Weill Cornell Investigators Discover a New Pathway that Prevents Chronic Inflammation in the Gut

Investigators Show How Immune Cells are "Educated" Not to Attack Beneficial Bacteria

New York (April 23, 2015) -- An international research team led by Weill Cornell Medical College investigators has discovered an answer to why the human immune system ignores roughly 100 trillion beneficial bacteria that populate the gastrointestinal tract. The findings, published April 23 in the journal Science, advance investigators' understanding of how humans maintain a healthy gastrointestinal tract, and may provoke new ways to treat inflammatory bowel disease -- including Crohn's disease and ulcerative colitis -- whose origins have been mysterious and treatment difficult.  

The investigators studied T cells -- critical components of the adaptive immune system -- which have the capacity to recognize, eliminate and remember foreign microbes that invade our bodies. T cells are named after the thymus, an organ where they develop and are taught not to attack normal human tissues and organs, leaving them free to target and eradicate disease-causing foreign invaders. One question that had puzzled scientists until now is how these cells learn to ignore beneficial bacteria in the intestine that are also foreign, but not harmful.

In the study, the research team discovered that once they leave the thymus, T cells are again educated in the gastrointestinal tract, or gut, to leave beneficial bacteria alone. This dual education strategy is vital to supporting healthy immune function, the investigators say. Disruption in the pathway that facilitates this education, they add, causes the immune system to attack beneficial bacteria in the intestine, which is often linked to the development and progression of diseases like inflammatory bowel disease, HIV, viral hepatitis, cardiovascular disease, obesity, diabetes and cancer. Therapeutic strategies to promote and boost the activity of this education pathway may be beneficial in treating patients with these chronic inflammatory disorders, the investigators say.

"In many chronic human diseases, the immune system attacks bacteria in the intestine that are normally beneficial. Although we do not yet know whether this is a cause or consequence of these complex diseases, experimental evidence suggests that this inflammatory process contributes to disease progression," says senior author Dr. Gregory F. Sonnenberg, an assistant professor of microbiology and immunology in medicine and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell. "Our study demonstrates that there may be an efficient way to eliminate pro-inflammatory T cells in the intestine that attack beneficial bacteria. This would not only help our patients with inflammatory bowel disease, but also might give us clues about how to treat other chronic inflammatory diseases caused by abnormal T cell responses, such as allergic and autoimmune disorders."

In earlier research, Dr. Sonnenberg and his team identified that a recently discovered member of the innate immune system -- innate lymphoid cells (ILCs) -- critically regulate immune cell interactions with bacteria. These ILCs, and other cells of the immune system, are found in the intestine, which is constantly exposed to and colonized by beneficial bacteria. "There is a physical separation between the immune system and most beneficial bacteria," Dr. Sonnenberg says. 
The researchers had previously found that ILCs reinforce a physical barrier between the immune system and intestinal beneficial bacteria, but in this study, they uncovered a new key role for these cells -- that they act like the cells in the thymus that educate T cells.

In a process that developed over evolution, bits of human tissues and organs are introduced to T cells in the thymus so they "know" what not to attack after leaving the organ. Specialized cells in the thymus teach T cells this behavior by interacting with a molecule known as the Major Histocompatibility Complex class II (MHCII). Any T cells with the potential to attack the human body and organs and cause auto-immunity are destroyed before they can leave the thymus. However, T cells with the potential to attack beneficial bacteria are not educated or eliminated in the thymus. It was therefore unclear what stopped these T cells from attacking beneficial bacteria in the intestine. 

The scientists found a similar process happening directly within the GI tract, an organ that contains the majority of the body's total immune system.

"Due to the similarities of what we know happens in the thymus, we have called this new process 'intestinal selection,'" says first author Dr. Matthew R. Hepworth, a postdoctoral associate in medicine who works in Dr. Sonnenberg's laboratory. "ILCs also interact with T cells through MHCII machinery to educate T cells in the intestine. 
"In the thymus, T cells are educated not to attack our organs," he adds, "and in the GI tract, using ILCs, they are further educated not to attack beneficial bacteria." 

Using mice to test their findings, the researchers discovered that ILCs destroy T cells with the potential to attack beneficial bacteria, and that impairing ILC function led to severe intestinal inflammation. Then, with the help of researchers at Children's Hospital in Philadelphia, the team looked at intestinal biopsies of pediatric patients diagnosed with Crohn's disease, one of the major forms of inflammatory bowel disease.

