The watchdog didn't bark at the intruder because he recognized him ashis own master, the man who fed him every day.A pregnant woman doesn't reject her own fetus, although its cells arestudded with foreign paternal antigens, because her watchdog immunesystem recognizes the prenatal intruder as "self." By the same token,that unborn child accepts its mother's placenta and nutrients as its"self."But in autoimmune diseases, the immune system mistakes its body'sown DNA, cells and tissues as alien, non-self, and attacks them.Systemic lupus erythematosus (SLE) is an autoimmune disease thatstrikes one American woman in 1,000, early in her reproductive life.Men get SLE too, but only one in 10,000."Lupus is hard to diagnose," said rheumatologist Barbara Finck of theUniversity of California, San Francisco (UCSF). "It can affect almostany system in the body." she told BioWorld Today, "Its manifestationsare different in each patient. It's difficult to live with, and it can befatal."She explained that "lupus is a disease we think is driven by productionof antibodies against `self' tissues. Against one's DNA, blood cells,skin and so on. They all end up in the kidney, mess up the works, andcause nephritis."Finck is the lead author of a paper in today's Science titled "Treatmentof Murine Lupus With CTLA4Ig." She and her two co-authors trustthat their ponderously named fusion-protein acronym will some daymake a medical difference in the lives of SLE victims.The mouse CTLA4Ig, they reported, had a "dramatically" curativeeffect on mice with SLE that closely mimics the human malady. "Ithink at some point," Finck said, "that the human protein will go intothe human therapeutic armamentarium. But at this point we're probablyseveral years away."Molecular biologist Peter Linsley supplied both murine and humanCTLA4Ig to the researchers. A co-author of the Science paper, hemade the fusion proteins in his laboratory at the Bristol-Myers SquibbCo. Pharmaceutical Research Institute in Seattle. Linsley toldBioWorld Today that he hopes it will be possible to initiate clinicaltrials of human CTLA4Ig "in the next year or so." He added, "It hasalready shown efficacy in a variety of animals" modeling variousautoimmune manifestations and heart transplants.Meanwhile, Linsley is "continuing studies with Finck and DavidWofsy to better understand the role of this lupus pathway." Wofsy ischief of rheumatology/immunology at the Veterans Affairs MedicalCenter, a UCSF teaching hospital.First Generation OffspringThe UCSF team's spontaneously-affected SLE-imitating mice are thefirst-generation offspring of two non-lupus murine strains, NewZealand black and New Zealand white. "These animals contract lupusat about seven months of age," Finck said. "Like human SLE patients,they get anti-DNA antibodies, develop immune-complex glomerularnephritis, and usually die of their renal disease." She added, "Our goalis to cure lupus in people by first curing it in mice."She did the latter with Linsley's murine fusion protein, CTLA4Ig.Something like a weirdly elaborate football play, the immune system'sT cells signal B cells to make antibody against a foreign antigen. Theydo so, scientists have discovered in the last year or so, not by one signalbut two.The first signal, Finck explained, "goes through the T cell receptor andthe presentation of the target antigen on the cell surface _ like handingyou a hot dog in a bun.""That first signal," she went on, "links up antigen and T cell, so B cellscan start producing antibody. The signal is augmented by CD4, anotherreceptor on the T cell." She said that "Wofsy, the first author on ourpaper, showed you could improve lupus in these mice if you took awaythe CD4+ cell."The second signal involves CD28 and molecules called B7 on thatantigen-presenting cell. "If you block that second signal," Finckcontinued, "the T cell becomes quiescent. It doesn't signal the B cellsto mount an antibody attack. It basically becomes tolerant."Tolerance is the phenomenon that explains how mother and childrecognize each other as "self," and why that hound kept quiet.Blocking the second signal is what the CTLA4Ig fusion protein did inthose mice. One end of the molecule is CTLA4, a look-alike homologof CD28, which binds B7 molecules. The party of the second part,which is there for production purposes, is the tail portion of animmunoglobulin receptor, similar to a monoclonal antibody."We put it in our mouse model," she said, "and were able to block thedevelopment of lupus in young mice, before they ever developed anySLE symptoms. This early-treatment group did not produce any anti-DNA antibodies, they did not develop proteinuria (a hallmark ofkidney disease) and they had a prolonged survival.She then went to a late group of mice eight months old, by which timehalf of them had already died of lupus. Some of them received thefusion protein, the controls a placebo. "It was pretty dramatic;" Finckrecalled. "mice that got the control proteins went on to develop lupus,and were all dead by 12 months of age. By that time, 50 percent of thefusion-protein recipients were still alive, without anti-DNA antibodiesor proteinuria."Now the team is setting up experiments to see how this therapeuticproduct affects the immune system. "For instance," Finck pointed out,"does it prevent the production of all antibodies? This could be a badthing, keeping you from mounting any defense against all foreignantigens. "She concluded: "What we had hoped to do is stop this signal that goesbetween the T calls and B cells, turn off this overdrive. I think we'vesucceeded in doing that. But we've got a lot of work ahead to prove it."

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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