Try this multiple-choice quiz:The mucus-membranes that line the human respiratory, digestive andgenito-urinary tracts, if unfolded and spread out, would cover: (a) aping-pong table; (b) a lawn-tennis court; (c) a football gridiron.The answer: none of the above. That combined membrane surface hasan area of 400 square meters, which is twice the size of a tennis court.All of those bodily passageways offer a temptingly vulnerable targetfor foreign antigens. From hayfever to the common cold to anuncommon inhaled bacterium, the oral and nasal tract linings are thebattleground between foreign pathogens and infection-fighting cells ofthe immune system. So is the urinary tract.That leaves the digestive plumbing, from esophagus to colon, whichaccounts for about 300 of those 400 square meters. Three times a dayor so, with snacks in between, it receives a diverse influx of foreignfood proteins, without mounting an immune reaction."The gut has a whole immune system of its own," explains neuro-immunologist Howard Weiner, of Boston's Brigham and Women'sHospital (BWH). "It reacts to food in a unique fashion, he toldBioWorld Today, "by generating suppression of immune rejection,because we cannot become sensitized to something that we eat."What protects food from an immune backlash is a long-knownphenomenon called oral tolerance. The intestines know enough totolerate nutritive proteins, and if properly conditioned, they can alsolearn how to shrug off more aggressive foreign antigens."If you immunize an animal by injection against a strange protein,"Weiner observed, "you get a specific immune response. But if you feedit that protein first, it doesn't respond as well, or at all." He added, "It'slike that old remedy, `a hair of the dog that bit you.'"Over several years, Weiner's research has determined that feeding theforeign substance stimulates specific immune-system cells in the gutwall, and that these cells then migrate via the gastro-intestinal tract'smesenteric lymph node, through the spleen, into the bloodstream andthen permeate the body via the lymphoid network.Though the molecular mechanism was unclear, this muchunderstanding led BWH to encourage venture capitalists to found acommercial biotech company, AutoImmune Inc. of Lexington, Mass.,with Weiner as its chief scientific advisor. The company is nowconducting a series of large-scale clinical trials, feeding patients withseveral autoimmune diseases edible versions of the proteins that theirimmune systems attack.Thus, it treats multiple sclerosis (MS) with oral doses of myelin,rheumatoid arthritis with ingestible collagen, uveitis with a relevant eyeprotein, diabetes with insulin.This may strike some as akin to witch-doctoring, but Weiner reportedefficacy a year and a half ago in Science (Feb. 26, 1993). In a one-yearPhase I/II trial of the myelin swallowed by 15 MS patients, only sixsuffered a major exacerbation, while 12 of their 15 placebo controlshad such an attack. (See BioWorld Today, March 31, 1994, p. 3.)Now, says AutoImmune's president and CEO, "13 centers in the U.S.and Canada have enrolled 350 individuals so far in a two-year, PhaseIII trial of Myloral (the company's myelin formulation), fed to MSpatients. "Our goal," he told BioWorld Today, "is to have all of themore than 500 patients enrolled by very close to year-end."Meanwhile, Weiner has within the last year cloned and characterizedthe cells that produce oral tolerance, and then, he said, "showed thatthey could, when you inject them into animals, suppress theautoimmune disease." His announcement of this news appears in lastFriday's Science, titled, "Regulatory T Cell Clones Induced by OralTolerance: Suppression of Autoimmune Encephalomyelitis."Experimental Autoimmune Encephalomyelitis (EAE) is a disease givento mice, which turns them into animal models of MS. It does so byexposing the myelin sheathing on their nerve cells to attack by theirown immune cells, which is what happens in multiple sclerosis as well.Weiner and his co-authors at BWH tolerized their MS-mimicking miceto oral doses of myelin, then extracted the putative immunity-suppressing cells from their rendezvous in the mesenteric lymph node.These CD4+ T cell clones secreted a natural immunosuppressant,transforming growth factor-beta (TGF-b), and anti-inflammatorycytokines, mainly interleukin-4 and interleukin-10."The major question," Weiner said, "was whether these mucosallyderived CD4+ clones were biologically active, and could suppress EAEin vivo." For proof, he injected the cloned cells into cohorts of MS-model mice. "We were able to show that the clones suppressed thedisease. Fewer animals got paralysis, and fewer died."Clinical Pay-Offs In OffingThe finding also suggests, he added, "a very important point: thesetolerance-promoting, inflammation suppressing clones suppress everyimmune response in the relevant tissue. That means that by feeding abrain protein you can suppress inflammation in the brain, irrespectiveof the initial cause. The effect is called bystander suppression."In other words," Weiner continued, "the suppression generated in thegut moves through the lymphoid network, eventually hits the brain, andsuppresses the inflammation. In a way, it's like a natural drug deliverysystem that bypasses the blood-brain barrier."Weiner's team has now moved on to test transgenic mice, which modelvarious autoimmune diseases and immune processes. "In our EAEtransgenics," he said, "every cell in the animal responds to the myelinbasic protein, and we're now doing oral tolerance experiments inthem."AutoImmune's Robert Bishop sees Weiner's elucidation in Science ofthe oral tolerance mechanism as "laying the scientific foundation" forclinical pay-offs, such as "developing surrogate markers to enhance theproductivity of clinical trials."The oral-tolerance cells make their way to the circulation, he explained,where a simple blood test "might theoretically identify the productionof those specific cells, and cause their antigen-release of theappropriate suppresser cytokines."Because autoimmune diseases wax and wane, Bishop noted, they aredifficult to study medically. The newly cloned peripheral tolerancecells, he suggested, "could well be a tool that allows us to get a goodread on everything from dosing effects to susceptibility of differentpopulations, based on their genetic backgrounds, to whole new areasthat you might want to look at for an appropriate target antigen."Weiner cautions: "How strong will the effect be in people, and whatother manipulations will first be necessary?" n

-- David N. Leff Science Editor

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