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October 25, 2016  

Modulation of Scramblase: a novel paradigm to fight chronic infection and cancer 

Scramblase
T lymphocytes, or T-cells, are critical sentinels that eliminate viruses and tumors. However, their strength to find and destroy their diseased targets often declines during chronic infections and cancer - a state referred to as T-cell exhaustion.

Reversal of T-cell exhaustion by blocking of the immune checkpoints by programmed cell death protein 1 (PD-1) has been demonstrated to be remarkably successful in treating a wide range of cancers.

Understanding the cause and regulation of T-cell exhaustion could help to discover novel therapeutic targets and to improve current therapies for chronic infections and cancer.
 

 

Related Investigator

Florian Winau, M.D. 

FlorianWinau


   
September 8, 2016  

Keeping up with HIV mutations: Building a nimble vaccine test system

An AIDS vaccine able to fight any HIV strain has thus far eluded science. HIV frequently mutates its coat protein, dodging vaccine makers’ efforts to elicit sufficiently broadly neutralizing antibodies.

Yet sometimes HIV-infected people can produce such antibodies on their own. This usually requires years of exposure to the virus, allowing the immune system to modify its antibodies over time to keep up with HIV mutations. But the goal is generally achieved too late in the game to prevent them from being infected.

“Only a small fraction of patients are able to develop broadly neutralizing antibodies, and by the time they do, the virus has already integrated into the genomes of their T-cells,” says Ming Tian, PhD, of Boston Children’s Hospital’s Program in Cellular and Molecular Medicine (PCMM).

Tian is part of a group led by PCCM director Frederick Alt, PhD, that developed a technology to greatly speed up HIV development. Described today in Cell, the group’s method generates mouse models with built-in human immune systems. The model recapitulates what the human immune system does, only much more rapidly, enabling researchers to continuously test and tweak potential HIV vaccines.

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Related Investigator

Fred Alt, Ph.D. 

   
September 1, 2016  

CD1a molecule as a potential therapeutic target in inflammatory skin diseases 

Poison ivy: an insidious plant that, when brushed up against, quickly initiates an allergic reaction comprising red skin, swelling, burning, and intense itching that can last for weeks. What's more? Poison ivy grows in all but four states in the U.S., as well as in parts of Asia. The threat of this allergic reaction is ubiquitous, and no immediate cure has been found - yet. Enter, the molecule CD1a. 

CD1aIn a report published online this week in Nature Immunology, Dr. Ji Hyung Kim and Dr. Florian Winau, Boston Children's Hospital's Program in Cellular and Molecular Medicine and the Department of Microbiology and Immunobiology at Harvard Medical School, have been studying the role of CD1a on Langerhans cells in skin immunity through the use of a transgenic mouse model that expresses human CD1a. As human Langerhans cells express CD1a and those in mice do not, studying CD1a's role on Langerhans cells was not feasible in a mouse model. The Winau laboratory's study will be the first published on the role of CD1a in skin immunity using an in vivo system.



 

Related Investigator

Florian Winau, M.D. 

FlorianWinau


   
July 7, 2016  

When antibiotics fail: A potential new angle on severe bacterial infection and sepsis 

Bacterial infections that don’t respond to antibiotics are of rising concern. And so is sepsis — the immune system’s last-ditch, failed attack on infection that ends up being lethal itself. Sepsis is the largest killer of newborns and children worldwide and, in the U.S. alone, kills a quarter of a million people each year. Like antibiotic-resistant infections, it has no good treatment.

Reporting  in Nature, scientists in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine (PCMM) describe new potential avenues for controlling both sepsis and the runaway bacterial infections that provoke it.

It was already known that bacterial invasion causes protein complexes called inflammasomes to become activated, triggering a “death pathway” known as pyroptosis: the infected cells explode open, releasing bacteria as well as chemical signals that sound an immune alarm.

But there needs to be a balance: too strong an alarm can trigger sepsis, causing fatal blood-vessel and organ damage.

“The immune system is trying like hell to control the infection, but if the bacteria win out, the immune response can kill the patient,” explainsJudy Lieberman, MD, PhD, senior investigator on the study together with Hao Wu, PhD, also in the PCMM. “Most attempts to quiet the immune response haven’t worked in treating sepsis in the clinic, because the parts that trigger it haven’t been well understood.”

Lieberman, Wu and colleagues set out to fill in these details, revealing the final cellular events necessary for both sepsis and stemming the bacterial attack.


 
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Related Investigators

Judy Lieberman, M.D., Ph.D. 

Hao Wu, Ph.D. 

