By David N. Leff

One day a young woman in her childbearing years notices a weird rash across her face. The red blemish extends from her left cheekbone to the right one, resembling the outspread wings of a butterfly. When her doctor looks at this mark of Cain, he or she immediately suspects SLE - systemic lupus erythematosus - a protean autoimmune disease, of which that butterfly logo is a hallmark.

Red, scaly patches of skin spread from face to trunk, as SLE stuffs epidermal capillaries with huge deposits of autoantibodies, spewed forth by the immune system's B cells. In fact, the word "erythematosus" describes that harsh skin reaction.

"Systemic" is the word that sets SLE apart from many autoimmune diseases - e.g., myasthenia gravis - which strike individual organs. SLE attacks the whole body, devastating kidneys, joints, blood cells - even DNA. Like multiple sclerosis and rheumatoid arthritis - other systemic autoimmune ailments - its painful symptoms may wax and wane over years and decades. ("Lupus," the Latin word for wolf, apparently highlights the wolfish facial mask and predations that feature SLE's pathology.)

Its arsenal consists of ever-proliferating B cells, which manufacture immunoglobulins - autoantibodies - that perceive every body tissue as a foreign antigen. These antibodies execute this anti-self death sentence against those target tissues. (See BioWorld Today, March 12, 1997, p. 1.)

There's no across-the-board therapy for SLE, observed immunologist Jane Gross, "only corticosteroids. These are not designed to treat the symptoms, only to lessen their severity." She is a principal scientist at ZymoGenetics Inc. in Seattle, researching treatments for autoimmune diseases.

As such, Gross is lead author of a report in today's Nature, dated April 27, 2000, and titled: "TACI and BCMA are receptors for a TNF homolog implicated in B-cell autoimmune disease."

"These two receptors, TACI and BCMA, which we have identified," Gross told BioWorld Today, "bind to a recently described molecule that belongs to the TNF [tumor necrosis factor] cytokine family. TNF - specifically zTNF4 - is the ligand that we believe activates B cells in vitro and in vivo. So when this molecule is overexpressed in transgenic mice, they develop symptoms of lupus. This Nature paper," Gross added, "is really the first identification of the receptors for that molecule."

TACI Receptor Proved Therapeutic In SLE Mice

She went on to say, "We have made a soluble form of one of those two receptors, TACI, that is a human immunoglobulin G fusion protein, and demonstrated that when we treated a mouse model that spontaneously develops SLE, that receptor inhibits the course of the disease, or at least some of its symptoms, such as proteinurea - proteins the kidneys spill into the urine - and increases the animal's survival."

Charles Hart, ZymoGenetics' director of business development and strategic planning, told BioWorld Today: "There's a large number of SLE patients - over 1 million - in the U.S. today. Some 200,000 of them have significant organ failure. In those patients, the disease may be life-threatening."

When two strains of New Zealand mice, one black, the other white, crossbreed, their first-generation offspring closely emulates the human disease, Gross noted. "These mice," she added, "spontaneously develop SLE-like symptoms at around 5 months of age, and die at 10 to 12 months of renal failure and high levels of proteinurea and autoantibodies."

She continued: "Those antibodies form immune complexes that are deposited in the kidney, and are in part responsible for renal failure. But SLE is a multigenic disease, so it cannot be attributed solely to the development of autoantibodies.

"In our animal experiments," Gross recounted, "we treated those mice, beginning at 5 months of age for 5 weeks, by injecting our soluble TACI receptor, or an irrelevant control vehicle, three times a week for five weeks." Gross explained that the receptor "works by capturing the TNF cytokine molecule in the blood, which, it's our belief, stimulates immune system B cells to make antibodies - in this case, autoantibodies. Our New Zealand mouse model of SLE, when treated with the TACI receptor, prevented the TNF from acting on B cells. The proportion of those cells decreased, and those diseased mice lived longer, with less severe symptoms."

Separately, the co-authors generated a transgenic mouse that overexpressed human zTNF4. "Those animals confirmed our hypothesis that zTNF4 levels somehow exacerbate B-cell autoimmunity," Gross observed, "and led us to conclude that our soluble receptor may have an effect on lupus."

That same therapeutic strategy, the ZymoGenetics group reasoned, might well be extended to the 50 other known autoimmune ailments. "We believe that in its current form," Gross predicted, "we could be treating other autoimmune diseases - such as myasthenia gravis, rheumatoid arthritis, multiple sclerosis and psoriasis, without having to change our TACI therapeutic molecule."

New Animal Models For New Autoimmune Ills

"What we do need to do next," she pointed out, "is design animal experiments to test the use of the molecule in those other autoimmune diseases. That's because myasthenia gravis, for example, involves in part a B cell component, too, where antibodies are made. So we believe that this human soluble receptor would act the same. We just need to find and test it in the appropriate animal model."

Myasthenia gravis, an autoimmune ailment that is organ-specific (in muscle) rather than systemic, like SLE, is in line for such preclinical testing of TACI. "It has autoantibodies with a different specificity," Gross pointed out. "And we don't believe the specificity is important, just that they're producing the antibodies in an unregulated way. So our therapy will inhibit part of the B-cell function. Therefore, the specificity to the acetylcholine receptor - which is specific to myasthenia gravis - is irrelevant. It's just the unregulated secretion of these antibodies."

As for eventual human trials, Hart said: "Moving it down a development pathway is certainly a fast-track top priority within our company right now. There are a number of different animal models that we need to run first, so I think it would be premature to try and set a date at present."

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