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Artemisinins in Malaria Therapy, written by WRAIR researchers Dr. Qugui Li, Dr. Wilbur K. Milhous, and Dr. (COL) Peter J. Weina (Division of Experimental Therapeutics at the WRAIR, Silver Spring, MD) provides a fascinating overview of the historical use and recent developments in the treatment of one of the oldest and still one of the most prevalent scourges of mankind - malaria.

WRAIR, initially known as the Army Medical School, was founded in 1893 by then U.S. Army Surgeon General George Sternberg. In 1900 General Sternberg sent the newly appointed U.S. Army Yellow Fever Commission to Cuba headed by Major Walter Reed. Major Reed and his team became the first to confirm the theory that yellow fever was transmitted by a mosquito vector. Since this historic discovery, WRAIR’s many contributions to mankind in its 100 plus year history includes the discovery of the etiology and treatment of many of mankind’s leading killers.

More than half of the routine vaccines given to service members were co-developed by the military. Development of other licensed vaccines was supervised by investigators who began their careers at military research centers (e.g. yellow fever vaccine by former Army Surgeon General William Gorgas, mumps, measles, and varicella vaccines by Maurice Hilleman, and oral polio vaccine by Albert Sabin). Vaccines currently in advanced development stages include new adenovirus vaccines, and vaccines for malaria, dengue, and hepatitis E.

The history of using artemisinins for malarial like conditions dates back more than 2000 years to when it was a part of the herbal arsenal utilized in Traditional Chinese Medicine as a treatment for malarial like conditions. Artemisinins are derived from the sweet wormwood plant Artemisia annua which not only grows in China but also just down the road from WRAIR along the Potomac River. Revival of the use of artemisinins in the era of modern medicine began in China in the 1970’s with the first purified crystalline artemisinins produced in Shandon Province in 1972.

Although lead author Dr. Qigui Li received his MD and pharmacology degrees in China in the early 1980s, he did not become aware of artemisinins until the late 1980s, while a Post-doctoral Fellow at the Free University of Berlin, Germany. Dr. Li stated that “the Chinese had first published their findings in the Chinese Medical Journal in 1979, but when the WHO approached Chinese scientists for samples of the plant so they could conduct their own assays they were rebuffed. In retrospect, we can appreciate that this was just after the Nixon era, Mao Tse-tung was still in power, and the Chinese were very skeptical about sharing information for fear it would be utilized by the commercial pharmaceutical companies in the West for monetary gain.” Since joining the WRAIR team in 1991, Dr. Li has performed or supervised the majority of the pharmacodynamics and pharmacokinetics on all of the artemisinin derivatives.

In December of 2005, the World Health Organization stated, for the first time, artemisinins are the first line of therapy for most cases of malarial illnesses. Artemisinins are also being investigated as antiviral and anticancer agents.

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Dr. Dr. Qigui Li is currently the senior staff Pharmacologist and Section Chief of Pharmacokinetics/Pharmacodynamics in the Department of Pharmacology, Division of Experimental Therapeutics at the Walter Reed Army Institute of Research. He has received the WHO Research Fellowship Award, the NRC Research Associate Fellowship Award, and Best Investigator/PhD. Candidate from Schering Pharmaceuticals. Dr. Li received his Pharmacology/MD degree from Tongji Medical University, Wuhan, PR China in 1983 and his PhD in pharmacokinetics from the Free University of Berlin, West Berlin, FR Germany in 1989. Following the PhD in pharmacokinetics, Dr. Li completed a Postdoctoral Fellowship at the Free University of Berlin in 1991. He joined WRAIR in 1991.

