News and Trends-May 2015

| May 1, 2015

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, New York—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 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).

For more information, visit weill.cornell.edu.

American Association of Clinical Endocrinologists/
American College of Endocrinology Release New, Comprehensive Clinical Practice Guidelines and Updated Algorithm for Developing a Comprehensive Diabetes Mellitus Care Plan
JACKSONVILLE, Florida—The American Association of Clinical Endocrinologists (AACE) announced the publication of new, expansive diabetes clinical practice guidelines and an updated diabetes algorithm to assist clinical caregivers with the medical management of patients with diabetes mellitus (DM).

The 2015 guidelines advocate for comprehensive control of diabetes beyond a simple focus on glycemic control to address multiple DM risk factors. The guidelines promote individual patient goals and the development of a personalized management plan. To that end, comprehensive clinical recommendations are offered for assessing and managing obesity, lipid disorders, hypertension, kidney disease, cardiovascular disease, hypoglycemia and anti-hyperglycemic therapy to prevent complications; most have been modified substantially over previous guidelines.

The document also includes important information about vaccinations, cancer risks, and management of prediabetes, sleep disorders and depression among those with DM.
The diabetes management algorithm, first published in 2013, is presented as an illustrated treatment pathway companion to the guidelines and emphasizes the importance of medical and surgical interventions as primary therapeutic approaches in overweight and obese patients with DM, as well as in the prevention of diabetes in high-risk patients with prediabetes, using AACE’s obesity treatment algorithm.

The algorithm includes every FDA-approved class of medications for diabetes and stratifies therapy options based on initial A1c.

The chair of the guidelines task force, Dr. Yehuda Handelsman, MD, FACP, FNLA, FACE, adds that although the guidelines and algorithm are comprehensive in nature and cover the spectrum of DM management, the resulting recommendations should be easy for healthcare providers to incorporate into their medical decision-making.

“Both the guidelines and algorithm, while detailed, have been constructed in such a way, such as a question-and-answer format within the guidelines, to address specific problems in diabetes care in a concise, practical and actionable manner that will assist in developing patient care plans,” Dr. Handelsman said.

“With this updated algorithm, clinicians have a definitive, point-of-care tool to assess critical factors that accompany diabetes and its treatment,” said Dr. Alan Garber, MD, PhD, FACE, chair of the algorithm task force.

The two documents are published online at https://www.aace.com/files/dm-guidelines-ccp.pdf and https://www.aace.com/publications/algorithm and in the April 2015 issue (Volume 21, Issue 4) of the association’s peer-reviewed scientific journal Endocrine Practice.
About the American Association of Clinical Endocrinologists (AACE). The American Association of Clinical Endocrinologists (AACE) represents more than 7,000 endocrinologists in the United States and abroad. AACE is the largest association of clinical endocrinologists in the world. The majority of AACE members are certified in endocrinology, diabetes and metabolism and concentrate on the treatment of patients with endocrine and metabolic disorders including diabetes, thyroid disorders, osteoporosis, growth hormone deficiency, cholesterol disorders, hypertension and obesity. Visit our site at http://www.aace.com.
About the American College of Endocrinology (ACE). The American College of Endocrinology (ACE) is the charitable, educational and scientific arm of the American Association of Clinical Endocrinologists (AACE). ACE is the leader in advancing the care and prevention of endocrine and metabolic disorders by: providing professional education and reliable public health information; recognizing excellence in education, research and service; promoting clinical research and defining the future of Clinical Endocrinology. For more information, please visit http://www.aace.com/college/.

About the Journal. Endocrine Practice, the official journal of the American College of Endocrinology (ACE) and the American Association of Clinical Endocrinologists (AACE), is a peer-reviewed journal published twelve times a year. The Journal publishes the latest information in the treatment of diabetes, thyroid disease, obesity, growth hormone deficiency, sexual dysfunction and osteoporosis, and contains original articles, case reports, review articles, commentaries, editorials, visual vignettes, as well as classified and display advertising. Special issues of Endocrine Practice also include AACE clinical practice guidelines and other AACE/ACE white papers. Complete content is available on the Endocrine Practice Web site at www.endocrinepractice.org.

News from the OBESITY ACTION COALITION (OAC)
About the OAC. The Obesity Action Coalition (OAC), a nearly 50,000 member-strong National non-profit organization, is dedicated to improving the lives of individuals affected by the disease of obesity through education, advocacy and support.

The OAC Releases New Your Weight Matters Campaign-National Television Public Service Announcement
Tampa, Florida—Affecting more than 93 million Americans, the disease of obesity is associated with more than 40 related conditions such as diabetes, hypertension, heart disease, sleep apnea, some cancers and more. In an effort to raise awareness of the importance of excess weight and obesity, the Obesity Action Coalition (OAC) is excited to release a new Your Weight Matters Campaign National television public service announcement (PSA) focusing on family, relationships and their impact on weight and health.

“On average, Americans spend approximately $60 billion each year on weight-loss products; however, often times, individuals are not discussing the issue of weight with their healthcare provider. Today, there are many evidence-based treatment options available for individuals to utilize, under the care of their healthcare provider, to manage their weight and health. The Your Weight Matters Campaign helps individuals prepare for that important conversation and offers valuable resources,” said Joe Nadglowski, OAC President and CEO.

The Campaign, also available in Español, consists of a variety of FREE resources, such as the Your Weight Matters Campaign Toolkit, which provides readers with information on weight‐loss options, exercise, nutrition, sample questions for their provider and a food journal.

“The OAC is very excited to release our second national television public service announcement for the Your Weight Matters Campaign. Our first commercial debuted in 2013 and was extremely successful in encouraging thousands of individuals to take the Campaign challenge. The new television PSA emphasizes how the family dynamic and relationships play an important role in dealing with weight and health issues,” said James Zervios, OAC Vice President of Marketing and Communications.

To view the OAC’s newest Your Weight Matters television PSA, please visit http://bit.ly/1yWlv9A. Individuals wanting to learn more about the Your Weight Matters Campaign can do so by visiting www.YourWeightMatters.org.

The Your Weight Matters Campaign is part of the Your Weight Matters Brand, which includes the OAC’s highly-successful Your Weight Matters National Convention, set for San Antonio, August 13-16, 2015 and the OAC’s exclusive membership benefit, Your Weight Matters Magazine.

OAC Urges the Food and Drug Administration to Protect Consumers from Unsafe Weight-loss Supplements
Tampa, Florida—In response to new research that found BMPEA1 (an amphetamine-like substance) in weight-loss and athletic performance substances, the OAC is urging the Food and Drug Administration (FDA) to further evaluate the safety and efficacy of these supplements.

“As Americans, we rely on the FDA to be the inherent watchdogs of certain things, such as our food and medications. Additionally, they also have the responsibility to evaluate the safety of other products, such as weight-loss supplements. Individuals affected by obesity are often easy targets for supplement companies promising fast weight-loss results with potentially unsafe, non-evidence-based products. With today’s media reports on the presence of BMPEA in various supplements, the OAC is urging the FDA to take a closer look at these supplements and also take a more proactive stance in educating consumers on their safety,” said Ted Kyle, RPh, MBA, OAC Chairman.

Kyle continued, “While the OAC recognizes there is no one-size-fits-all approach to weight-loss, supplements have long been under scrutiny for their bold package-based promises of ‘fast weight-loss.’ We simply do not know enough about the safety of these supplements, and as it has been reported today, some may contain potentially harmful substances. Until the FDA takes a stronger stance with weight-loss supplements, we strongly encourage consumers to talk to their healthcare provider before taking any weight-loss supplement.”

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