An Off-Switch for Allergy: Starving the Immune System Prevents Allergic Inflammation in the Lung

Body: 
Starving immune cells of key nutrients stymies their ability to launch an allergic response, according to new research from a multi-institutional collaboration led by Weill Cornell Medicine investigators. The findings illuminate how nutrients help drive tissue inflammation caused by the immune system — an insight that could lead to new treatments for a wide range of inflammatory conditions from hay fever and food allergies to asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF).
Dr. David Artis

Dr. David Artis. Photo credit: John Abbott

Scientists know from both animal model systems and patient-based studies that a class of immune cells, called innate lymphoid cells (ILCs), play a role in promoting allergic diseases in the lung and other organs. In this new study, published April 4 in Nature Immunology, Weill Cornell Medicine investigators discovered that inhibiting the activity of an enzyme called Arginase-1 changes the metabolism within ILCs, cutting off a critical nutrient supply. Furthermore, disrupting this metabolic pathway in mice shuts down pathologic immune responses that would otherwise promote allergic inflammation in the lung.

"These findings are very exciting and propel us to look deeper into how the immune system is regulated in the context of health and chronic inflammatory diseases," said senior investigator Dr. David Artis, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease and the Michael Kors Professor of Immunology at Weill Cornell Medicine. "This report gives us new mechanistic insight to understand how we might be able to design more selective drugs that specifically target ILCs to treat a range of allergic diseases."

The researchers, led by first author Dr. Laurel Monticelli, a postdoctoral associate in Dr. Artis' lab, used mice genetically engineered to delete the gene for Arginase-1 in ILCs, leaving the rest of the immune system intact. They found that when the genetically engineered mice were exposed to an allergen called papain, which is derived from the papaya plant, the mice were unable to mount an allergic response, which in turn prevented the development of lung inflammation. Dr. Monticelli and her colleagues went on to show that the lack of an allergic response was due to the missing Arginase-1 enzyme, which normally provides energy to the cells by breaking down the amino acid arginine into other metabolic nutrients needed by ILCs. Without these nutrients, the ILCs were essentially starved and became unable to proliferate or function.

To explore the potential clinical implications of these findings for human disease, the Weill Cornell Medicine investigators analyzed lung tissue samples from patients with the chronic inflammatory lung diseases COPD or IPF. The researchers studied the human ILCs within these inflamed tissues and found evidence that these cells expressed Arginase-1.

"While these are still early days in this research, our patient-based analysis, coupled with our mouse model studies, suggests altering Arginase-1 metabolism within these innate immune cells may offer a therapeutic target for multiple inflammatory diseases," Dr. Monticelli said.

Allergies are the sixth-leading cause of chronic illness in the United States with an annual cost in excess of $18 billion. More than 50 million Americans suffer from allergies each year. The investigators' findings have implications for a broad range of allergic diseases. One of these conditions is the "allergic march," a medical phenomenon in children in which one allergic disease, such as eczema, rapidly progresses to multiple allergic diseases including asthma and life-threatening food allergies. Because ILCs have been shown to contribute to tissue inflammation and immunity in multiple disease settings, not just the lung, the investigators said it is possible that therapies aimed at changing the Arginase-1 metabolism of these cells may offer relief for inflammation caused by a variety of allergic diseases.

This collaborative study between five institutions was supported by the National Institutes of Health, the Burroughs Wellcome Fund, the Crohn's and Colitis Foundation of America, the Edmond J. Safra Foundation/Cancer Research Institute, the National Science Foundation, The Robert Wood Johnson Foundation, The Thoracic Surgery Foundation, and the German Research Foundation.

Featured Image: 
Monticelli
Type of News: 
News from WCM
Highlight this Story: 
No

Lung Inflammation Contributes to Metastasis

Body: 

Pre-existing inflammation in the lungs may increase the risk that cancers beginning elsewhere will spread to the organ, according to new research from Weill Cornell Medicine.

Physicians have long noted an association between lung inflammation — seen in smokers or in people with lung diseases such as asthma, COPD and its subset emphysema, and pneumonia — and the development of lung tumors. But it's been unclear whether inflammation also increases the risk of pulmonary metastasis from other tumors. In their study, published Dec. 14 in the Proceedings of the National Academy of Sciences, the investigators reveal a mechanism by which this occurs, shedding light on how pre-existing lung inflammation creates an environment ripe for cancer spread to the organ. The findings may provide doctors new insights into how to treat and possibly prevent metastases.

