Drug discovery veteran Dennis Liotta and his team continue to look for ways to fight against HIV. Working with pharmaceutical industry colleagues, he and graduate student Anthony ProsserÂ have discovered compounds that are active against three different targets: immune cells’Â entry gates for the virus (CCR5 and CXCR4), and the replication enzyme reverse transcriptase. That’s like one arrow hitting three bulls eyes. AnÂ advantage for these compounds: it could be less likely for viral resistance to develop.
For more, please go toÂ the American Chemical Society — there will be a press conference from the ACS meeting in Denver on Monday, and live YouTube.
Several drugs now used to treat cancer and autoimmune diseases are actually repurposed tools derived from the immune system. One of the ways these “therapeutic antibodies” work is to grab onto malignant or inflammatory cells and escort them to their doom.
Emory researchers have found that in a mouse model of chronic viral infection, a kind of traffic pileup inside the body limits how effective therapeutic antibodies can be.
The results, published this week inÂ Immunity, have implications for biotechnology researchers who continue to refine antibodies for therapeutic purposes, as well as bolster our understanding of how chronic viral infections impair the immune system.
Researchers led by Rafi Ahmed, PhD, director of the Emory Vaccine Center, were studying mice infected by LCMV (lymphocytic choriomeningitis virus). They injected several antibodies with the goal of removing various types of immune cells from the mice. Â One end of the antibody molecule is supposed to bind the target cell, while another acts as a flag for other cells to get rid of the target cell.
However, during a chronic LCMV infection, the mouseâ€™s immune system is producing its own antibodies against the virus, which form complexes with viral proteins. These immune complexes prevented the injected antibodies from having the effect the scientists wanted, which was to deplete their target cells.
Excessive amounts of immune complexes appear to be â€œcloggingâ€ the Fc gamma receptors that immune cells would use to grab the antibodies bound to the target cell, says postdoctoral fellow Andreas Wieland, PhD, first author of theÂ ImmunityÂ paper. That these immune complexes form was not news; but how much they interfere with other antibodies was, Wieland says. Fc gamma receptors were already known to be important for antibodies to be effective against influenza and HIV. Read more
Immunologists have identified two bigÂ groups of TÂ cells:Â “helper” CD4+ cells and “killer” CD8+ cells.* The helper cells can produce immune regulatory molecules and promote antibody responses, while the killer cells recognize and destroy virally-infected cells.
A vaccine against a virus that stimulatesÂ only helper CD4+ cells leads to uncontrolled lethalÂ inflammation in mice once the animals are challenged with the virus, a recent paper in Science shows. Emory Vaccine Center director Rafi Ahmed is a co-author.
Senior author Dan Barouch, from Harvard/Beth Israel Deaconess Medical Center, tellsÂ The Scientist that CD4+ cells are like generals directing the battleÂ of the immune system and “if you just have strategic generals and no soldiers,Â it turns out to be worse than having no army at all.” Rebalancing the system with antiviral CD8+ T cells or antibodies helps limit the problems.
The findings mesh with work by Yerkes investigators [Guido Silvestri and colleagues]Â suggestingÂ that HIV vaccines that boost CD4+ cells in gateway mucosal tissues lead to higher rates of infection. In both cases, the lesson is: having more helper CD4+ T cells aroundÂ actually does not help. Read more
Donor antibodies, administered intravenously or subcutaneously, make up a commercial product used to treat both immunodeficiencies and inflammatory or auto-immune diseases.
These preparations contain a complex mix of antibodies against glycans, the carbohydrate molecules on the outsides of cells, a Jan. 7Â paper in Science Translational Medicine reveals.
At first glance, the findings are remarkable because:
A. Immunologists have long thought that carbohydrates, by themselves, are not good at provoking the immune system. (The assumption was: you need some protein for antigen presentation and getting T cells interested.) The data shows exceptions to the rule.
B. Some of the antibodies react against human carbohydrate structures. Instead of attacking them in an auto-immune fashion, they may actually be blocking viruses or bacteria from using those structures as gateways to infection.
The lab of Stephan von Gunten at the University of Bern collaborated with the National CenterÂ for Functional Glycomics led by biochemists Rick Cummings and David Smith at Emory to analyze the spectrum of carbohydrate structures bound by donor antibodies. Read more
Emory’s Max Cooper was celebrated this week in Nature for his discovery of B cells in the 1960s, while working with Robert Good at the University of Minnesota.
Cooper in Good’s laboratory in the 1960s (source: National Library of Medicine)
B cells are immune cells that display antibodies on their surfaces, and can become antibody-secreting plasma cells. Without B cells: no antibodies to protect us against bacteria and viruses. Where B cellsÂ come from, and how they can developÂ such a broad repertoire of antibody tools, was a major puzzle of 20th century immunology, which Cooper contributed toÂ solving. (See the Nature piece to learnÂ why the “B” comes from theÂ name of an organ in chickens.)
The authorsÂ did not mention that Cooper is now at Emory studying lampreys’ immune systems, which are curiouslyÂ different fromÂ those of mammals. The similarities and differences provide insights into the evolution of ourÂ immune systems. In addition, scientists here are exploring whether lamprey’s antibody-like molecules might be turned into anticancer drugs.