Dr. Wilbur K. Milhous is currently a Professor of Global Health & Internal Medicine and serves as the Associate Dean for Research at the College of Public Health, University of South Florida (USF) in Tampa. He gained his 28 years of experience as a small molecule drug developer in numerous assignments at the WRAIR serving more recently as Chief Science Officer for Therapeutics and the Research Coordinator for the MIDRP. Under the mentorship of former WRAIR scientists Bob Desjardins and Craig Canfield, Dr. Milhous underwent his infectious disease chemotherapy training in a combined doctoral (University of North Carolina) and training with industry (GlaxoSmithKline) program prior to arriving at WRAIR in 1983. He was the first scientist to conduct in vitro testing of artemisinin extracts and has since been totally fascinated with the molecule resulting in numerous publications and patents. Dr. Milhous, along with former WRAIR colleague, Dennis Kyle, is currently teaching Critical Path Method as an academic discipline in the Global Health Infectious Diseases Research Program at USF Health.

Dr. (COL) Peter J. Weina is currently Chief, Pharmacology, , and Medical/Laboratory Director, Leishmaniasis Diagnostics Laboratory with the Division of Experimental Therapeutics at the Walter Reed Army Institute of Research, Silver Spring, MD. He is also Chair, Integrated Product Team for the Development of Intravenous Artesunate, Military Infectious Diseases Research Program and Medical Research and Material Command, Fort Detrick, MD. He received a PhD (Zoology & Pathology) from the University of Wisconsin-Madison in 1988 and completed his MD degree from the Uniformed Services University of Health Sciences in 1996. He completed a residency in Internal Medicine in 1999 and a Fellowship in Infectious Disease in 2002. Dr. Weina is currently a Fellow with the American College of Physicians and has been awarded one of America’s Top Physicians - Infectious Diseases (2004-2005).

When faced with cancer, the immune system dispatches cells, called T cells, to kill the tumor. But these killer cells often fail to completely eliminate the tumor because they’re deactivated by a distinct population of T cells known as regulatory T cells. Past attempts to get rid of these regulatory T cells have largely failed, in part because they share many features with the killer T cells, making it difficult to eliminate one population without also eliminating the other.

In the new study, the researchers focused on a cell-surface protein called OX40 that had previously been shown (in culture dishes) to turn off the regulatory T cells, but turn on the killer T cells. When this protein was activated in mice, the new study shows, the animals eliminated existing tumors and were protected against developing new ones.

The potential drawback of this approach is that selective inhibition of regulatory T cells could provoke naturally self-reactive T cells to attack the body’s own tissues (autoimmunity). The mice in the study, however, showed no signs of autoimmune disease, suggesting that OX40 may be a promising target for anti-cancer therapy.

Source: Hema Bashyam
Journal of Experimental Medicine

The discovery of the ubiquitous nature and influence of the human immune system on health and disease has led to the emergence of a number of powerful drugs that are bringing relief to patients afflicted with heretofore intractable conditions. These drugs include Enbrel, Remicade, and Humira for the treatment of inflammatory autoimmune diseases, Herceptin for oncology, and Avonex and Betaseron for multiple sclerosis. Each of these drugs had more than US $1 billion in sales in 2007. The ability of these and other drugs based on immune medicine to reap significant success in both human and commercial terms is fueling an accelerating level of interest in immune factor drugs for a growing list of ailments.

Therapeutic drug candidates based on immune factors currently in development include a diverse range of cytokines, immune cascade elements, and regulatory factors. These potential future drugs are targeting a spectrum of chronic and/or progressive indications that individually and as a group represent an enormous level of patient morbidity, mortality and diminished quality-of-life. In addition to a growing list of autoimmune and oncology indications, targeted therapeutic applications for pipeline immune factor drug candidates include infectious diseases, hereditary conditions, and metabolic diseases. More than three dozen pharmaceutical and biotechnology companies are now active in this sector.

The value of Immune factor drugs worldwide exceeded US $18 billion in 2007. Based on our projections of approved and likely-to-be-commercialized drugs, we expect the value of drugs in this sector to double by 2011.

These findings are contained in a new and comprehensive report: Immune Factor Drugs: Targets, Receptors and Therapeutics. The report analyzes fourteen approved and development-stage therapeutic immune factor drug segments representing sixty individual drugs and pipeline candidates, and examines their probably commercial impact on a dozen important chronic diseases.

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A team of Washington State University scientists has devised a method that could lead to the development of vaccines against some of the most troubling infectious diseases we face diseases that have so far been difficult or impossible to vaccinate against.