"Identifying the molecular mechanisms by which pre-existing inflammation in the lungs enhances metastasis has huge clinical implications," said senior author Dr. Vivek Mittal, director of the Neuberger Berman Foundation Lung Cancer Laboratory and an associate professor of cell and developmental biology in cardiothoracic surgery and of cell and developmental biology at Weill Cornell Medicine. "Our research suggests that therapies could be designed to target this pathway to mitigate metastasis to the lung, particularly in cancer patients who exhibit lung inflammation due to exposure to cigarette smoke, bacterial infections, and other environmental pollutants."

Artist perception of lung with alveolar spaces and neutrophils

Artist’s perception of a lung showing alveolar spaces (white) and neutrophils (red). Some neutrophils are releasing the proteins Cathepsin G (CG) and Neutrophil elastase (NE) into the lung, which target and destroy the protein Thrombospondin 1 (Tsp-1). TSP-1 protects lung tissue from tumors; eliminating it enhances metastasis. Image credit: Puneeta Mittal (Lungs on Fire, Glazed ceramic panel)

Metastasis occurs when cells break away from a tumor and travel through the bloodstream or lymph vessels to other parts of the body. The lungs are a common site of metastasis from other cancers, including those of the bladder, breast, colon, kidney, prostate and brain. Lung metastases are hard to cure; in general, the five-year survival rate for patients with lung metastasis is near 30 to 40 percent.

"Metastasis is the major cause of death for people with cancer, so finding better ways to target metastatic tumors is critical," said Dr. Mittal, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

For their study, the researchers first induced inflammation in the lungs of mice by administering a bacterial toxin through the rodents' noses. They then injected the mice with melanoma cells, which grew into skin tumors and spread to the lungs.

"We found increased metastases in inflamed lungs compared to non-inflamed controls," Dr. Mittal said, "proving that inflammation plays a role in the spread of the cancer."

When they analyzed the inflamed lung tissue, the researchers found increased numbers of white blood cells called neutrophils, which release two enzymes into the lungs. These enzymes, neutrophil elastase (NE) and Cathepsin G (CG), target and destroy a protein known as Tsp-1, which protects lung tissue from tumors.

"Since Tsp-1 protects against metastasis, this creates an environment favorable to the spread of cancer," Dr. Mittal said.

Drs. Vivek Mittal and Tina El Rayes

Drs. Vivek Mittal and Tina El Rayes. Image credit: Mittal lab

The investigators say their findings could lead to new treatment strategies that focus on changing the environment inside the lungs that allows metastatic cancer cells to grow. A synthetic form of Tsp-1 that is resistant to the action of NE and CG, but contains characteristic cancer-suppressive properties could protect the lungs from metastatic cells, Dr. Mittal said.

Another option is a drug called Sivelestat, which is a known inhibitor of NE and used to treat patients with acute lung injury. Importantly, the investigators found that it also inhibits CG, making it an ideal therapeutic choice. Both of these strategies would allow Tsp-1 to function normally and target cancer cells that travel to the lungs, preventing metastasis.

"The preclinical data obtained from these studies will generate unique translational opportunities, and may lead to the design of future clinical trials for cancer patients who exhibit pulmonary inflammation," said first author Dr. Tina El Rayes, a postdoctoral associate who finished her doctorate from the Weill Cornell Graduate School of Medical Sciences with this study.

Dr. Mittal believes that an intervention against inflammation-driven cancer spread can lead to the development of an anti-metastatic therapy. He is leading a preclinical study that investigates whether dual inhibition of NE and CG can effectively prevent breast cancer from metastasizing to inflamed lungs.

Dr. Mittal's research also points to the need to understand whether inflammation in other organs might contribute to the spread of cancers as well.

"It should be applicable to any tumor with metastatic potential," he said. "It's really a hopeful finding for cancer treatment."

Featured Image: 
Inflamed lungs
Type of News: 
News from WCM
Highlight this Story: 
No

Stress-Fighting Proteins Could Be Key to New Treatments for Asthma

Body: 
Immune cells called eosinophils store granule proteins in a form known as amyloid. Linked to Alzheimer's disease.

Immune cells called eosinophils store granule proteins in a form known as amyloid. Regulated amyloid formation is a stable way to compress proteins together to save space, but irregular formation can be linked to disease, such as Alzheimer's disease. The Glimcher lab discovered that a deficiency in the protein XBP1 prevents amyloid formation within eosinophil granules, suggeting that eosinophil amyloid formation might be critical to the immune cells' development, and that XBP1 is linked to this process. This image illustrates wild-type bone marrow-derived eosinophils. In blue is the nucleus, red is a stain for specific eosinophil proteins and green is a dye that reacts with amyloid structures. Scientific images: Sarah Bettigole and Raphael Lis

Investigators have discovered the precise molecular steps that enable immune cells implicated in certain forms of asthma and allergy to develop and survive in the body. The findings from Weill Cornell Medical College reveal a new pathway that scientists could use to develop more effective treatments and therapies for the chronic lung disorder.