Researchers at Emory have been revealing several connections between cellsâ€™ responses to starvation and immunological memory. The latest example of this is a paper in Nature Immunology from Rafi Ahmedâ€™s lab, showing that the cellular process of autophagy (literally: self-consumption) is essential for forming and maintaining memory T cells.
This finding has some practical implications for vaccination and could point the way to additives that could boost vaccine effectiveness in elderly humans. Researchers at Oxford have demonstrated that autophagy is diminished in T cells from aged mice, and T cell responses could be boosted in older mice using the autophagy-inducing compound spermidine. Read more
Chorioamnionitis is a complication of pregnancy: inflammation of the membranes surrounding the fetus, caused by a bacterial infection. It has the potential to inflict damage to the brain of the fetus, especially when combined with fetal hypoxia, and is a known risk factor for developing cerebral palsy.
Chia-Yi (Alex) Kuan and his team, who study fetal brain injury in the Department of Pediatrics, have a new paper in Journal of Neuroscience on a strategy for inhibiting fetal brain inflammation. Postdoctoral fellows Dianer Yang, Yu-Yo Sun and Siddhartha Kumar Bhaumik are co-first authors.
The researchers show that a typeÂ of immune cells called Th17 cells seems to be driving inflammation because the rest of the fetal immune system is still immature. A marker of Th17 cells is elevated in blood samples from human infants with chorioamnionitis, the researchers found. Th17 cells are thought to be important for both autoimmunity and anti-microbial responses.
A drug called fingolimod, which stops immune cells from circulating out of the lymph nodes, was effective in reducing inflammation-induced fetal brain injury in animal models. Fingolimod has been approved by the FDA for use with multiple sclerosis and has been studied in clinical trials of kidney transplantation. The authors write that it may be a potential add-on to hypothermia as a treatment for infants in danger of hypoxia + infection-induced brain damage.
It may seem like a stretch to compare an enzyme to a notorious criminal, especially one as distinctive as Omar Little, a character from the HBO drama The Wire played by Michael Kenneth Williams.
But stick with me, Iâ€™ll explain.
Omar is a stick-up man who robs street-level drug dealers. When drug dealer henchmen Stinkum and Weebay ambush him, they are unsuccessful and Stinkum is killed. Omar tells Weebay, who is hiding behind a car: â€œCome at the king, you best not miss.â€
At Emory, Ed Mocarski, Bill Kaiser and colleagues at GlaxoSmithKline have been studying an enzyme called RIP3. RIP3 is the king of a formÂ of programmed cell death called necroptosis. RIP3 is involved in killing cells as a result of several inflammation-, infection- or injury-related triggers, so inhibitors of RIP3 could be useful in modulating inflammation in many diseases.
In a new Molecular Cell paper, Mocarski, Kaiser and their co-authors lay out what happened when they examined the effects of several compounds that inhibit RIP3 in cell culture. These compounds stopped necroptosis, but unexpectedly, they unleashed apoptosis, another form of programmed cell death.Â Read more
Flagellin is a bacterial protein that activates the innate immune system. Its name comes from flagella, the whips many bacteria use to propel themselves.
On Thursday, a team of researchers led by immunologist Andrew Gewirtz reported in ScienceÂ that treatment with flagellin can prevent or cure rotavirus infection in animals. Rotavirus infection is one of the most common causes of severe diarrhea and is a major cause of death for children in developing countries.
Andrew Gewirtz, PhD
Gewirtzâ€™s lab is now at Georgia State, but he and his colleagues initiated this research while at Emory and several co-authors are affliliated with Emory, including immunologist Ifor Williams.
These findings are remarkable for several reasons. One is: give the immune system something from bacteria, and itâ€™s better at fighting a virus? As Gewirtz says in a GSU news release: â€œItâ€™s analogous to equipping an NFL defense with baseball bats. Blatant violation of all the rules but yet, at least in this case, very effective.â€
For me, what was most surprising about this paper was that treatment with flagellin, or immune signaling proteins activated by flagellin, can get mice with severely impaired immune systems â€“ no T cells or B cells at all — to evict rotavirus. These are mice that have to be reared under special conditions because they are vulnerable to other infections. Interferons, well-known antiviral signaling molecules, are also not involved in resisting or evicting rotavirus infection, the researchers found. Read more
This piece in the Los Angeles Times gives a helpful preview of what Paul Offit’s talk at Emory next weekÂ may be like. He also gave a keynote speech at the Association for Health Care Journalists meeting this spring.
OffitÂ isÂ the chiefÂ ofÂ theÂ DivisionÂ ofÂ Infectious DiseasesÂ andÂ theÂ DirectorÂ ofÂ the VaccineÂ EducationÂ CenterÂ at theÂ Childrenâ€™sÂ HospitalÂ ofÂ Philadelphia. He is speaking at noon at the Health Sciences Research Building Auditorium on Nov. 18.
Offit is also speaking that morning at Childrens’ Scottish Rite hospital on the 1991 measles outbreak in Philadelphia.Â The emails I’ve been getting for the noonÂ eventÂ ask people to register.