluten. For example, Flows to certain gene variants encoding proteins known tissues as histocompatibility leukocyte antigens (HLAs) Bloodstream play a role. Ninety-five percent of people with CD possess either the DQ2 or the DQ8 HLA forms at an early stage allows gluten to be re- gene, whereas just 30 to 40 percent of the gen-

) moved from the diet before more serious com- eral population have one of those versions. This

credit plications develop. finding and others suggest that HLA DQ2 and DQ8 are not the sole cause of immune hyperac- From Gluten to Immune Dysfunction tivity but that the disease, nonetheless, is nearly Celiac disease provides an enormously valuable impossible to establish without one of them. [The Author] ); author photo ( model for understanding autoimmune disorders The reason these HLAs are key becomes obvi- because it is the only example where the addi- ous from studies of the function of the proteins micrographs tion or removal of a simple environmental com- they specify. ponent, gluten, can turn the disease process on The HLA DQ2 and DQ8 proteins are made and off. (Although environmental factors are by antigen-presenting cells. These immune sen- suspected of playing a role in other autoimmune tinels gobble up foreign organisms and proteins, diseases, none have been positively identified.) chop them, fit selected protein fragments into To see how gluten can have a devastating ef- grooves on HLA molecules, and display the re- fect in some people, consider how the body resulting HLA-protein complexes on the cell sur- sponds to it in most of the population. In those face for perusal by immune system cells called Alessio Fasano is professor of pediatrics, medicine and physiolo- without CD, the body does not react. The nor- helper T lymphocytes. T cells that can recognize gy and director of the Mucosal mal immune system jumps into action only and bind to the displayed complexes then call in Biology Research Center and the when it detects significant amounts of foreign reinforcements. Center for Celiac Research at the proteins in the body, reacting aggressively be- In patients with CD, tissue transglutaminase University of Maryland School of cause the foreigners may signal the arrival of released by intestinal epithelial cells attaches to Medicine. Much of his basic and clinical research focuses on the disease-causing microorganisms, such as bacte- undigested gluten and modifies the peptides in role of intestinal permeability in ria or viruses. a way that enables them to bind extremely the development of celiac disease

center for celiac research, university of maryland school of medicine ( A major way we encounter foreign proteins strongly to DQ2 and DQ8 proteins. In conse- and other autoimmune disorders.

www.ScientificAmerican.com SCIENTIFIC AMERICAN 35 [Overview] instance they do no good and harm the intesti- A Trio of Causes nal cells responsible for absorbing nutrients. CD patients also tend to have other genetic Three factors underlie celiac disease: an environmental trigger, a genetic susceptibility and, according to the author’s research, an unusually permeable gut (below). The predispositions, such as a propensity for over- author suspects that the same basic triad contributes to other autoimmune diseases, producing the immune stimulant IL-15 and for although each disorder will have its own triggers and genetic components. harboring hyperactive immune cells that prime the immune system to attack the gut in response to gluten. Wheat kernel Guilt by Association What role might antibodies to tissue transglutaminase play in this pathological response to Endosperm gluten? The answer is still incomplete, but scien- Gluten Bran tists have some idea of what could happen. When intestinal epithelial cells release tissue transglu- TRIGGER The gluten protein, abundant in the taminase, B cells of the immune system ingest endosperm of wheat kernels, sets off it—alone or complexed to gluten. They then the aberrant immune response. Germ Related proteins in barley and rye release antibodies targeted to the enzyme. If the (hordein and secalin) do the same. antibodies home to tissue transglutaminase sit- ting on or near intestinal epithelial cells, the anti- GENETIC PREDISPOSITION bodies might damage the cells directly or elicit Almost all patients harbor the other destructive processes. But no one yet genes HLA-DQ2 or HLA-DQ8, or both. These genes give rise to knows whether they, in fact, cause such harm. proteins of the same name that In the past nine years my colleagues and I display gluten fragments to Gluten fragment have learned that unusual intestinal permeabil- immune system cells, which then direct an attack on the intestinal ity also appears to participate in CD and other lining. Other genes are likely to be autoimmune diseases. Indeed, a growing body involved as well, but these HLA-DQ2 of evidence suggests that virtually the same trio additional culprits may differ from or HLA-DQ8 person to person. of factors underpins most, and perhaps all, auto Immune system cell immune diseases: an environmental substance that is presented to the body, a genetically based tendency of the immune system to overreact to Indigestible LEAKY SMALL INTESTINE gluten In most people, links known as the substance and an unusually permeable gut. fragment tight junctions “glue” intestinal cells together. In those with celiac disease, the junctions Finding the Leak come apart, allowing a large It is fair to say that the theory that a leaky gut amount of indigestible gluten contributes to CD and autoimmunity in general fragments to seep into the underlying tissue and incite was initially greeted with great skepticism, part- Tight immune system cells. Treat- ly because of the way scientists thought of the junction ments that reduced leakiness could potentially ease not only intestines. When I was a medical student in the celiac disease but also other 1970s, the small intestine was described as a pipe autoimmune disorders involving composed of single layer of cells connected like Enterocyte unusually permeable intestines. tiles with an impermeable “grout,” known as tight junctions, between them. The tight junctions were thought to keep all but the smallest quence, when antigen-presenting cells under in- molecules away from the immune system com- testinal epithelial cells take up the complexes of ponents residing in the tissue underlying the tissue transglutaminase and gluten, the cells tubes. This simple model of the tight junctions as join the gluten to the HLAs and dispatch them inert, impermeable filler did not inspire legions to the cell surface, where they activate T cells, of researchers to study their structure, and I was inducing the T cells to release cytokines and among the unenthused. chemokines (chemicals that stimulate further It was only an unexpected twist of fate, and