"We found ILCs in intestinal biopsies from pediatric patients diagnosed with Crohn's disease, but they were not functioning properly because, in many cases, they were lacking MHCII machinery, so T cells were not educated to ignore beneficial bacteria," Dr. Sonnenberg says. "In fact, we found the loss of MHCII correlated with an increase in pro-inflammatory cells from matched biopsies of children with Crohn's disease. That tells us that this education process may be impaired in patients with inflammatory bowel disease, and that restoring adequate levels of MHCII might help to eliminate pro-inflammatory T cells and reduce chronic intestinal inflammation."

Dr. Sonnenberg says there are likely many causes of inflammatory bowel disease, and other pathways that help control T cells in the gut. "But our work shows a previously unrecognized pathway whereby ILCs educate our immune system not to attack beneficial bacteria," he says. 

Dr. Sonnenberg, his laboratory and the Jill Roberts Institute for Research in IBD are now exploring how scientists can utilize this knowledge and design novel therapeutic strategies to boost MHCII on ILCs and limit chronic intestinal inflammation.

Co-authors include Thomas C. Fung from Weill Cornell Medical College; Terri M. Laufer from the University of Pennsylvania; Samuel H. Masur, Judith R. Kelsen and Robert N. Baldassano from Children's Hospital of Philadelphia; Fiona M. McConnell and David R. Withers from University of Birmingham, United Kingdom; Juan Dubrot, Stephanie Hugues and Walter Reith from the University of Geneva Medical School in Switzerland; Michael A. Farrar from the University of Minnesota; Gerard Eberl from Institut Pasteur, France; and Charles O. Elson from the University of Alabama at Birmingham.

Research in Dr. Sonnenberg's laboratory is supported by the National Institutes of Health (DP5OD012116), the NIAID Mucosal Immunology Studies Team (MIST), Scholar Award in Mucosal Immunity and the Institute for Translational Medicine and Therapeutics, Transdisciplinary Program in Translational Medicine and Therapeutics (UL1-RR024134 from the U.S. National Center for Research Resources). Other investigator support includes a research fellowship from the Crohn's, and Colitis Foundation of America (CCFA, #297365), a Cancer Research Institute Student Training and Research in Tumor immunology (STaRT) grant, a Wellcome Trust Research Career Development Fellowship, and the National Institutes of Health (DK071176).

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, the Medical College is the first in the U.S. to offer its 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.

"Rare" Gene Is Common In African Descendants And May Contribute To Risk Of Heart Disease

"Rare" ApoE Gene Variant Now Believed to be Common in Africans and African Descendants Worldwide. The Gene Can Increase Levels of Triglyceride Fats in Blood, Which May Contribute to Risk of Heart Disease and Other Disorders.

NEW YORK (November 25, 2013) -- Researchers at Weill Cornell Medical College have found that a genetic variation that is linked to increased levels of triglycerides -- fats in the blood associated with disorders such as heart disease, type 2 diabetes, obesity and stroke -- is far more common than previously believed and disproportionally affects people of African ancestry. Investigators say their discovery, reported in the American Journal of Cardiology, reinforces the need to screen this population for high levels of triglycerides to stave off disease.

The finding offers a clue as to why Africans and people of African descent have an increased risk of cardiovascular disease and type 2 diabetes compared to many other populations, says the study's senior author, Dr. Ronald G. Crystal, chairman of genetic medicine at Weill Cornell. African Americans with the variant had, on average, 52 percent higher triglyceride levels compared with blacks in the study who did not have the variant.

"The prevalence of the ApoE mutation may put large numbers of Africans and African descendants worldwide at risk for a triglyceride--linked disorder," Dr. Crystal says. "But we don't yet know the extent of that risk or its health consequences.

"Inheriting this genetic variant does not mean a person is going to get heart disease and other diseases. It increases their risk, and screening for fats in the blood -- both cholesterol and triglycerides -- as well as maintaining a healthy lifestyle is important," Dr. Crystal says. "There are many factors at work in these diseases. This may be one player."

The number of Africans and African descendants who may have this gene variant is significant, Dr. Crystal says. "Based on our findings, we estimate that there could be 1.7 million African Americans in the United States and 36 million sub-Saharan Africans worldwide with the variant, which increases risk of the lipid disorder and, to some unknown extent, the diseases associated with it," he says.

So Rare No One Paid Attention

The study began in Qatar, at Weill Cornell Medical College in Doha. 