More than 1 in 12 Americans are affected by asthma, a disorder characterized by an overactive immune response to normally harmless substances such as pollen or mold. Scientists had previously discovered that an overabundance of immune cells that help defend the body against parasites and infection, called eosinophils, were implicated in certain forms of asthma, as well as in allergic reactions. But little was known about how eosinophils develop and survive.

In their study, published July 6 in Nature Immunology, the investigators discovered that a signaling pathway, formed by two proteins that help cells survive stressful conditions, also plays a critical role in eosinophil development. When the investigators altered the function of either of those proteins, the eosinophils, but not other cell types, underwent excess stress and were completely wiped out, suggesting that this pathway could serve as a new therapeutic target for patients who respond poorly to current asthma therapies.

"Our findings demonstrate that individual cell types, particularly eosinophils, interpret and manage stress in distinct ways," said lead author Dr. Sarah E. Bettigole, a postdoctoral fellow at Weill Cornell. "If we disrupt the ability to respond to stress, sensitive cells like eosinophils die off. These subtle differences could be leveraged to develop novel therapies for diseases like asthma and eosinophilic leukemia."

Eosinophils belong to a group of cells called granulocytes, which develop in the bone marrow before migrating into blood. During early stages of development, these cells produce a large number of proteins that are critical for survival, as well as toxic proteins that are later released in response to an immune trigger, such as bacteria or viruses. Intense bursts of protein production during normal biological processes put strain on a cell structure called the endoplasmic reticulum, which plays a crucial role in protein synthesis and transport. If the ER is overwhelmed by such strain, the cell enters a state known as ER stress.

In response to ER stress, a protein called IRE1α helps to generate a highly active form of a second protein called XBP1, which in turn regulates the activity of various genes involved in the cell stress response. This signaling pathway reduces ER stress and prevents cell death by enhancing the ER's protein synthesis capacity while reducing overall protein production.

"Because XBP1 supports the survival of certain mature cell types that make a lot of protein throughout their lives, we suspected that XBP1 might also help cells like eosinophils cope with intense bursts of protein production during development," said senior author Dr. Laurie H. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College.

XBP1-deficient bone marrow-derived eosinophils without amyloid structures.

This image illustrates XBP1-deficient bone marrow-derived eosinophils without amyloid structures. The nucleus is colored in blue and specific eosinophil proteins are stained red.

In support of this idea, the research team found that the IRE1α/XBP1 pathway became increasingly active in differentiating eosinophils as they produced more and more proteins during progressive developmental stages. Moreover, genetically modified mice that were deficient in XBP1 completely lacked eosinophils in the bone marrow, spleen and blood, while other granulocytes were unaffected.

"So far, XBP1 is the only transcription factor to our knowledge that distinguishes the development of eosinophils from that of other granulocytes," Dr. Glimcher said. "This suggests that subtle differences in cellular biological processes provide a previously unappreciated handle for fine-tuning the production of different types of granulocytes."

The loss of XBP1 in eosinophils also altered the activity of genes that are critical for the ER stress response, leading to the accumulation of incorrectly processed proteins, substantial ER swelling and severe granule dysfunction. Without XBP1, the researchers discovered that developing eosinophils underwent too much stress. This stalled their differentiation by blocking a molecule called GATA1, which ensures that young eosinophils finish maturing into adult eosinophils. The researchers found that too much stress and not enough GATA1 eventually killed the eosinophils. Taken together, the findings suggest that ER health is crucial for eosinophil development and survival, highlighting the IRE1α/XBP1 pathway as a potential therapeutic target in a wide variety of eosinophil-mediated diseases.

The investigators are currently testing whether experimental XBP1 or IRE1α inhibitors can be effective treatments for asthma and eosinophil leukemia.

"We now know that XBP1 is required for normal eosinophil development, but we need to figure out whether eosinophil-mediated respiratory illnesses and cancers are also dependent on this pathway," Dr. Bettigole said. "If these diseases are eosinophil- dependent, blocking IRE1α or XBP1 with pharmaceuticals would be an exciting new treatment strategy."

