Allergies _ notably, asthma andhayfever _ and infections happen whenthe body's immune system sends outtrained antibodies to fight offcertain foreign antigens, such asplant pollen or microbes.
Autoimmune diseases _ such as multiplesclerosis, lupus, rheumatoid arthritisand Type 1 diabetes _ occur when theimmune system shoots itself in thefoot.
Taking care of those two pieces ofwork are a couple of helper T cells,namely, TH1 and TH2. When the system'srecruiting agents call up rookie Tlymphocytes, which have never seencombat, to mobilize as one or anotherhelper cell subset, the right balancebetween TH1 and TH2 makes for anefficient immune response.
But if a lot more TH1s than TH2sanswer the call, they rain downfriendly fire on the body's own home-grown antigens. Ergo: Autoimmunediseases ensue from the TH1 excess. Onthe other hand, if too many TH2s tipthe balance, cancer and certain extra-stubborn infections, such astuberculosis, may arise.
The arsenal of weapons deployed bythese two trigger-happy T helper cellsconsist of soluble messenger moleculescalled cytokines. Among the best knownof these are interferon, tumornecrosis factor, and a whole platoonof interleukins.
"Nobody really understands fully yethow cytokines are regulated," observedimmunologist Laurie Glimcher ofHarvard Medical School. Her particularresearch focus is the T helper celland its joined-at-the-hip cytokine,interleukin-4 (IL-4).
Like all proteins, cytokines come intothe world at the behest of theirgenes. A gene in turn depends onpromoters and transcription factors toexpress its programmed protein.
One of the factors that turns on genetranscription of IL-4 is called NF-AT_ standing for Nuclear Factor ofActivated T cells. How it pulls thisoff was a mystery until Glimcher andher co-workers identified the co-factor without which NF-AT can't takeaction. They named it NIP45 _ NF-ATInteracting Protein45.
An article in today's Science reportstheir discovery. Its title: "NF-AT-driven Interleukin-4 transcriptionpotentiated by NIP45."
Glimcher, the paper's senior author,told BioWorld Today: "We've foundanother piece of the puzzle ofcytokine control, by identifying thisnew protein."
Earlier this year, she reportedisolation of c-maf, a proto-oncogeneprotein, which together with NF-AT andnow NIP45, round out the three-prongedfactors "able to make IL-4 atsubstantial levels."
NIP: New Player On Cytokine Block
"NIP is totally novel," Glimchercontinued, "with no homology toanything, and we don't yet know how itworks. But it's a new player, whichreally can give IL-4 production a bigboost."
To harness this trio of playerstherapeutically, Glimcher suggested:"If we were to over-express NIP, let'ssay, using a promoter region specificfor TH2 cells, we could give a patientwho had an autoimmune disease a heckof a lot of IL-4, which would probablybe good in terms of combating thatdisease."
Conversely, she foresees blocking NIP,thereby decreasing cytokine output."Manipulating cytokines in vivo,"Glimcher pointed out, "is clearlyrelevant not only to autoimmunediseases but to tumors, infectiousdiseases, and so on."
But not to HIV.
"That's very controversial," Glimchersaid. "Some would claim that as AIDSpatients worsen, they become more TH2-like, and make more IL-4. There areproponents and adversaries of thatposition. But whether AIDS or not,these new factors are clearly relevantin other diseases, like TB, leprosy,parasitic infections." She added: "Youprovide IL-4, you can make a lot ofautoimmune diseases better."
In administering such treatment, shesees two ways to go: "One is genetherapy, providing maf and NIP inretroviral vectors. The other is doinghigh through-put screens, looking forpharmacologic agents that either blockor enhance NIP or c-maf for NF-ATexpression. We're certainly workingalong those lines."
So is Glimcher's long-time researchand development partner, Boston LifeSciences Inc. That firm's executivevice president and chief scientificofficer, Mark Lanser, told BioWorldToday: "When Laurie came up with thisdiscovery of c-maf, it was logicalthat we obtained the intellectualproperty, that is, Harvard's licenseto the patents. Because we saw rightaway that this was an importantfundamental discovery, leading topotential breakthrough products."
The company is underwriting furtherdevelopment of Glimcher's technology,Lanser said, "the total being $5million or more over five years."
The c-maf patent application, he wenton, "was filed last spring, and thaton NIP45 just a few weeks ago." Theformer, he explained, "claims bothinserting c-maf to switch from TH1 toTH2, and inhibiting c-maf to do thereverse. And thereby using that methodto treat autoimmune diseases, as wellas allergies and cancer."
Similarly, the NIP45 composition-of-matter filing claims its use "eitherto markedly increase IL-4 expression,or to inhibit it."
How does the switch operate?
"That's a good question," Lanserreplied, "which Laurie is working onright now."
Aim: In Clinic By 1998
Boston Life's "immediate goal is todevelop a first-generation, ex vivogene therapy product to drive theswitch from TH1 to TH2 cells, for thetreatment of virtually all autoimmunediseases." He added: "We hope to getthat particular product into theclinic within 18 months."
Lanser continued: "The Holiest Grailof this whole field is how one would,in a practical manner, switch from oneT helper subset to the other. Theproblem was that no one had a TH2-specific transcription factor; c-mafwas the first one ever discovered. AndLaurie has identified the exact spoton the IL-4 promoter that c-maf turnson."
He is now "in serious discussions withmajor pharmaceutical partners todevelop, first, small-moleculeinhibitors of c-maf for the treatmentof allergies; second, small-moleculeactivators of c-maf to treatautoimmune diseases." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.