While humans have been consuming fermented foods such as yogurt and kimchi for centuries, a visitor to a modern grocery store can see the recent commercial enthusiasm for adding probiotic bacteria to foods.Â A recent article inÂ SlateÂ explores the confusion over potential health benefits for these added bacteria.
The bacteria that live inside us seem to play an important role regulating metabolism, the immune system and the nervous system, but scientists have a lot to learn about how those interactions take place.
Can it really be possible to transform a person’s own cells into a weapon against various forms of disease? And what if those very cells could be retrained to attack cancer cells or to prevent autoimmune diseases?
Answers to these questions and many more are about to soon be realized, as Emory University Hospital will serve as the launch site for the very appropriately-named EPIC (Emory Personalized Immunotherapy Center).
The new Center, which is the creation of Dr. Jacques Galipeau, MD, professor of hematology and medical oncology & pediatrics of Emory University, will soon be operational after final touches have been put on construction of the lab. This cell processing facility will foster development of novel personalized cellular therapies for Emory patients facing catastrophic ailments and unmet medical needs.
According to Galipeau, the premise of EPIC and its overlying mission will focus on cellular and biological therapies that use a patientâ€™s own cells as a weapon to seek and destroy cells that actually make a person sick. In partnership with the Winship Cancer Institute of Emory University, Childrenâ€™s Healthcare of Atlanta, Aflac Cancer & Blood Disorders Center and the Emory School of Medicine, EPIC seeks to improve the health of children and adults afflicted with cancer and immune disease.
â€œFirst and foremost, we seek to bring a level of care and discovery that is first in Georgia, first in human and first in child. Blood and marrow derived cells have been used for more than a quarter century to treat life threatening hematological conditions and are now established therapies worldwide. More recently, the use of specific adult somatic cells from marrow, blood and other tissues are being studied in cellular medicine of a wide array of ailments including heart, lung, neurological and immune diseases,â€ says Galipeau. â€œThe use of blood borne immune cells can also be exploited for treatment of cancer, autoimmune disease, organ transplantation and chronic viral illnesses such as HIV.â€
Galipeau said that once operational, EPIC willÂ begin by working with Crohnâ€™s disease in pediatric and adult patients, an inflammatory bowel disease. Symptoms of Crohnâ€™s disease include severe abdominal pain, diarrhea, fever, weight loss, and the inability for a child to properly grow. Resulting bouts of inflammation may also affect the entire digestive tract, including the mouth, esophagus and stomach.Â In some cases, a radical surgery involving the removal of part of the lower intestinal tract is required.
â€œThere is no current answer for what specifically causes Crohnâ€™s disease, nor is there a cure. But we hope that through our research and efforts, we will be able to first target the inflammatory mechanisms in these patients through immunotherapy, and in turn reduce the amount of flare-ups and limitÂ the damage that occurs from this disease,â€ says Galipeau.
Galipeau says the EPIC program could represent a powerful cornerstone to the launch and the development of an entirely new, Emory-based initiative which bundles the strengths of the School of Medicine, Emory University Hospital, Children’s Healthcare of Atlanta, and many Woodruff Health Sciences Center centers of excellence,â€ says Galipeau.
â€œMy ultimate goal is to elevate the biomedical scientific and scholarly enterprise to aÂ higher level – making a difference in the lives of people. The EPIC program and multi-levels of support could be a fundamental underpinning to our success.â€
HIV presents a challenge to vaccine design because it is always changing. If doctors vaccinate people against one variety of virus, will the antibodies they produce stop the virus that they later encounter?
A recently published report on an experimental HIV vaccineâ€™s limited effectiveness in human volunteers illustrates this ongoing puzzle in the HIV vaccine field.
Paul Spearman, now chief research officer for Childrenâ€™s Healthcare of Atlanta and vice chair for research for Emoryâ€™s Department of Pediatrics, began overseeing the study when he was at Vanderbilt. The report is in the April 15 issue of the Journal of Infectious Diseases.
Paul Spearman, MD
The vaccine was designed to elicit both antibody and T cell responses against HIV and in particular, to generate broadly neutralizing antibodies. Unfortunately, it didnâ€™t work. Volunteers who received the vaccine made antibodies that could neutralize the virus in the vaccine, but not related viruses thought to be like what participants in a larger study might encounter.
â€œHigh levels of neutralizing antibodies can be raised against HIV, while at the same time, breadth of neutralization has never yet been achieved in a vaccine,â€ Spearman says. â€œThe essential problem is that the antibodies raised have a narrow specificity, while the virus is extremely variable. In contrast, about 20% of HIV-infected individuals will demonstrate neutralization breadth.â€
Last year, scientists demonstrated a method for identifying these broadly neutralizing antibodies in HIV-infected individuals. However, having a vaccine hit that target reliably is still elusive.
Spearman reports that he is in charge of a new trial that will be boosting the same individuals that participated in the previous trial with HIV protein from a clade C virus, starting later this year. Clade C is the predominant HIV subtype in southern Africa, while clade B, used in the published trial, is the predominant subtype in North America and Western Europe.
