David N. LeffScience Editor

Mice don't get AIDS; they get MAIDS (murine acquiredimmunodeficiency syndrome). Any resemblance between thetwo diseases may be purely coincidental.

Still, lacking a proper animal model for HIV infection, AIDSresearchers infect mice with murine leukemia virus, whichproduces some symptoms similar to AIDS in humans. Thus, asthe rodents come down with MAIDS, their CD4-positive T cells,the prime target of HIV attack, begin to malfunction. Then,when the disease takes hold, the T cells begin to churn out IL-4, IL-10 and other immune-response chemical messengers.

One of these cytokines in particular, IL-4, is under suspicion ofcomplicity in the T cell dysfunction that lays low the immunesystem in AIDS. A paper in today's issue of Science reports anin vivo experiment that adds evidence to indict IL-4 as a keyco-conspirator in the AIDS process. Titled "Resistance of MiceDeficient in IL-4 to Retrovirus-Induced ImmunodeficiencySyndrome (MAIDS)," it tells how cellular immunologist OsamiKanagawa at Washington University in St. Louis made all thedifference between life and death to mice lacking the IL-4gene.

Kanagawa infected 28 normal rodents with murine leukemiavirus, which produces some of the same symptoms as HIV:swollen lymph nodes, hyperactive B cells, immunodeficient Tcells and development of certain tumors. At the Max PlanckInstitute for Immunobiology in Freiburg, Germany, he injectedthe same viral dose into 28 knockout mice born to parents inwhose embryonic stem cells the IL-4 gene had been ablated.

Twenty-five weeks later, all of the intact animals were dead;all of the IL-4-minus ones were alive.

From six to 20 weeks following infection, the 28 intact micehad developed the stigmata of MAIDS: visiblelymphadenopathy, grossly enlarged spleens and activated Tcells. Few of the IL-4-minus mice showed these symptoms.

"We do not know whether this lack of T cell activation in IL-4-deficient mice is due to a lack of IL-4 or a secondary effect ofresistance to the disease," Kanagawa said cautiously.

But the main point of his findings is to add testimony to acurrent theory in AIDS research circles that IL-4 puts a thumbon the scale of probability that the viral infection willeventuate in overt clinical symptoms and death. The covertthumb that tips the balance to favor this fatal outcome is called"Th2," standing for T helper cell, version 2.

This version incriminates a subset of T helper cells that secretethe "bad" cytokine, IL-4, along with IL-10 and others. Th1denotes "good" T cells, which secrete IL-2 and trigger thecellular arm of the immune system. The Th2 subset allegedlyturns on the B cells that generate antibodies.

Scientists at the National Cancer Institute discovered thatpeople infected with HIV switched from the Th1 healthy stateto the ominous Th2 response as their disease progressed.

Only 8 percent of HIV-positive patients with strong Th2 wenton to develop full-blown AIDS vs. nearly 50 percent with weakTh2. The researchers speculated that IL-10, a Th2 cytokinethat downregulates Th1 responses, may cause this shift. AScience commentary on Kanagawa's results explained that "astrong Th1 response inhibits a strong Th2 response and viceversa."

"These human studies didn't reveal, however, whether the shiftin T cell populations directly contributed to the patients'worsening conditions," the commentary noted. It creditsKanagawa's just-reported work with forging this missing link,by showing that dispelling the IL-4 gene -- and presumably itsassociated Th2 response -- protected these knockout mice fromthe ravages of MAIDS.

Science reported that Genetics Institute Inc. "hopes to soonbegin tests of IL-12, a recently discovered Th1 cytokine, inHIV-infected patients." GI's corporate communications director,Dennis Harp, told BioWorld that such a Phase I/II trial of IL-12is planned for the first half of 1994, with specific dates to befirmed up by December or January.

Harp said that GI, together with the Wistar Institute, reporteddiscovering IL-12 in December 1990. They had previouslycalled the cytokine natural killer-cell stimulatory factor(NKCSF). By another name, cytolytic lymphocyte maturationfactor (CLMF), Hoffmann La-Roche independently but almostsimultaneously reported finding it in February 1991.

Other research groups using different knockout strains aretrying to replicate Kananga's experimental murine results andaffirm or deny the controversial Th1/Th2 connection, with aview toward possible future therapeutic measures, Kanagagatold BioWorld. "We ourselves are still trying to see clearly theIL-4 involvement in T cell dysfunction in MAIDS."

That still leaves unclarified the main question: How applicablea model is MAIDS for AIDS? "If we can learn something fromthe mouse," Kanagawa said, "we can ask questions (as to)whether it's happening in humans. Phenomena are shared bythe two diseases. The viruses may be using a common pathwayto inactivate T cells PP but they may not be."

(c) 1997 American Health Consultants. All rights reserved.