immune activity). These chemicals and en- one of the most disappointing moments of my Inc. Services, publishing electronic hancement of immune defenses would be valu- career, that drew me to study tight junctions. In

able in the face of a microbial attack, but in this the late 1980s I was working on a vaccine for kimmoss

36 Scientific American August 2009 [Mystery] cholera. At that time, the cholera toxin was be- lieved to be the sole cause of the devastating diarrhea characteristic of that infection. To test A Clue to Delayed Onset this hypothesis, my team deleted the gene en- eople with celiac disease are born with a genetic susceptibility to it. So why do some coding the cholera toxin from the bacterium Pindividuals show no evidence of the disorder until late in life? In the past, I would Vibrio cholerae. Conventional wisdom suggest- have said that the disease process was probably occurring in early life, just too mildly to ed that bacteria disarmed in this way would cause symptoms. But now it seems that a different answer, having to do with the bacte- make an ideal vaccine, because the remaining ria that live in the digestive tract, may be more apt. proteins on a living bacterial cell would elicit a These microbes, collectively known as the microbiome, may differ from person to person and from one population to another, even varying in the same individual as life strong immune response that would protect progresses. Apparently they can also influence which genes in their hosts are active against diarrhea. at any given time. Hence, a person whose immune system has managed to tolerate But when we administered our attenuated gluten for many years might suddenly lose tolerance if the microbiome changes in bacteria to volunteers, the vaccine provoked a way that causes formerly quiet susceptibility genes to become active. If this idea is enough diarrhea to bar its use. I felt completely correct, celiac disease might one day be prevented or treated by ingestion of selected disheartened. Years of hard work were literally helpful microbes, or “probiotics.” —A.F. down the toilet, and we were faced with two un- attractive options: giving up and moving on to another research project or persevering and try- several jobs—including regulating the move- ing to understand what went wrong. Some intu- ment of fluid, large molecules and immune cells ition that there was more to this story prompted between body compartments. us to choose the latter path, and this decision led Discovery of zonulin prompted us to search us to discover a new toxin that caused diarrhea the medical literature for human disorders char- by a previously undescribed mechanism. It acterized by increased intestinal permeability. It changed the permeability of the small intestine WHY was then that we first learned, much to my sur- by disassembling those supposedly inert tight prise, that many autoimmune diseases—among junctions, an effect that allowed fluid to seep REPLACING them, CD, type 1 diabetes, multiple sclerosis, from tissues into the gut. This “grout” was in- WHEAT rheumatoid arthritis and inflammatory bowel teresting after all. IS HARD diseases—all have as a common denominator ab- Indeed, at nearly the same time, a series of Gluten is a major reason that errant intestinal permeability. In many of these seminal discoveries clarified that a sophisticated wheat-based baked goods diseases, the increased permeability is caused by meshwork of proteins forms the tight junctions; are light and airy. During abnormally high levels of zonulin. And in CD, it baking, gluten strands trap however, little information was available on how is now clear that gluten itself prompts exagger- water and carbon dioxide these structures were controlled. Therefore, the gas (from yeast and other ated zonulin secretion (perhaps because of the discovery of our toxin, which we called the leavening agents) and patient’s genetic makeup). “zonula occludens toxin,” or Zot (zonula oc- expand. To make gluten-free This discovery led us to propose that it is cludens is Latin for “tight junction”), provided a items, bakers generally the enhanced intestinal permeability in CD pa- combine several flours valuable tool for clarifying the control process. It tients that allows gluten, the environmental fac- (as well as starches and revealed that a single molecule, Zot, could loos- additives), because no tor, to seep out of the gut and to interact freely en the complex structure of the tight junction. single variety mimics the with genetically sensitized elements of the im- We also realized that the control system that properties of wheat flour. mune system. That understanding, in turn, sug- made this loosening possible was too complicat- This demand adds signif gests that removing any one factor of the auto- icantly to the cost of the ed to have evolved simply to cause biological immunity-causing trinity—the environmental resulting product. It also harm to the host. V. cholerae must cause diarre- explains why gluten-free trigger, the heightened immunity or the intesti- ha by exploiting a preexisting host pathway that foods have a hard time nal permeability—should be enough to stop the regulates intestinal permeability. rivaling their gluten- disease process. Five years after the formulation of this hy- containing counterparts pothesis, we discovered zonulin, the protein that for taste and texture. —A.F. Therapies to Topple the Trinity in humans and other higher animals increases As I mentioned before, and as this theory would intestinal permeability by the same mechanism predict, removing gluten from the diet ends up as the bacterial Zot. How the body uses zonulin healing the intestinal damage. Regrettably, a to its advantage remains to be established. Most lifelong adherence to a strict gluten-free diet is likely, though, this molecule, which is secreted not easy. Gluten is a common and, in many coun- by intestinal epithelial tissue as well as by cells tries, unlabeled ingredient in the human diet. in other organs (tight junctions have important Further complicating adherence, gluten-free roles in tissues throughout the body), performs products are not widely available and are more www.ScientificAmerican.com SCIENTIFIC AMERICAN 37 The theory expensive than their gluten-containing counter- ments into the form where they bind so effective- parts. In addition, sticking perfectly over years ly to DQ2 and DQ8 proteins. that a leaky to any diet for medical purposes is notoriously No one has yet come up with safe and ethical gut contributes challenging. For such reasons, diet therapy is an ways to manipulate the genes that make people incomplete solution. susceptible to disease. But researchers are busy to CD and Consequently, several alternative therapeutic developing therapies that might dampen some of autoimmunity strategies have been considered that disrupt at the genetically controlled factors that contribute least one element of the three-step process. Al- to the immune system’s oversensitivity. For ex- in general vine Pharmaceuticals in San Carlos, Calif., has ample, the Australian company Nexpep is work- was initially developed oral protein-enzyme therapies that ing on a vaccine that would expose the immune completely break down gluten peptides normally system to small amounts of strongly immuno- greeted with resistant to digestion and has an agent in clinical genic forms of gluten, on the theory that repeat-