Sooty mangabeys are a variety of Old World monkey that can be infected by HIV’s cousin SIV, but do not get AIDS. Emory immunologist and Georgia Research Alliance Eminent Scholar Guido Silvestri, MD, has been a strong advocate for examining non-human primates such as the sooty mangabey, which manage to handle SIV infection without crippling their immune systems. Silvestri is division chief of microbiology and immunology at Yerkes National Primate Research Center.
Research shows sooty mangabeys have T cells that can do the same job as those targeted by SIV, even if they don't have the same molecules on their surfaces
A recent paper in the Journal of Clinical Investigation reveals that sooty mangabeys have T cells that perform the same functions as those targeted by SIV and HIV, but have different clothing.
Silvestri and James Else, the animal resources division chief at Yerkes, are co-authors on the paper, while Donald Sodora at Seattle Biomedical Research Institute is senior author.
One main target for SIV and HIV is the group of T cells with the molecule CD4 on their surfaces. These are the “helper” T cells that keep the immune system humming. Doctors treating people with HIV infections tend to keep an eye on their CD4 T cell counts.
In the paper, the scientists show that sooty mangabeys infected with SIV lose their CD4 T cells, without losing the ability to regulate their immune systems.Â What’s remarkable here is that sooty mangabeys appear to have “double negative” or DN T cells that can perform the same functions as those lost to SIV infection, even though they don’t have CD4.
CD4 isn’t just decoration for T cells. It’s a part of how they recognize bits of host or pathogen protein in the context of MHC class II (the molecule that “presents” the bits on the outside of target cells). Somehow, the T cells in sooty mangabeys have a way to get around this requirement and still regulate the immune system competently. How they do this is the topic of ongoing research.
The authors write:
It will be important to assess DN T cells in HIV-infected patients, particularly to determine whether these cells are preserved and functional in long-term nonprogressors. These efforts may lead to future immune therapies or vaccine modalities designed to modulate DN T cell function. Indeed, the main lesson we have learned to date from this cohort of SIV-infected CD4-low mangabeys may be that managing immune activation and bolstering the function of nontarget T cells through better vaccines and therapeutics has the potential to contribute to preserved immune function and a nonprogressive outcome in HIV infection even when CD4+ T cell levels become low.
Emory and University of Rochester researchers have discovered an extra way by which HIV adapts to survive in a hiding spot in the human immune system.Â The results are published in the Journal of Biological Chemistry.
A team led by Baek Kim from the University of Rochester and Raymond Schinazi from Emory found that when HIV faces a shortage of the building blocks it usually uses to replicate, the virus adapts by using different building blocks. The discovery may offer scientists a new way to try to stop the virus.
One of HIV’s favorite hiding spots is an immune cell called a macrophage, whose job is to chew up and destroy foreign invaders and cellular debris. One can think of macrophages as worker bees: they don’t reproduce because they’re focused on getting stuff done.
Raymond Schinazi, PhD, DSc, is director of the Laboratory of Biochemical Pharmacology at Emory's Center for AIDS Research
Normally, HIV uses “dNTPs” (building blocks of DNA), but dNTPs are found at very low levels in macrophages because they’ve stopped dividing and making new DNA. Current drugs generally target dNTPs, and aim at the infection in a different type of cells: T cells.
Macrophages do have high levels of RNA building blocks (“rNTPs”). The team found that HIV uses primarily rNTPs instead of dNTPs to replicate inside macrophages. When the team blocked the ability of the virus to interact with rNTPs, its ability to replicate in macrophages was cut by more than 90 percent.
“The first cells that HIV infects in the genital tract are non-dividing target cell types such as macrophages,” Kim says. “Current drugs were developed to be effective only when the infection has already moved beyond these cells. Perhaps we can use this information to help create a microbicide to stop the virus or limit its activity much earlier.”
Compounds that interfere with the use of rNTPs already exist and have been tested as anti-cancer drugs.
“We are now developing new anti-HIV drugs jointly based on this novel approach that are essentially non-toxic and can be used to treat and prevent HIV infections,” Schinazi says.
Baek Kim, PhD
The first authors of the paper are graduate students Edward Kennedy from Rochester and Christina Gavegnano from Emory. Other authors include graduate students Laura Nguyen, Rebecca Slate and Amanda Lucas from Rochester, and postdoc Emilie Fromentin from Emory.
The research was funded by the National Institute of Allergy and Infectious Disease and the Department of Veterans Affairs.
Scientists at Emory and the University of Chicago have discovered that the 2009 H1N1 flu virus provides excellent antibody protection. This may be a milestone discovery in the search for a universal flu vaccine.
Researchers took blood samples from patients infected with the 2009 H1N1 strain and developed antibodies in cell culture. Some of the antibodies were broadly protective and could provide protection from the H1N1 viruses that circulated over the past 10 years in addition to the 1918 pandemic flu virus and even avian influenza or bird flu (H5N1).
The antibodies protected mice from a lethal viral dose, even 60 hours post-infection.