The gene variant the scientists studied is a single point mutation -- a replacement of one of DNA amino acid with another -- in the ApoE gene, which carries fats and other molecules through the blood. 

Scientists have believed that more than 95 percent of the world's population has one of three common ApoE variants -- 2, 3, or 4. The rest have one of 38 rare ApoE mutations, among them the R145C variant studied in this research. In the three decades since the variant's discovery, only 32 instances of it have been reported in the scientific literature, Dr. Crystal says. 

"This ApoE variant was believed to be so extremely rare that no one paid much attention to it," he says. 

Weill Cornell researchers in Qatar decided to investigate the mutation in their work evaluating the genetics of Qatari natives -- people who have lived in the country for three generations or more. That population is made up of three genetic subpopulations: Arab, Persian, and sub-Saharan African. The researchers were able to look at the genomes of 228 Qatari participants.

To their surprise, investigators found that 17 percent of the African-derived genetic subgroup had the rare ApoE variant. None of the Arab or Persian participants had the mutation.

The team then expanded their study. They looked at participants in the worldwide 1000 Genomes Project (1000G), and found that while the R145C variant is rare to non-existent in populations that are not African or of African descent, it is common (occurring 5 to 12 percent of the time) among African-derived populations, especially those from sub-Sahara.

Weill Cornell Medical College researchers then looked for the variant in New York--area participants taking part in a study on smoking--related lung health. They found that R145C was rare (occurring 0.1 percent of the time) in the 1,012 Caucasians they studied, but common in the 1,266 African-American participants, 4 percent of whom carried the variant.

 

"This research is a good example of how studying a small population can give you insights that are very relevant to the rest of the world," Dr. Cyrstal says.

The study was supported, in part, by Weill Cornell Medical College-Qatar and the Qatar Foundation, Doha, Qatar; and the National Institutes of Health (UL1-RR024996). 

Co-authors include Maen D. Abou Ziki, Yael Strulovici-Bare, Dr. Neil R. Hackett, Dr. Juan L. Rodriguez-Flores, Dr. Jason G. Mezey, Jacqueline Salit, Sharon Radisch, Dr.  Charleen Hollmann, Dr. Lotfi Chouchane, Dr. Joel Malek, and Dr. Antonio M. Gotto, from Weill Cornell Medical College; and Dr. Mahmoud A. Zirie and Amin Jayyuosi from Hamad Medical Corporation in Qatar.

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, the Medical College is the first in the U.S. to offer its 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.

New Bioengineered Ears Look and Act Like the Real Thing

Weill Cornell Medical College and Cornell University's Bioengineered Ears, the First to Survive Long-Term and Grow Cartilage, May Provide Children and Adults in Need with a New Healthy Ear

 

NEW YORK (Feb. 20, 2013) -- Physicians at Weill Cornell Medical College and biomedical engineers at Cornell University have succeeded in building a facsimile of a living human ear that looks and acts like a natural ear. Researchers believe their bioengineering method will finally succeed in the long quest by scientists and physicians to provide normal looking "new" ears to thousands of children born with a congenital ear deformity.
 

In their PLOS ONE study, the researchers demonstrate how 3D printing and new injectable gels made of living cells can be used to fashion ears that are identical to a human ear. Over a three-month period -- the length of the study -- these flexible ears steadily grew cartilage to replace the collagen that was used to help mold them.
 

"I believe this will be the novel solution reconstructive surgeons have long wished for to help children born with absence or severe deformity of the ear," says the study's co-lead author, Dr. Jason Spector, director of the Laboratory for Bioregenerative Medicine and Surgery (LBMS) and associate professor of surgery of plastic surgery in the Department of Surgery at Weill Cornell Medical College and an adjunct associate professor in the Department of Biomedical Engineering at Cornell University. "A bioengineered ear replacement like this would also help individuals who have lost part or all of their external ear in an accident or from cancer." 
 

Currently, replacement ears are constructed using materials that have a Styrofoam-like consistency or, sometimes, surgeons will build ears from rib that is harvested from a young patient. "This surgical option is very challenging and painful for children, and the ears rarely look totally natural or perform well," says Dr. Spector, who is also a plastic and reconstructive surgeon at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. "All other attempts to 'grow' ears in the lab -- including one 1997 study widely publicized by photos of ears implanted on the backs of mice -- have failed in the long term." 
 

This Cornell bioengineered ear is the best to date in appearing and acting like a natural ear, the researchers report. Also, the process of making the ears is fast -- it takes a week at most.
 