Featured Image: 
Drs. Sarah Bettigole and Dr. Laurie H. Glimcher plan their paper on eosinophil development
Type of News: 
News from WCM
Highlight this Story: 
No

$25 Million Gift from Gale and Ira Drukier Creates the Drukier Institute for Children's Health at Weill Cornell Medical College

Body: 

NEW YORK (December 4, 2014) — Weill Cornell Medical College announced today that it has received a $25 million gift from Gale and Ira Drukier to establish a premier, cross-disciplinary institute dedicated to understanding the underlying causes of diseases that are devastating to children. Its goal will be to rapidly translate basic research breakthroughs into the most advanced therapies for patients.

The extraordinary gift names the Gale and Ira Drukier Institute for Children's Health and will enable the medical college to recruit a team of leading scientists, including a renowned expert who will serve as the Gale and Ira Drukier Director, to pursue innovative research that improves treatments and therapies for the littlest patients. The Drukier Institute, a marquee program that will be headquartered on the 12th floor of Weill Cornell's new Belfer Research Building, will also expand and enhance the medical college's already-distinguished research and clinical care programs that strive to end diseases and disorders that affect children and adolescents, including asthma, autism, cancer, cardiovascular disease, infectious diseases and schizophrenia."We couldn't be more grateful to Gale and Ira, whose generous gift exemplifies their commitment to advancing human health and their steadfast support of Weill Cornell Medical College," said Sanford I. Weill, chairman of the Weill Cornell Board of Overseers. "The Drukiers' investment will better the lives of children in New York and beyond, and will leave a lasting mark on our next generation."

"We are greatly appreciative of Gale and Ira Drukier, whose remarkable gift will enable Weill Cornell to expand its world-class research and clinical care programs for children, who can't be treated like little adults," said Dr. Laurie H. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College. "The Drukiers' generosity is critical in allowing us to attract the best and brightest minds in pediatric research, who will lead the way as we pursue innovative treatments and therapies that will ensure the health of children now and in the future."

"As parents and grandparents, Gale and I appreciate the tremendous impact medicine can have on growing children," said Dr. Ira Drukier, a member of the Weill Cornell Board of Overseers. "When you cure children, you give them their entire life back. It's with immense pride that we are able to make this investment, which will empower Weill Cornell Medical College to focus and direct all of its outstanding pediatric research under the auspices of one institute and provide vital resources to develop tomorrow's treatments and cures."

"It gives us great joy to be able to support Weill Cornell Medical College and make such a tremendous difference in children's lives," Dr. Gale Drukier said. "This gift also continues our enduring relationship with Cornell University, with which we have been connected for 40 years."

The Drukiers have a legacy of philanthropy at Cornell University, having provided generous support to its Herbert F. Johnson Art Museum and College of Architecture, Art and Planning.

"We at Cornell are immensely grateful to Gale and Ira Drukier for their extraordinary leadership and generosity, which has already been felt across the university," President David Skorton said. "With this spectacular new gift, the Drukiers are enabling us to achieve an unprecedented level of excellence in pediatric research. The bench-to-bedside approach of the Drukier Institute will have a lasting impact on children and their families, giving hope when they need it most."

"The gift from Gale and Ira Drukier establishing the Drukier Institute for Children's Health makes a powerful statement about the importance of focusing the energies of a major research institution on improving the health and wellbeing of children," said Dr. Gerald M. Loughlin, the Nancy C. Paduano Professor of Pediatrics and chairman of the Department of Pediatrics at Weill Cornell Medical College and pediatrician-in-chief at NewYork-Presbyterian/Weill Cornell Medical Center. "It is a wonderful legacy for these visionary philanthropists."

Caring for children is particularly challenging because their bodies are constantly changing as they grow, and their metabolisms and immune systems are vastly different than those of adults. Understanding the factors that spur growth in children can present possible lines of inquiry into other diseases, such as cancer, because tumors are also programmed to grow. There are also many genetic and developmental diseases that arise in childhood and pose serious health risks during adulthood. But treating these conditions can be arduous for pediatric patients. Many of the common treatments and therapies available to adults have toxic effects on children, making it critical to devise new and better interventions.

Using genomics and other cutting-edge research approaches, the cross-disciplinary Drukier Institute will drive excellence and innovation in pediatrics, seeking to rapidly and seamlessly catalyze research breakthroughs into the most advanced, safe and effective patient care. The Drukiers' generosity will empower the medical college to recruit five top-flight investigators — including a faculty member who conducts clinical research in pediatric genetics — to augment the distinguished team of physician-scientists already at Weill Cornell, as well as train the next generation of researchers in the field.

To help realize this vision, the Drukiers' gift will enable Weill Cornell to secure the latest research equipment, such as sequencing and informatics technology, as well as develop an infrastructure to establish a biobank. Investigators at the institute will work in close collaboration with clinicians in Weill Cornell's Department of Pediatrics to ensure that children immediately benefit from the latest research advances.

