Before the snobbish immune system can take notice of anintruding microbe, it demands what seems like a propersocial introduction to the interloping antigen.
In any immune response to an alien invader, the firstevent occurs when an antigen-presenting cell, usually amacrophage, links up with a T lymphocyte _ somethinglike presenting a debutante at court _ so the T cell can"see" the foreign immunogen decorating the presentingcell's surface.
That particle recognition is the first signal. But one isn'tenough. It takes a second alert, called the costimulatory oraccessory signal, to prod the T cells into action. Thatlymphocyte mobilization against infection usually beginsby summoning a spectrum of cytokine hormones toorganize the counter-offensive.
In 1989, molecular immunologist John Rhodes, a seniorscientist at the Wellcome Research Labora-tories inBeckenham, England, discovered that during induction ofthat immune response one important element is theformation of chemical links between ligands on theantigen-presenting cell's surface and the T cell.
This chemical coupling takes the form of a so-calledSchiff base _ a reversible covalent reaction that formswhen certain organic molecules hook onto an NH2 or anamine. "This is an important chemical reaction in a wholenumber of metabolic processes, enzyme-substrateinteractions, for example," Rhodes told BioWorld Today.
He added, "We were the first to show that these reactionsare important between ligands on antigen-presenting cellsand T lymphocytes during induction of an immuneresponse."
Rhodes and his colleagues at Beckenham subsequentlydemonstrated "that one could mimic this effect by usingsmall synthetic chemicals that would form Schiff baseson T cell surface amines, thus providing an alternativecostimulatory second signal."
"The great advantage of this substitution," Rhodesexplained, "is that we could give these small moleculesorally, and they would still produce systemic effects _enhancing and strengthening immune responses to viraland bacterial antigens. So that is what we are essentiallydoing." He added, "We're mimicking physiologicalsystems by using a small molecule that can be given bymouth."
So far, that mouth belongs to mice and macaquemonkeys; the small molecule they received is a candidateoral immunopotentiator that Glaxo Wellcome has named"tucaresol." It makes its preclinical in vivo debut intoday's Nature. Rhodes' paper bears the title:"Therapeutic potentiation of the immune system bycostimulatory Schiff base-forming drugs."
An accompanying editorial by experimentalimmunologist Gene Shearer of the National CancerInstitute, of Washington, notes that "Oral administrationof one of [Rhodes'] compounds to mice provoked anincrease in production of interleukin-2 (IL-2) andinterferon-g, and a decrease in the production of IL-4 andIL-6."
"Tucaresol," Rhodes said, "was originally developed foranother purpose _ to modify the hemoglobin in sickle-cell anemia. By the same piece of chemistry," heexplained, "it formed the Schiff base of one of thehemoglobin molecule's chains, changed its conformationfor some reason, stabilized it and reduced the sickling."
Despite this apparent clinical success, Rhodes went on,"Tucaresol is no longer being developed for sickle-cellanemia, because of other pronounced effects that it hadon the immune system." In very early clinical trials,volunteers and patients "developed symptoms of immunehyper-reactivity. From what we now know about theimmune system," he observed, "we would have expectedthis reaction."
Tucaresol: Sickle-Cell's Loss, Immune System's Gain
That cloud on sickle-cell therapy with tucaresol turnedout to have a silver lining for treating a range of diseasesinvolving the immune system, notably infectious hepatitisB, metastatic melanoma and HIV infection.
These three afflictions are the targets of Phase I/II dose-ranging clinical trials of tucaresol that began early thisyear in the U.S. and Europe.
"We have eight patients on board for the hepatitisprotocol," biostatistician Donna Goldstein of GlaxoWellcome, Research Triangle Park, N.C., told BioWorldToday. "Approximately seven patients," she added, "areon board for the melanoma; three in HIV trials, now onhold."
She explained that the HIV patients, all in France, "beganto experience symptoms and clinical signs ofimmunopotentiation, fevers, lymphadenopathies _precisely the types of events that occurred in the sickle-cell patients. They weren't unexpected; just the timingwas."
Glaxo-Wellcome now is revising the HIV protocol andthe dosing regimen, Goldstein said. "They expect tocomplete hepatitis and melanoma by early 1996; therevamped HIV study by mid-year," she said.
"The effects of tucaresol on the immune system occur atrelatively low doses," Rhodes observed; those onhemoglobin only at very high doses."
His paper in Nature reports on an unpublishedobservation by other investigators of four macaquesinfected with simian immunodeficiency virus, two ofwhom received tucaresol. The drug "produced noexacerbation of infection," he wrote, "rather . . . reductionin viral loads was noted in the two treated animals . . . ."
From Parasitic Infections To AIDS
In his commentary, Shearer observed that "Cytokine-based therapy has been considered for a spectrum ofdiseases and conditions, ranging from parasitic infectionsand tuberculosis to cancer and AIDS. But," he continued,"experience has shown that there are problems withsystemically administering cytokines directly to patients,including toxicity, short half-life and delivery to theimmunologically active sites where they will beeffective."
He sees the use instead of tucaresol-like Schiff-base smallmolecules as a possible "way around these obstacles,[if]the potential advantages [yet to be demonstrated] ofreduced toxicity and production of the necessarycytokines at the appropriate immunologically active sites"are confirmed.
On this score, Rhodes observed, "We don't want toencourage over-optimism. We're just at the very earlystages of clinical trials, and it's too soon to speculate onthe potential clinical efficacy of this drug. It will be manymonths before we have any clinical data to analyze."
He concluded: "If we see encouraging signs of efficacy,then we would move to larger-scale Phase II trials." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.