"This is such a win-win for both medicine and basic science, demonstrating what we can achieve when we work together," says the study's other lead author, Dr. Lawrence J. Bonassar, associate professor and associate chair of the Department of Biomedical Engineering at Cornell University.

Scanning, Printing and Molding a Human Ear in a Week 
 

The deformity that both Dr. Spector and Dr. Bonassar seek to remedy is microtia, a congenital deformity in which the external ear is not fully developed. Although the causes for this disorder are not entirely understood, research has found that microtia can occur in children whose mothers took an acne medication during pregnancy. Typically, only a single ear is affected. 
 

The incidence of microtia varies from almost one to more than four per 10,000 births each year. Many children born with microtia have an intact inner ear, but experience hearing loss due to the missing external ear structure, which acts to capture and conduct sound. 
 

Dr. Spector and Dr. Bonassar have been collaborating on bioengineered human replacement parts since 2007, and Dr. Bonassar has also been working with other Weill Cornell physicians. For example, he and Weill Cornell's neurological surgeon Dr. Roger Härtl are currently testing bioengineered disc replacements using some of the same techniques demonstrated in this current study.
 

The researchers specifically work to develop replacements for human structures that are primarily made of cartilage -- joints, trachea, spine, nose -- because cartilage does not need to be vascularized with a blood supply in order to survive.
 

To make the ears, Dr. Bonassar and his colleagues first took a combination laser scan and panoramic photo of an ear from twin girls, which provided a digitized 3D image of their ears on a computer screen. That took 30 seconds, and did not involve any ionizing radiation. The researchers then converted that image into a digitized "solid" ear and used a 3D printer to assemble a mold of the ear. The mold is like a box with a hole in the middle that is in the shape of the mirror image of the ear, say researchers. 
 

They injected animal-derived collagen into that ear mold, and then added nearly 250 million cartilage cells. The collagen served as a scaffold upon which cartilage could grow. Collagen is the main structural protein in the body of every mammal. Animal-based collagen is frequently used for cosmetic and plastic surgery. This high-density collagen gel, which Cornell researchers developed, resembles the consistency of flexible Jell-O when the mold is removed.

"The process is fast," Dr. Bonassar says. "It takes half a day to design the mold, a day or so to print it, 30 minutes to inject the gel and we can remove the ear 15 minutes later. We trim the ear and then let it culture for several days in a nourishing cell culture medium before it is implanted."
 

During the three-month observation period, the cartilage in the ears grew to replace the collagen scaffold. "Eventually the bioengineered ear contains only auricular cartilage, just like a real ear," says Dr. Spector. 
 

Previous bioengineered ears have not been able to maintain their shape or dimensions over time, and the cells within them did not survive.  
 

The researchers are now looking at ways to expand populations of human ear cartilage cells in the laboratory so that these cells can be used in the mold.
 

Dr. Spector says the best time to implant a bioengineered ear on a child would be when they are about 5- or 6-years-old, because at that age, ears are
80 percent of their adult size. "We don't know yet if the bioengineered ears would continue to grow to their full size, but I suspect they will," says Dr. Spector. "Surgery to attach the new ear would be straightforward -- the malformed ear would be removed and the bioengineered ear would be inserted under a flap of skin at the site."
 

Dr. Spector says that if all future safety and efficacy tests work out, it might be possible to try the first human implant of a Cornell bioengineered ear in as little as three years.

"The innovation in this study is two-fold," says Dr. Bonassar. "The use of imaging technology to rapid and accurately make the shape of the ear implant is new, as is the high-density collagen gel for the mold." 

"These bioengineered ears are highly promising because they precisely mirror the native architecture of the human ear," Dr. Spector says. "They should restore hearing and a normal appearance to children and others in need. This advance represents a very exciting collaboration between physicians and basic scientists. It is a demonstration of what we hope to do together to improve the lives of these patients with ear deformity, missing ears and beyond."

Other co-authors of the study are Dr. Alyssa J. Reiffel, Dr. Karina A. Hernandez, and Justin L. Perez from the Laboratory for Bioregenerative Medicine and Surgery at Weill Cornell Medical College; and Concepcion Kafka, Samantha Popa, Sherry Zhou, Satadru Pramanik, Dr. Bryan N. Brown and Won Seuk Ryu, from the Department of Biomedical Engineering at Cornell University. 

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, the Medical College is the first in the U.S. to offer its 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 the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.