Immunity Inflammation and Microbiology Archives - Page 5 of 5 - Sanford Burnham Prebys

Tag: Immunity Inflammation and Microbiology

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Rheumatoid arthritis drug works by restoring balance to immune cells

AuthorJessica Moore
Date

September 29, 2016

Hands with joints made swollen and stiff by rheumatoid arthritis, holding an apple

In rheumatoid arthritis, the immune system’s patrollers—T cells—see the membrane that surrounds joints as a threat, and engage other immune cells to destroy it. Worse, those misguided T cells become hyperactive. Instead of dying when they should, they continue to fuel inflammation that breaks down the joint tissue.

Scientists led by Salvatore Albani, MD, PhD, an adjunct professor in the Immunity and Pathogenesis Program, have now found a way to return these manic, long-lived T cells to normal—and conveniently, in a drug called hydroxychloroquine, which is already approved to treat symptoms of rheumatoid arthritis. The new results are published in the European Journal of Immunology.

“Hydroxychloroquine is already being used to treat various autoimmune diseases including rheumatoid arthritis,” said Albani. “But, by revealing its mechanisms, we will now be able to develop a better drug for these disabling diseases.”

Rheumatoid arthritis is one of the most common autoimmune diseases, affecting 1.5 million adults in the U.S. Severe joint pain, swelling and stiffness make it challenging for patients to accomplish everyday tasks, and many are easily fatigued. Even with new treatments that have become available in recent years, only 20-40% of patients can keep symptoms at bay over the long term.

 

In the new study, Albani and his team wondered how overactive T cells survive in rheumatoid arthritis. They realized that the cells might require more energy and molecular building blocks than they could generate using standard metabolic pathways. An important cellular process called autophagy—the breakdown of large molecules and organelles for reuse, which is ramped up during starvation—was the first place they thought to look.

Just as they suspected, rates of autophagy were higher in the T cells of patients with rheumatoid arthritis, compared with healthy individuals. Applying hydroxychloroquine to those T cells restored their normal lifespans. The researchers also used a well-established mouse model of rheumatoid arthritis to show that hydroxychloroquine reduced joint swelling.

According to Albani, not all patients respond to hydroxychloroquine. “We think it may work best at early stages of the disease, when T cells are most important,” he said. “We plan to further explore that possibility, as well as ways to improve the outcomes of treating rheumatoid arthritis with autophagy inhibitors.”

The paper is available online here.

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Zika virus may affect adult brain cells in those with immune deficiencies

AuthorJessica Moore
Date

August 19, 2016

mosquito sucking blood from a person

Concerns over the Zika virus have focused on pregnant women due to mounting evidence that it causes brain abnormalities in developing fetuses. However, new research to which Alexey Terskikh, PhD, associate professor in the Development, Aging, and Regeneration Program, contributed, provides tentative evidence that certain adult brain cells may be vulnerable to infection as well. These cells replace lost or damaged neurons throughout adulthood, and are critical to learning and memory.

 

“We examined whether the Zika virus can get into the adult brain by infecting mice. Since normal adult mice are resistant to Zika, we used special mice that lack a major antiviral response,” said Terskikh. “We found that in these mice the virus infects neural progenitor cells (NPCs). This suggests that people who have been infected with Zika might, in the long term, develop neurological symptoms such as memory or mood problems—and people with weakened immune systems would be especially vulnerable.”

The investigation, published in Cell Stem Cell, was co-led by Joseph Gleeson, MD, adjunct professor at Rockefeller University, and Sujan Shresta, PhD, professor at the La Jolla Institute of Allergy and Immunology. Terskikh’s lab performed the experiments, which he helped design, in parallel with the other teams.

In adults, NPCs are found in two small regions of the brain. Infection correlated with evidence of cell death and reduced generation of new neurons in these regions. Similar deficits have been linked to cognitive decline and depression.

Since Zika infections in healthy humans lead to much lower viral counts than those in the mice in the study, whether the virus enters the brain in typical cases remains unclear.

“The majority of adults who are infected with Zika rarely show detectable symptoms,” said Shresta. “Its effect on the adult brain may be subtle, and now we know what to look for.”

To better understand the effects of Zika on normal adult brains, Terskikh’s lab is now using a different mouse line with a dampened, rather than absent, antiviral response.

The paper is available online here.

This post is based in part on a press release from Rockefeller University and the La Jolla Institute for Allergy and Immunology.