To encourage and support faculty development, research and education, the gift will endow the Drukier Lectureship, an annual lecture at Weill Cornell on a research or clinical topic in the field of children's health. It will also establish the Drukier Prize, which will be awarded once a year to a junior faculty member in the United States or abroad for excellence and achievement in advancing research on childhood diseases or disorders.

About Gale and Ira Drukier

A Cornell University graduate, Ira Drukier is co-owner of BD Hotels, LLC, a real estate development company that owns and operates more than two-dozen hotel properties in New York City, including the Mercer, Hotel Elysee and the Maritime.

Dr. Drukier graduated from Cornell in 1966 with a Bachelor of Science in Engineering with a focus on solid-state physics and in 1967 with a Master in Engineering, earning a doctorate in electrical engineering in 1973 from the Polytechnic Institute of Brooklyn. Upon graduation, he joined RCA Corporation's David Sarnoff Research Center, conducting research in the field of microwave semiconductors, which culminated in his development of the first high-power compound semiconductor field effect transistor. In 1976, he joined Microwave Semiconductor Corporation (MSC) and established a division to develop and manufacture high-power microwave transistors for commercial and military use. Siemens Corporation acquired MSC in 1981, and Dr. Drukier stayed on as corporate vice president until 1983, when he ventured into a career in real estate.

Dr. Drukier has served on the Weill Cornell Board of Overseers since 2012, sat on Cornell University's Board of Trustees for eight years and was a member of the Cornell Tech Task Force to help develop the Cornell NYC Tech campus on Roosevelt Island. He is chair of the council for the Johnson Art Museum at Cornell, chair of the board of trustees building committee of the Parrish Art Museum in Southampton, N.Y., and serves on the Metropolitan Museum of Art's President's Council. Dr. Drukier is vice-chair of the American Society for Yad Vashem and is a member of the Museum of Jewish Heritage's Board of Overseers. He has also published numerous papers and given lectures in the field of microwave electronics and has contributed a chapter to a book on Gallium Arsenide Field Effect Transistors.

Gale Drukier graduated from New York University's Steinhardt School of Culture, Education and Human Development in 1972 with a degree in speech pathology and audiology, later earning a Master of Science ('73) and a Doctor of Education degree ('79) in audiology from Teacher's College at Columbia University. Dr. Drukier began her career as an audiologist at Bellevue Hospital and at Veterans Affairs hospitals in metropolitan New York, later joining Trenton State University — now the College of New Jersey — as a professor. During her 17-year tenure there, Dr. Drukier conducted research, taught and developed the college's nationally accredited graduate program in audiology. She was consistently recognized by her students as the "Best Teacher." After retiring from teaching, Dr. Drukier joined her family's business, BD Hotels, and has managed and renovated properties on Manhattan's West Side for more than 12 years.

Dr. Drukier has continued to serve NYU since her graduation. She has been a member of the Steinhardt Dean's Council since 2005 as a supporter of the educational and fundraising initiatives of the school. In 2007, Dr. Drukier joined the NYU Board of Trustees and presently chairs its Academic Affairs Committee. In 2010, Dr. Drukier endowed and named the deanship of NYU's Steinhardt School of Education. She was awarded the Meritorious Service Award by NYU in 2013.

Dr. Drukier has also been active at Cornell University, chairing the Herbert F. Johnson Museum of Art's Program Committee and is a member of the Plantations Council. Dr. Drukier and her husband endowed the deanship at Cornell's College of Architecture, Art and Planning, endowed the curator of prints and drawings at the Herbert F. Johnson Museum and created a garden at Plantations at Cornell University. The couple is also active in the Parrish Art Museum in Southampton, N.Y., and serves on the Metropolitan Museum of Art's President's Council. Dr. Drukier is an animal lover, particularly of felines, and is on the board of directors of the Animal Rescue Fund of the Hamptons. The Drukiers have one daughter and four grandchildren.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, Cornell University is the first in the U.S. to offer a M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with Houston Methodist. For more information, visit weill.cornell.edu.

This release was updated on Dec. 16, 2014.

Featured Image: 
Gale and Ira Drukier
Type of News: 
Press Releases
Mission: 
Institutional Research
People: 
Dr. Laurie H. Glimcher Sanford I. Weill
Deck (Subtitle): 

Institute Devoted to Bench-to-Bedside Research to Advance New Treatments and Therapies that Target Childhood Diseases and Disorders

Highlight this Story: 
No
Unit: 
External Affairs Gale and Ira Drukier Institute for Children’s Health Pediatrics