We have met the enemy, and it is us -- namely, our anti-enemy immune system.
When human cellular and humoral weapons for repellinginvading pathogens turn against their own bodily tissues, theresulting "friendly fire" triggers such autoimmune diseases asrheumatoid arthritis, multiple sclerosis, systemic lupuserythematosus (SLE) and psoriasis, to name just a few. The listkeeps growing with science's ability to discover new self-destructive autoimmune responses.
Today's Science reports an early preclinical attempt atcountermeasures to deter the immune system from wreakingmayhem against its own body, albeit in mice. The paper, byDartmouth's Randolph J. Noelle, et al., reports "Prevention ofCollagen-Induced Arthritis with an Antibody to gp39, theLigand for CD40."
More than 2 million adult American adults suffer fromrheumatoid arthritis, said the Arthritis Foundation's pressspokesman, Dennis Bowman. Of these, 1.5 million are womenand 600,000 are men. Add 71,000 juvenile patients, plus131,000 adults with SLE. "The data in this study," says Science,"establish gp39 as a potential target for therapeuticintervention" in autoimmune diseases.
At the center of the autoimmune cascade is gp39, a 39-kilodalton type II membrane glycoprotein expressed on thesurface of CD4+ T cells, activated to ward off an alien attack.Helper T cells enlist B cells to make antibody. Gp39 transmitsthe T-cell signal to waiting B cells by connecting with areceptor on their surface, CD40.
To block this T-to-B connection, the Dartmouth immunologistsraised a hamster monoclonal antibody against mouse gp39.They used it to try to check the onset of disease in 6-week-oldmice made arthritic by two injections of chick collagen at thebase of their tails. In fighting off this foreign collagen, theirimmune systems also attacked their own collagen, especiallyinflaming the joints of their fore- and hind-limbs.
To prove that their anti-gp39 monoclonal could stop thisdestruction in its tracks, the investigators set up three groupsof eight mice each, all immunized against the arthritis-triggering collagen II.
The first bunch got no antibody, the second received anti-gp39every four days for 40 days, and injections of irrelevanthamster immunoglobulin went into the third octet, acting ascontrols.
By the 40th day of the trial, 75 to 80 percent of the first andthird groups had developed full-blown arthritis. The secondcohort was not only free of disease, but had not raised anyantibodies of its own against the foreign hamster anti-gp39molecules.
Furthermore, a month after treatment with the anti-gp39monoclonals stopped on day 40, these animals had no clinicalsigns of arthritis, with "a complete lack of synovial (joint)inflammation."
As in vitro studies confirmed, the anti-gp39 blocked helper Tcells from binding their gp39 ligand to B cells' CD40 mitogenicreceptors and triggering B cell activation.
"Patients with HIM -- hyper-IgM syndrome -- bear out thefunctional significance of this antibody in targeting the gp39molecule for therapeutic intervention," Noelle told BioWorld.HIM is an autoimmune disease in which a point mutation onthe X-linked gene for gp39 renders it non-functional (seeBioWorld, Feb. 11).
Noelle confided that he already has a panel of humanmonoclonal antibodies against gp39, "but it's just too early topredict Phase I clinical trials."
Meanwhile, he and his group are pursuing a number of otherautoimmune models -- multiple sclerosis, graft-versus-hostdisease and SLE.
Noelle, who teaches microbiology at Dartmouth, emphasizedthat "the most significant aspect of this gp39 molecule is thatits function is not redundant. If you knock it out, there'snothing else that can replace its activity. We've learned fromthe HIM patients that blocking that single molecule can haveprofound effects on your immune system."
The first author of today's paper in Science, Fiona Durie, toldBioWorld that the team is making progress attempting to blockthe murine arthritis post-onset, after it has taken hold in theunprotected mice.
"When the control animals have a couple of joints inflamed, westart giving them the antibody. No results to report yet onthat," she said.
Leonard Chess, director of rheumatology at ColumbiaUniversity, also has monoclonals against the CD40 ligand inhumans, a counterpart to mouse gp39. "Our antibody," he toldBioWorld, inhibits the ability of human cells to make IgE andIgA, so it is potentially useful in treating autoimmunediseases." Chess is "contemplating the possibility of using ourhuman antibody in human trials."
Noelle said that Columbia University had licensed the Chessmonoclonal to Biogen.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.