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Targeting gut microbes may help malnourished children grow

Authorjmoore
Date

March 7, 2016

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Malnutrition in infants and young children can have major life-long impacts—deficiencies in important nutrients stunt growth and impair development. Although aid organizations have developed fortified meals to make up for these deficiencies, they don’t completely compensate for the lack of nutrition. Now scientists know why malnourished children might not benefit as much as they should from added nutrients in their diet. Continue reading “Targeting gut microbes may help malnourished children grow”

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Researchers reawaken sleeping HIV in patient cells to eliminate the virus

Authorsgammon
Date

September 9, 2015

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Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a new class of drugs that may be used to purge pockets of dormant HIV from a patient’s body, eliminating the virus once and for all. Fortuitously, these agents are already being explored in clinical trials for treating cancer, which could speed up the route to approval for treating HIV.

Antiretroviral therapies have made it possible for people to live with AIDS for decades. However, small reservoirs of a patient’s cells hide the virus. That is, HIV’s genes live in the cells, but its genetic code is never read to make protein, and so the virus goes undetected by the immune system.

“If you take people off the antiretroviral therapies, some of these dormant cells reawaken to make more virus,” said lead author Lars Pache, PhD, a postdoctoral fellow in the lab of Sumit Chanda, PhD, director of the Immunity and Pathogenesis Program at SBP. “The key for a cure for HIV is to purge these cells that have dormant HIV.”

Reactivating latent HIV-infected cells so that they can be killed off once and for all is called ‘shock and kill.’ The approach has remained elusive so far, because drugs that reawaken the virus could also trigger massive immune system activation, which itself could be deadly, Chanda said.

The new study, published September 9 in the journal Cell Host & Microbe, “uses a class of drug called Smac mimetics to tap into a cell pathway that can be used to wake up the virus but, based on clinical studies and our data, doesn’t appear to activate the immune system,” Chanda added.

The study started with a broad search of genes within the host cells that help keep the virus silent. Chanda’s group identified 651 genes. They then created batches of cells in which each one of those genes was silenced, and they measured how much HIV the cells produced after they were exposed to the virus.

The scientists whittled the list of candidate genes down to 139, to 24, and then 12 using increasingly stringent criteria. The absence of one gene in particular, BIRC2, boosted the activity of HIV. Even better, Smac mimetics—already proven safe in early-stage clinical trials for cancer—works by inhibiting BIRC2 and related molecules.

“These experiments led us to develop a strategy of using Smac mimetics to reawaken dormant HIV so that we could then kill it with anti-viral therapy,” said Chanda.

Chanda’s colleague at SBP, Nicholas Cosford, PhD, professor in the Cell Death and Survival Networks Program, had recently described a potent BIRC2 inhibitor, SBI-0637142. “This drug is about 10-100 times more potent than the small molecules currently in clinic development, making it a promising candidate to tackle HIV latency,” says Chanda.

Part of the reason that HIV’s genes stay hidden in its host is that they cover themselves with tightly wound DNA. A class of drugs called histone deacetylase inhibitors, which unfurls the DNA, is used to treat a variety of conditions. Although most of these inhibitors haven’t worked well on their own to reactivate latent HIV, they might work well with Smac mimetics including SBI-0637142, Chanda’s group reasoned.

The key question was whether they could reactivate the virus in cells from HIV-infected patients undergoing antiretroviral therapy. They combined SBI-0637142 with a histone deacetylase inhibitor (panobinostat) and saw signs that the virus had reawakened without triggering immune cell death.

“We anticipated that we would see a synergy because the drugs work along parallel pathways. What we didn’t expect was the level of activation—the potency and efficacy with which we were able to reverse latency in patient samples,” Chanda said.

They saw similar results in patient cells treated with a combination of LCL161—a Smac mimetic that is already in phase 1 and 2 trials for treating cancer—and panobinostat. “This is a one-two punch for HIV,” said Chanda, adding that ultimately, a cocktail of drugs will be necessary to cure HIV.

The scientists hope to partner with a pharmaceutical company to develop these molecules for testing in animal models of HIV and then move them into the clinic if they meet the safety and efficacy criteria.

In addition to SBP, the study consortium included the University of Utah School of Medicine, The Salk Institute for Biological Studies, the Perelman School of Medicine at the University of Pennsylvania, the Icahn School of Medicine at Mount Sinai, the Paul-Ehrlich-Insitut, and the German Center for Infection Research.

This post was written by Kelly Chi, a freelance science writer.