skepticism. trials. Other investigators are considering ways ed small exposures would ultimately induce the Inc. Services, Publishing Electronic to inhibit tissue transglutaminase so that it does immune system to tolerate gluten.

not chemically modify undigested gluten frag- With an eye toward blocking the intestinal kimmoss

[Mechanisms of Disease] The Inside Story Investigators do not know every detail of how the immune system wreaks havoc with the intestinal lining of celiac patients, but they have identified a number of likely processes (below). Colored arrows indicate events that might be blocked by interventions now being investigated [see table on opposite page].

●1 Indigestible fragments of gluten induce enterocytes to release the protein zonulin, which loosens tight junctions.

Indigestible gluten fragment Zonulin

Disrupted junction T cell secretions (chemokines and TTG cytokines) ●4 Tissue transglutaminase IL-15 (TTG), an enzyme released by the damaged ●7 Helper T cells cells, modifies the gluten. spur killer T cells to Tight junction directly attack Modified gluten enterocytes.

Killer T cell Antigen- Intraepithelial presenting lymphocyte cell

●2 Gluten fragments ●3 The gluten induces cross the intestinal enterocytes to secrete Helper T cell Mature B cell lining in abundance interleukin-15 (IL-15), HLA-DQ2 and accumulate which arouses or -DQ8 under epithelial immune cells called cells (enterocytes). intraepithelial ●5 Antigen-presenting cells (APCs) ●6 Helper T cells that recognize the lymphocytes (IEL) of the immune system join the complexes secrete molecules that against enterocytes. modified gluten to HLA mole- attract other immune cells and cules and display the resulting can directly damage enterocytes. complexes to other immune cells: helper T lymphocytes.