HaoWu1


   
March 17, 2016

Democratizing high-throughput single molecule force analysis

New inexpensive technology platform enables multiplexed single molecule analysis under force

From the tension of contracting muscle fibers to hydrodynamic stresses within flowing blood, molecules within our bodies are subject to a wide variety of mechanical forces that directly influence their form and function. By analyzing the responses of single molecules under conditions where they experience such forces we can develop a better understanding of many biological processes, and potentially, develop more accurately acting drugs. But up until now experimental analysis of single molecule interactions under force have been expensive, tedious and difficult to perform because it requires use of sophisticated equipment, such as an atomic force microscope or optical tweezers, which only permit analysis of one molecule at a time.

Now, a research team led by Wesley Wong has made a major advance by developing an inexpensive method that permits analysis of the force responses of thousands of similar molecules simultaneously.

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Related Investigator

Wesley Wong, Ph.D. 

 
   
 March 1, 2016

This article originally appeared in Nature News & Views


From genetics to physiology at last

The identification of a set of genetic variations that are strongly associated with the risk of developing schizophrenia provides insights into the neurobiology of this destructive disease.

Schizophrenia is a devastating and chronic neuropsychiatric disorder that affects nearly 1% of the world’s population. It has long been hoped that the identification of genetic risk factors for schizophrenia would help to identify the physiological causes of the disease, but, despite decades of intensive research, the biological underpinnings of schizophrenia have remained elusive. Sekar et al. (PDF) present a remarkable genomic and neurobiological study that finally delivers on this long-standing hope.

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Related Investigator

Michael Carroll, Ph.D. 

MikeCarroll

 
   
 

February 11, 2016

Adopted from Boston Children's hospital News Release

DNA breaks in nerve cells' ancestors cluster in specific genes

Study reveals new avenue for thinking about brain development, brain tumors and neurodevelopmental/psychiatric diseases

By Tom Ulrich

The genome of developing brain cells harbors 27 clusters, or hotspots, where its DNA is much more likely to break in some places than others, according to research from Harvard Medical School and Boston Children’s Hospital.

Those hotspots appear in genes associated with brain tumors and a number of neurodevelopmental and neuropsychiatric conditions.

The findings, reported Feb. 11 in Cell, raise new questions about the origins of these conditions as well as how the brain generates a diversity of circuitry during development.

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Related Investigator

Fred Alt, Ph.D. 

 
   
 January 27, 2016

Microptosis: Programmed death for microbes?

By Tom Ulrich

Of the various ways for a cell to die — necrosis, autophagy, etc. — apoptosis is probably the most orderly and contained. Also called programmed cell death (or, colloquially, “cellular suicide”), apoptosis is an effective way for diseased or damaged cells to remove themselves from a population before they can cause problems such as tumor formation.

“Apoptosis has special features,” says Judy Lieberman, MD, PhD, an investigator in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine. “It’s not inflammatory, and it activates death pathways within the cell itself.”

Conventional wisdom holds that apoptosis is exclusive to multicellular organisms. Lieberman disagrees. She thinks that microbial cells — such as those of bacteria and parasites — can die in apoptotic fashion as well. In a recent Nature Medicine paper, she and her team make the case for the existence of what they’ve dubbed “microptosis.” And they think it could be harnessed to treat parasitic and other infections.

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Related Investigator

Judy Lieberman, M.D., Ph.D. 

 
   
 January 26, 2016

This article originally appeared in Lupus Research update (Volume 3, 2015)

Exploring The Effects Of Lupus On The Brain


Michael Carroll, PhD, from Boston Children's Hospital, is a leading scientific investigator who has been interested in lupus since he was a post-doctorate fellow at Oxford. In the intervening years, he has honed his focus in on lupus and the brain.

"Along the way, I became aware that lupus was not only affecting the immune system — but that there was a Central Nervous System (CNS) component,"said Dr. Carroll. Because his expertise is in immunology, not neurobiology, Dr. Carro

ll recruited Dr. Allison Bialas to his lab as a postdoctoral fellow. Dr. Bialas, who received her PhD in Neurobiology at Harvard, wanted to learn more about the peripheral immune system.

Lupus patients can experience a variety of neuropsychiatric symptoms, including anxiety, depression, mood disorders, and cognitive decline. In rare cases, patients may experience psychosis and seizures. Drs. Carroll and Bialas want to discover why.

Referring back to his earlier work, Dr. Carroll's investigation with Dr. Bialas builds on his research involving the complement system — an essential part of the body’s immune response. This important inquiry — entitled Investigating the Mechanisms of Lupus-associated CNS Dysfunction — is being funded by the ALR.

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Related Investigator

Michael Carroll, Ph.D. 

MikeCarroll

 
   
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