Some of the antibodies stuck to the â€œstalkâ€ region, or hemagglutinin (H in H1N1) protein part of the virus. Because this part of the virus doesnâ€™t change as much as other regions, scientists have proposed to make it the basis for a vaccine that could provide broader protection. The antibodies could guide researchers in designing a vaccine that gives people long-lasting protection against a wide spectrum of flu viruses.
The paperâ€™s first author, Emory School of Medicineâ€™s Jens Wrammert, PhD, says â€œOur data shows that infection with the 2009 pandemic influenza strain could induce broadly protective antibodies that are very rarely seen after seasonal flu infections or flu shots. These findings show that these types of antibodies can be induced in humans, if the immune system has the right stimulation, and suggest that a pan-influenza vaccine might be feasible.”
A recent paper in Journal of Immunology suggests that a platform for an HIV vaccine developed by Yerkes National Primate Research Center scientists wonâ€™t run into the same problems as another HIV vaccine.Â Postdoc Sunil Kannanganat is the first author of the JI paper, with Emory Vaccine Center researcher Rama Amara as senior author.
Harriet Robinson, MD and Rama Rao Amara, PhD
Many HIV vaccines have been built by putting genes from HIV into the backbone of another virus. Some have used a modified cold virus (adenovirus 5). The vaccine developed at Yerkes uses modified vaccinia Ankara (MVA), a relative of smallpox and chicken pox.
Itâ€™s a knotty, complex question, and one thatâ€™s nearly 30 years old: how does HIV causeAIDS? That is, how does the virus slowly destroy the immune system?
Emory immunologist and Georgia Research Alliance Eminent Scholar Guido Silvestri, MD, and his colleagues are using a method called comparative AIDS research to try and answer that question. In other words, the scientists compare humans infected with HIV who develop AIDS and nonhuman primates from Africa who are infected with SIV, or simian immunodeficiency virus.
Although SIV is very similar to HIV in terms of genetic and molecular structure, once infected with this virus, the Old World Monkey, the sooty mangabey, does not get sick.
â€œItâ€™s a major mystery in AIDS research because these animals have virus replication that remains active in their body as long as theyâ€™re alive,â€ says Silvestri. â€œSo, itâ€™s not just the infection and the virus replicating that kills people. Thereâ€™s something more that happens.â€
A small minority of individuals infected with HIV — about one in 300 –Â are naturally able to suppress viral replication with their immune systems, and can keep HIV levels extremely low for years. Doctors have named these individuals “elite controllers.”
“These individuals have naturally achieved the outcome sought by HIV vaccine researchers worldwide. Â Studying them will ultimately inform the design of a more effective HIV vaccine,” saysÂ Vincent Marconi, a physician-scientist at Grady Health System’s Infectious Disease Clinic on Ponce de Leon and an associate professor in the Emory School of Medicine.
Vincent Marconi, MD
Marconi is a co-author (along with investigators at over 200 institutions) on a genomics study of elite controllers published Thursday in Science Express. Led by Bruce Walker at Massachusetts General Hospital and Paul de Bakker at the Broad Institute and Brigham and Women’s Hospital in Boston, the team of researchers scanned through the genomes of close to 1,000 elite controllers and 2,600 people with progressive HIV infection. They identified several sites linked with immune control of HIV, all in a region encoding HLA proteins.
HLA proteins play key roles in activating T cell immunity, and are also necessary for the development of T cells. They grab onto segments of proteins, called peptides, inside the cell and carry them to the cell membrane. In the right context, certain viral peptides can mark infected cells for destruction by “killer” T cells.
Previously, MGH/MIT researchers theorized that people with certain forms of their HLA genes develop T cells with a restricted repertoire, yet broader activity. Their T cells would be more likely to still recognize HIV when the virus mutates. A drawback is that these individuals may have a higher risk for developing autoimmune diseases.Â The theory is described in more detail in this Nature News article.
Marconi is continuing his part of this research into what makes elite controllers’ immune systems special, which he began at the Department of Defense Infectious Disease Clinical Research Program, in collaboration with Eric Hunter, co-director of Emory’s Center for AIDS Research, and research associate Ling Yue at Emory Vaccine Center. The research is supported by the Center for AIDS Research and the National Institute of Allergy and Infectious Diseases.
Two presentations on Emory research at last week’s AIDS Vaccine 2010 conference concerned adjuvants. These are substances that act as amplifiers, stimulating the immune system while keeping its focus on the specific components of a vaccine.
Charlie Janeway (1943-2003)
Immunologist Charlie Janeway once described adjuvants as immunology’s “dirty little secret,” because for a long time scientists did not know how they worked. Some adjuvants can sound irritating and nasty, such as alum and oil emulsion. Alum is the only vaccine adjuvant now licensed for human clinical use in the US. Over the last few years, scientists have learned that adjuvants rev up what is now known as the “innate immune system,” so that the body knows that the vaccine is something foreign and dangerous.
Rama Rao Amara, a vaccine researcher at Emory Vaccine Center and Yerkes National Primate Research Center, and Harriet Robinson, former head of microbiology and immunology at Yerkes and now chief scientific officer at the firm GeoVax, both described extra ingredients for the DNA/MVA vaccine that Robinson designed while at Yerkes in collaboration with NIH researchers.