38 Scientific American August 2009 barrier defect, I co-founded Alba Therapeutics ➥ More To placebo. More important, the first, smaller study to explore the value of a zonulin inhibitor named Explore demonstrated that the agent reduced gluten-in- Larazotide. (I am now a scientific adviser for duced intestinal barrier dysfunction, production Alba and hold stock options, but I no longer Mechanisms of Disease: The Role of inflammatory molecules and gastrointestinal of Intestinal Barrier Function participate in making decisions for the compa- symptoms in celiac patients. And the second, in the Pathogenesis of Gastroin- ny.) Larazotide has now been tested in two hu- testinal Autoimmune Diseases. large study, reported at a conference in April, man trials examining safety, tolerability and Alessio Fasano and Terez Shea- showed that CD patients who received a placebo signs of efficacy in celiac patients who ate glu- Donohue in Nature Clinical Practice produced antibodies against tissue transglutami- ten. These were gold-standard trials—random- Gastroenterology & Hepatology, nase but the treated group did not. As far as I Vol. 2, No. 9, pages 416–422; ized, placebo-controlled tests in which neither know, this result marks the first time a drug has September 2005. the drug deliverers nor the patients know who halted an autoimmune process, interfering spe- receives treatment and who receives a sham, un- Diagnosis and Treatment of Celiac cifically with an immune response against a par- til the trial is over. Disease. L. M. Sollid and K.E.A. Lun- ticular molecule made by the body. Other drugs Together the tests showed no excess of side ef- din in Mucosal Immunology, Vol. 2, that suppress immune activity act less specifical- No. 1, pages 3–7; January 2009. fects in patients given Larazotide rather than the ly. Recently Alba received approval from the U.S. Food and Drug Administration to expand stud- [looking ahead] ies of Larazotide to other autoimmune disorders, including type 1 diabetes and Crohn’s disease. The Inside Story treatment IDEAS These new prospects for therapy do not mean Today patients with celiac diseasehave one therapeutic option: that CD patients can abandon dietary restric- avoid all foods that contain gluten. But because following a restrict- tions anytime soon. Diet could also be used in a ●9 T he various ed diet can be difficult, investigators are exploring other options for new way. Under the leadership of Carlo Catassi, assaults disable patients, such as those listed below. These are early days in the my team at the University of Maryland has be- and kill anuary 2009 process; no drug in the table has yet reached the advanced clinical gun a long-term clinical study to test whether

enterocytes. o 1; J trials needed to gain marketing approval.a having infants at high risk eat nothing contain- ol. 2, N

V ing gluten until after their first year can delay the DRUG NAME THERAPY (Investigator/Status) onset of CD or, better yet, prevent it entirely.

unology, unology, “High risk,” in this case, means infants possess Avoid gluten in the diet of infants No drug (University of Mary- mm susceptibility genes and their immediate family

through their first year of life land and, separately, Marche I al Politechnic University, Italy/ s has a history of the disorder.

in human trials) Muco We suspect the approach could work because Degrade otherwise indigestible glu- ALV003 (Alvine and, sepa- the immune system matures dramatically in the undin,in ten fragments, so they cannot evoke rately, ANPEP at VU Univer- L first 12 months of life and because research on . A . E an immune response sity Medical Center, the . susceptible infants has implied that avoiding glu- K Netherlands/in human trials) ten during the first year of life might essentially Block zonulin from making Larazotide (Alba Therapeu- train that developing immune system to tolerate ollidand S

the gut permeable tics/in human trials) .

M gluten thereafter, as healthy people do, rather . Keep tissue transglutaminase from No name (Numerate and L than being overstimulated by it. So far we have Antibody modifying gluten fragments in ways Stanford University/under against enrolled more than 700 potentially genetically

gluten that stimulate the immune system study in the laboratory) isease,” by

D susceptible infants in this study, and preliminary Antibody against TTG Stop HLA-DQ2 from attaching to Mimics of gluten (Leiden findings suggest that delaying gluten exposure re- eliac gluten peptides and displaying University, the Netherlands, C duces by fourfold the likelihood that CD will de- them to helper T cells and, separately, Stanford velop. It will be decades, however, until we know University/under study in the for certain whether this strategy can stop the dis- Mature B cell reatmentof

laboratory) T ease from ever occurring. Vaccinate patients with selected Nexvax2 (Nexpep, Given the apparently shared underpinning of gluten fragments to induce Australia/in human trials) autoimmune disorders in general, researchers helper T cells to tolerate, rather iagnosisand ●8 B cells release antibody than react to, gluten displayed by who investigate those conditions are eager to molecules targeted to HLA-DQ2 molecules. learn whether some therapeutic strategies for CD gluten and TTG. Those antibodies might cause Block migration of killer T cells CCX282-B (Chemocentryx/ might also ease other autoimmune conditions further damage when into the intestinal lining in human trials) that currently lack good treatments. And with they hit their targets on or near enterocytes, but Start a hookworm infection (the Hookworm parasites several different approaches in the pipeline to the role of antibodies in parasites dampen a host’s immune (Princess Alexandra Hospital, treat CD, we can begin to hope that this disease, : www.clinicaltrials.gov;: “ D the disease is unclear. responses in the gut) Australia, and collaborators/ which has followed humanity from the dawn of in human trials)

SOURCES civilization, is facing its last century on earth. ■