The new method allows researchers to rapidly screen large numbers of pathogen proteins, called antigens, for their ability to prompt an immune response in a host. Proteins with that ability are good candidates for use in vaccines. The method will be especially valuable in the quest for vaccines against persistent diseases such as malaria, sleeping sickness and syphilis.

“It’s very slick,” said immunologist Wendy Brown, who led the research effort. “Now we have a high-throughput way of finding antigens from any pathogen, as long as you have the genome sequence. To me this was a huge breakthrough, because I’ve been spending my whole career trying to figure out ways to do this.”

The research team included scientists at WSU and at the Rocky Mountain Laboratories of the National Institutes of Health.

A vaccine works by showing the body’s immune system a pathogen or part of a pathogen (usually a protein) so that it can develop cellular memory and antibodies that will recognize and attack the pathogen in the future. A key step in the development of a vaccine is identifying which protein(s) to use. Until now, screening pathogen proteins to find those few that might be good candidates has been laborious, time-consuming, and in the case of persistent diseases, not very successful. Brown said prior methods required about three months to produce and purify a single protein to test. With her new method she is able to screen dozens of proteins within a few weeks.

Brown’s group worked with Anaplasma, a bacterium that causes severe anemia in cattle. Anaplasma is the most common tick-borne pathogen of cattle worldwide and costs an estimated $100 million per year in lost animals and lowered productivity in the United States alone.

The new method starts with the pathogen’s DNA. Previous work by WSU scientists had determined the whole genome sequence of Anaplasma. By comparing that sequence with the genome sequences of better-known microbes, Brown’s team was able to pinpoint genes that code for proteins that stick out of the pathogen’s cell membrane. Brown reasoned that since those proteins are exposed on the surface of the cell, they should be visible to antibodies and immune system cells, and therefore could be a good way to target the pathogen.

Once the genes were isolated, Brown’s team made the proteins they coded for by using chemical ‘machinery’ derived from E. coli bacteria. They then purified each protein to get rid of any E. coli proteins that were present. They did that by using a chemical that would specifically bind to the Anaplasma proteins. Brown attached the chemical to tiny synthetic beads and then poured the protein mixture over the beads. Anaplasma proteins stuck to the beads, while E. coli proteins did not and were discarded. This purification step represented a big advance over other methods, which have been plagued by contamination with irrelevant proteins.

Each purified test protein was then presented to T cells from cows that had previously been exposed to Anaplasma outer membrane proteins. T cells are the immune system’s “memory cells.” In the body, when they recognize an antigen they have seen before, they trigger antibody production by other immune system cells. In Brown’s test, if the T cells recognized a protein, they started dividing and making interferon.

Using the new procedure, Brown’s team found T cells responded to about 20 proteins, including many that had never before been shown to stimulate a T cell response. The researchers are now testing whether any of these might form the basis for an effective vaccine against Anaplasma.

Brown said the new technique also will be a boon to researchers working on vaccines against pathogens that are highly contagious or especially deadly, such as the Ebola virus and the bacterium that causes anthrax. She is using it to screen proteins from Coxiella, a bacterium that causes Q fever and is considered a possible bioterrorism threat.

“If you have the genome, you don’t have to touch the organism. You can just start expressing all these proteins and test them,” Brown said.

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Nearly half of all HIV-positive African adults who become infected with Salmonella die from what otherwise would be a seven-day bout of diarrhea. Now, UC Davis School of Medicine scientists have discovered how salmonella becomes lethal for AIDS patients. Their findings also implicate a mechanism by which HIV evades the powerful drugs used to treat AIDS.

“We have found the defect in the immune response that allows Salmonella to cross the mucosal barrier of the gut, enter the bloodstream and infect other organs,” said Andreas Bäumler, a UC Davis professor of medical microbiology and immunology and co-author of the study.

The results of the study, which will be published online by Nature Medicine March 23, revealed that viral infection of the intestine results in the depletion of a type of white blood cell, called Th-17, in the gut mucosa. This T helper lymphocyte produces IL-17, a cytokine or chemical messenger that plays a crucial role in the inflammatory response, recruiting other immune system cells to the site of infection.

