"We have met the enemy and he is us."

Walt Kelly's Pogo might have been talking about the friendly fire leveled at autoimmune diseases. There are dozens of these destroy-it-yourself ailments in which the immune system goes berserk and savages the body's cells, tissues and organs. One such notorious suicidal malady is systemic lupus erythematosus - SLE or lupus for short.

Lupus devastates all sorts of bodily organs at great cost in pain and impairment. There are half a million SLE sufferers in the U.S., with major symptoms ranging from kidney dysfunction to skin rashes to joint inflammation to death. SLE is an inflammatory connective-tissue disease with variable features - from fever, fatigue and weakness to joint pain that mimics rheumatoid arthritis, which often occurs jointly with lupus.

Pogo's "enemy" consists largely of immune-system T lymphocytes. Their job is to hunt down and wipe out pathogenic viruses, bacteria, fungi and the like. When diverted from such protective gigs to self-destruction, these autoimmune T cells go after hapless, healthy targets instead.

At the University of Chicago, clinical and research immunologist Yang-Xin Fu wages war on autoimmunity. "Like so many autoimmune diseases," he pointed out, "lupus is a very difficult disease to treat. And currently there is no good therapeutic method for it."

Fu is senior author of an article in Nature Medicine, released online Nov. 11, 2002. Its title: "Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease."

"To treat autoimmune disease traditionally," he told BioWorld Today, "people now use antibodies that block T-cell activation. In the last 10 years, they began to develop this immunotherapy, trying to inhibit T-cell activation. For that approach, one needs to treat long term, and it is not very effective. The traditional blocking approach does not really work well, because if you stop treatment of the disease, it will come back in a year or two and get worse. Also, you accumulate a lot of angry cells, but they do not get deleted out, because you block them to go further. So if you stop the treatment, it's like organ transplantation; many times you have to treat patients their whole life.

"We went the opposite way to energize T cells," Fu observed. "And we used this very different novel approach to activate auto-reactive T cells, then delete them. So we hope that with this different strategy we can achieve much more efficient therapy, by depleting out all co-reactive T cells and B cells, thereby controlling the disease. Our whole paper is based on this new idea."

Mice With SLE Lead Way To Human Studies

"The strategy we tried was to treat mice that already had the disease. In animal models this is a lupus-like affliction. Lupus-like because it has the same syndrome where the friendly fire autoreactive T cell attacks the human body. What we did was give mice these B-cell-generated idiotypic antibodies, which spur T cells to greater reactivity. We believe that in this immune-complex process, some of those T cells die. When they see their own self tissue, they sometimes get abnormally activated spontaneously. Then most of them die out, so we have immune tolerance - the opposite of autoimmunity. But in some patients," Fu continued, "the anti-self T lymphocytes continue expanding uncontrollably, which is how one gets autoimmune disease.

"Traditionally," he reiterated, "researchers use many antibodies to block those T cells before they activate them. What we did, on purpose, was the contrary - activating the T cells by giving mice the agonistic monoclonal antibody, which can energize T cells.

"This antibody has many monitors on the T cell surface. We now identify more than 200 various molecules. That CD137 antigen is what the 2A antibody sees. It activates a marker for the T cell. Only activated T cells express it. And those fully pre-activated T cells, which are at a much higher level in lupus and multiple sclerosis patients, have higher anti-reactive T cells. And now we use this CD137 antibody so those T cells will die after a one-week treatment in mice.

"In order to activate T cells," Fu explicated, "you need to have a second molecule to stimulate it. The T-cell receptor agent is not enough to activate T cells fully. So we added another stimulatory molecule on the T cell - namely, that CD137. For costimulation you need two signals to activate T cells. That second one is a T-cell receptor, expressed on the T-cell marker. Then there are double-negative T cells. They are related to lupus, and those cells are unique in our animal model. They are very highly elevated, and normal healthy people don't harbor these particular T cells, but those mice do. When we treated them, those T cells disappeared."

Fu summed up the in vivo trials of his co-authors' lupus therapy: "At first," he recounted, "we gave adult mice, which already had the disease, a very small dose of the agonistic antibody - 100 micrograms injected. Then after two to three weeks, we stopped the treatment to observe the mice. They died in a few months. So we treated young mice at 3 months of age. Untreated, these animals spontaneously developed lupus-like autoimmune disease and died in about six months. So in the third or fourth month we treated them for a couple of weeks, and then those mice survived much longer without any sign of disease."

Clinical Trials In 2003, Sponsor Willing

"Ideally, in the near future," Fu noted, "we want to treat different types of autoimmune disease, each at a different stage, to get a better understanding of how this CD137 antibody would act in patient clinical trials. We actually tried Type I diabetes already. Eventually we will treat various autoimmune diseases in humans. It depends on where there's a pharmaceutical company that is interested, clinical trials being very expensive. If a company sponsored us, this could go to clinical trials as fast as next year. But if there is no sponsor, it would take a longer time.

"We applied for a patent one year ago, with me and one other co-author as co-inventors. If any company wants to do it, I would definitely help them out. I know exactly how this molecule may work and I'm also a physician, so I could suggest," Fu concluded, "what type of patient they should enroll."