Upwards of 100 transgenic mice, totally unable to synthesizeinterleukin-1 beta converting enzyme (ICE), will soon celebrate theirsixth month of life. ICE is a protein that turns on IL-1b, the immunesystem's key trigger of inflammation.
The ICE-minus rodents have something to celebrate: They arefeeling no pain in their enzyme deprivation, enjoy perfect health andfertility, are developing normally, and show no obvious signs of anyimmunological abnormalities for lack of the ICE gene.
This colony of knockout mice, constructed by VertexPharmaceuticals Inc., of Cambridge, Mass., jointly with YaleUniversity, made its bow on the world stage last Wednesday.
In an oral presentation, Vertex vice-president and senior scientistDavid Livingston reported the animals' role in curbing ICE to theInterscience World Conference on Inflammation, Antirheumatics,Analgesics and Immunomodulators in Geneva, Switzerland.
Normally, IL-1b does useful work in the body, promoting localinflammatory responses to deal with invading pathogens or otherbodily insults. Abnormally, Livingston told his Geneva audience, thecytokine "promotes arthritis, inflammatory bowel disease, boneresorption, myelogenous leukemia, pancreatic islet cell death, andpossibly neuroinflammatory diseases, such as Alzheimer's."
These autoimmune afflictions arise, presumably, when IL-1b escapesthe modulatory feedback control of ICE inhibitors and overproduces.This excessive and non-stop activity converts the inflammatoryprocess from therapeutic to pathogenic. The adverse reaction can beacute or chronic.
In one dramatically acute form of the attack, IL-1b, after being turnedon by ICE, reacts to a bacterial endotoxin, lipopolysaccharide (LPS),which is a powerful inflammatory stimulator. The resulting sepsis,and septic shock, are frequently fatal.
"We have demonstrated," Livingston said, "in an LPS-induced acutemurine inflammation model that ICE inhibitors selectively blockrelease of systemic IL-1b.
Polyarthritis is a paradigmatic example of chronic IL-1b over-production. "An ICE inhibitor administered daily by intraperitonealinjection . . ." the Vertex scientist reported, "inhibited the inductionof polyarthritis." The prototype ICE-blocker curbed cartilagedestruction and reduced joint swelling to a much greater degree thansuch potent anti-inflammatory drugs as indomethacin andprednisolone.
These results extended and updated a paper in today's Science byLivingston and other Vertex and Yale co-authors. Its title: "Alteredcytokine export and apoptosis in mice deficient in interleukin-1bconverting enzyme."
Apoptosis is another vital function of ICE, for good or ill. A T cellsurface antibody called Fas honchos this programmed cell suicide.
Vertex cell biologist and immunologist Matthew Harding, one of theScience co-authors, told BioWorld Today, "Apoptosis appears to bean intrinsic way for T cells to regulate their own over-proliferation.It's a mechanism where, when you have an immune response, youhave activation of T cells that can turn off that event, and diminishpopulations of cells that have reacted to that insult. It's part of acheck-and-balance system."
Another Vertex co-author, molecular biologist Michael Su, added,"Although we have evidence that ICE might play a role in Fas-mediated apoptosis, our knockout mice don't seem to have anyimmune disorders, any autoimmune disease, such as we see in Fas-deficient animals."
To which Harding commented, "But it's also important to point outthat the observation in the ICE-deficient mice may very well bedifferent from what the effect of an ICE inhibitor could be in the casewhere you're trying to control an already activated immune response.In arthritis or another kind of inflammatory syndrome, IL-1b, whichis principal in triggering a lot of other inflammatory events, is the keyelement you want to hit, to inhibit." He added, "If you can block that,you then have a lot of effect on some of the subsequent responses."
Structure-based drug design is the name of the game that Vertexplays in developing pharmaceutical compounds. (See BioWorldToday, Jan. 25, 1995; p. 1.) Harding said, "We now have very goodanimal models that allow us to compare how well different kinds ofcompounds are going to behave, how effective they will be. So wecan now merge our structural biology with the design of ICEinhibitors in developing our anti-ICE drug candidates." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.