Press Release for Nature Medicine:
February 2000

EMBARGO: 17:00 EST MONDAY January 31st 2000

PLEASE QUOTE Nature Medicine AS THE SOURCE OF THESE ITEMS

Scientists report value of antibody generation in potential AIDS vaccines

In the effort to develop a vaccine to protect against HIV transmission, the relative value of stimulating antibody production versus proliferation of cytotoxic T cells is a subject of controversy. Now, two papers in the February issue of Nature Medicine provide evidence that antibodies, or agents that stimulate antibody production, will be an important component of an effective vaccine. They show that passive immunization is highly effective in protecting against the mucosal transmission of HIV in monkeys-the route by which HIV is most commonly transmitted in humans.

John Mascola and colleagues at the Walter Reed Army Institute of Research demonstrate that macaque monkeys injected with a combination of neutralizing antibodies recognizing three antigenic sites on the virus were protected against infection with vaginally administered SHIV-a mixed simian/human immunodeficiency virus.

In a separate paper, Ruth Ruprecht and colleagues at the Dana-Farber Cancer Institute treated pregnant macaque monkeys with a combination of antibodies and showed that mothers were protected against intravenous SHIV challenge after parturition. They also showed that infants receiving the same antibody injection after birth were protected against infection with oral SHIV, suggesting that these antibodies could protect neonates from becoming infected during breast feeding.

Marjorie Robert-Guroff of the National Institutes of Health discusses the findings and their implications for vaccine development in an accompanying News & Views article. In addition, a Commentary article by Dennis Burton from the Scripps Institute reinforces the idea that HIV vaccine development should focus on a dual immune mechanism of antibody and T-cell production to be effective.

Blocking PAR2 could stop inflammation and pain

Nigel Bunnett and colleagues at the University of California San Francisco describe a previously unknown mechanism by which sensory neurons-nerves that transmit stimuli inwards to the central nervous system-are activated to cause inflammation. Their discovery could lead to new treatments for pain and inflammation.

Trypsin and mast cell tryptase are proteases (degradatory enzymes) involved in widespread inflammation. Bunnett's team has found that these proteases attach to a new class of receptor called proteinase-activated receptor 2 (PAR2), which is located on neurons causing them to release specific neuropeptides (substance P and CGRP) which cause inflammation. Thus, drugs that block the PAR2 site could be the basis for new anti-inflammatory medicines.

Susan Brain of King's College, London, discusses the findings in a News & Views article, and explains the potential involvement of PAR2 in other neurally-mediated conditions such as migraine.

MIF may be route to septic shock treatment

Despite extensive research efforts, septic shock syndrome-a lethal blood infection caused by bacterial toxins that leads to low blood pressure and the loss of function of organs such as the lungs and kidneys-has persisted as an insurmountable medical challenge. However, researchers at Vaudois University, Switzerland, have uncovered a molecule that may prove a new route of attack on this life-threatening condition.

Thierry Calandra and colleagues found that levels of the cytokine, migration inhibitor factor (MIF), which is released by the pituitary region of the brain and by cells of the immune system, are raised substantially in the plasma of septic patients and in a mouse model of sepsis. Moreover, inhibition of MIF activity by anti-MIF antibodies increased the survival of septic mice even when administered hours after the time of blood infection.

Although therapies directed against other cytokines that are involved in sepsis, such as TNF-alpha and IL1-beta, have not proven clinically useful, Thomas Martin of the University of Washington discusses in an accompanying News & Views article why neutralization of MIF activity might offer a new strategy for the treatment of septic shock.

Cell cycle protein involved in lupus

Lupus is a debilitating inflammatory autoimmune disorder that causes pain in the joints, skin rashes, and in the case of systemic lupus erythematosus, kidney, heart, blood and lung disorders. The disease affects around 8 times as many women as men.

Now, Dimitrios Balomenos and colleagues from Madrid's National Biotechnology Center have demonstrated that a protein known for its involvement in tumor formation may also be involved in lupus. They report that mice lacking the gene for the p21 protein show widespread proliferation of T lymphocyte immune cells, and reduced immune tolerance to nuclear antigens. Female mice lacking the p21 gene develop a syndrome similar to human lupus: they produce antibodies to DNA, and exhibit lymphadenopathy, and glomerulonephritis.

p21 has been studied previously because of its role in the cell cycle-the ordered sequence of events that controls cell division and growth-in which it inhibits the activity of the key cell cycle proteins, cyclin dependent kinases and cyclins. The discovery of its new role within the immune system could lead to new therapies for diseases such as lupus.

Water channel could be key to treatment for brain edema

Drugs that target the membrane water channel aquaporin-4 (AQP4) could alleviate the fatal brain swelling associated with head trauma, stroke and some infections. Evidence in support of this is reported in the February issue of Nature Medicine, where Geoffrey Manley and colleagues from the University of California San Francisco show that mice modeling stroke and water intoxication, and lacking the channel, had substantially less brain edema and associated neurological complications than normal mice.

Present methods to treat swelling of the brain are more than 70 years old an include the intravenous injection of hyperosmolar fluids and neurosurgical decompression. The scientists conclude, "AQP4 inhibitors might slow the accumulation of edema fluid in brain, thereby reducing the morbidity and death associated with many common neurological disorders."

Second protein discovered to target Her-2/neu cancers

Herceptin was approved in 1998 as a new anticancer drug for the treatment of breast cancers overexpressesing the Her-2/neu gene. Now researchers at M.D. Anderson Cancer Center, Texas, have discovered another protein that has the potential to inhibit tumors overexpressing this gene.

The Her-2/neu gene is activated when a protein (known as a transcription factor) binds to its promoter region. Mien-Chie Hung and colleagues discovered that for Her-2/neu, this activating protein is called PEA3, and comes from a family of proteins called 'Ets'. The scientists showed that PEA3 administration can prolong the survival of mice bearing human tumors and that it can block cancer formation in cells in culture.

Thus, PEA3 could be the basis for a new class of anti-cancer drugs that are effective against tumors overexpressing the Her-2/neu gene, and the findings also validates the idea that transcription factors from the Ets family could be used to switch off potentially cancer-causing genes.