This kind of interruption in the gut’s immune response could be allowing HIV to maintain reservoirs that evade drug treatments, said Satya Dandekar, professor and chair of the department of medical microbiology and immunology.

“It’s like putting out the fire, but leaving the embers smoldering,” Dandekar said.

The rise in patients with acquired immune deficiency syndrome (AIDS) in sub-Saharan Africa has led to a dramatic increase in the frequency of non-typhoidal Salmonella serotypes (NTS), the strains of the bacteria that cause acute food-borne disease world wide. Normally, this infection is limited to the intestine, causing gastroenteritis. In AIDS patients, however, the infection spreads to the bloodstream and causes what is called NTS bacteremia.

While at a conference, Bäumler was surprised to learn from epidemiologist and physician Melita Gordon of the University of Liverpool that Salmonella was quickly becoming one of the leading causes of death in parts of Africa. (Gordon is a co-author on the current paper.) Bäumler returned to Davis and approached Dandekar about collaborating.

Dandekar had been studying the role of gut-associated lymphoid tissue in HIV. In a 2006 study, she found that HIV continued to replicate in the gut mucosa and suppress immune function in patients being treated with antiretroviral therapy - even when T-cell counts from blood samples from the same individuals indicated antiretroviral treatment was working.

“We think the real battle between an individual’s immune system and HIV is happening in the gut mucosa where there is massive destruction of immune cells,” Dandekar said. Gut-associated lymphoid tissue, she pointed out, accounts for 70 percent of the body’s immune system.

In HIV-infected patients, there is a gradual loss of CD4+ T cells over time. These cells, also called T helper cells, organize the immune system’s attack on disease-causing invaders, like Salmonella. Unlike the steady decline of T cells in peripheral blood, there is a very rapid loss of CD4+ T cells in the gut mucosa, Dandekar said.

“We wanted to know whether the loss of the CD4+ T-cells in the gut contributed to the inactivation of the immune system one sees in HIV-infected patients,” she said.

Both Bäumler and Dandekar said the timing was perfect for their collaboration. Together, they developed a novel technique that allowed them to study early intestinal responses to Salmonella infection in rhesus macaques infected with simian immunodeficiency virus (SIV), an established model for HIV infection.

“We found that animals that had no SIV infection were able to generate immediate responses to bacterial exposure, producing Th17 cells in large amounts,” Dandekar said. The SIV-infected animals, however, had either a significantly lower response or lacked did not produce measurable amounts of the cytokine.

“This muted Th17 response led to dissemination of Salmonella from the gut to the peripheral blood,” Dandekar said.

The team of researchers also used mice that lacked the IL-17 receptor, an arm of the mucosal immune response, to confirm that IL-17 deficiency leads to increased systemic dissemination of Salmonella.

“We believe IL-17 deficiency causes defects in the mucosal barrier of the gut,” Dandekar said.

Both Bäumler and Dandekar agreed that the results of their collaboration have exciting implications for both HIV and Salmonella research and, more importantly, get scientists closer to finding treatments for HIV and the deadly form of Salmonella.

In terms of HIV, the results suggest that Th17 may make a good biomarker for monitoring HIV infection and testing the efficacy of vaccines and other therapies. They also suggest that efforts to enhance Th17 function may improve existing antiretroviral treatments.

“We are interested in looking at different molecules and compounds to see if we can boost mucosal immune defenses in the gut,” she said.

Dandekar is also interested in looking at Th17 function in those who respond well to treatment and in long-term non-progressors, those individuals who carry HIV for years without going onto develop AIDS.

“Now we know these cells are playing a big role, but we need to better understand how they are contributing to immune inactivation and inflammation,” Dandekar said.

In terms of Salmonella, Bäumler’s next step is to discover the mechanisms by which non-immunocompromised patients are able to rid themselves of the infections.

“We now know which cytokines orchestrate the mucosal barrier function, but we still don’t know what kills these bacteria,” he said.

This article was originally published in  MedicalNewsToday.com