Discovery Of Key Role Of Peptide Human α-defensin (HD6)
Researchers from Cleveland Clinic and four other U.S. institutions have discovered the role of one of two antimicrobial peptides deficient in patients with Crohn’s disease. Their study revealed that the peptide, called human α-defensin (HD6), protects the gut from invasion by enteric bacteria. Their discovery was published in recent issue of the journal Science.
“Patients with Crohn’s disease characteristically have an alteration in bacteria on the surface of the intestinal epithelium. Their predisposition to inflammatory bowel disease may, in part, be the result of a deficiency of human defensin-5 (HD5) and HD6,” says study participant Bo Shen, MD, a Cleveland Clinic gastroenterologist and professor of medicine at Lerner College of Medicine.
Collaborating to find answers
HD6 and HD5, the other peptide deficient in inflammatory bowel diseases, are expressed by Paneth cells in the epithelium of the small intestine. HD5 is known to be broadly antimicrobial and plays an active role in maintaining homeostasis. HD6 exerts little antimicrobial activity, and its function was unknown until the article by Shen et al was published.
The HD6 study was initiated by Charles Bevins, MD, a Cleveland Clinic alumnus now at University of California, Davis. A basic scientist and leading defensin investigator, Dr. Bevins developed a monoclonal antibody for HD5 while at Cleveland Clinic's Lerner Research Institute. “He was one of my mentors, and our relationship persists to this day,” says Dr. Shen.
Under Dr. Bevins’ direction, a transgenic mouse model that restricted HD6 gene expression to Paneth cells was developed. When these transgenic mice and littermate controls were challenged intragastrically with Salmonella typhimurium, 50 percent of the littermates, but none of the transgenic mice, died within six days. The intestines of all subjects were found to contain similar numbers of bacteria four days post infection; however, counts in the transgenic mice were significantly lower than in their littermates.
"When the intestinal epithelial cells were challenged with α-defensin-treated or untreated salmonella, the ability of the HD6-treated bacteria to invade epithelial cells was impaired. This suggests that HD6 does not protect by altering host cells,” says Dr. Shen. The researchers then performed invasion assays with Yersinia enterocolitica, a bacterium with a different mechanism of cell invasion. Again, HD6 reduced the bacteria to pre-invasion levels, proving its action is not pathogen-specific.
“It appears HD6 peptides bind to the protein molecules of any bacteria they encounter, then form fibrils and nanonets that surround and entangle the bacteria, possibly impeding the close physical contact with epithelial cells required for attachment or invasion,” Dr. Shen explains.
Although their experiments involved two Gram-negative bacteria, the general mechanism that emerged could apply to many other bacteria, as well as to fungi and some protozoan parasites, says Dr. Shen.
The researchers are excited about the implications of their discovery.
“It is possible that the deficiency of defensin contributes to the development of Crohn’s disease or other forms of IBD, and in this case, supplementation may help. The next step is to investigate this possibility,” he says.
New Technology For Organ Preservation Being Tested
By using a heart-lung machine and whole blood to perfuse organs that are awaiting transplantation, it’s possible to minimize the damage of “marginal organs” that do not thrive during the traditional cold storage process. The new technology is called normothermic oxygenated perfusion of the liver, and it involves providing oxygen and nutrition to organs for a smooth, “live” transition from donor to patient. Fewer than five medical institutions in the world are implementing this technology.
This perfusion method is being studied by researchers, including Cristiano Quintini, MD, liver surgeon of the Liver and HPB programs at Cleveland Clinic. “The same heart-lung machine used during in open heart surgery is used to keep a perfusion solution [blood] pumping through the liver,” Dr. Quintini says. Essentially, the organ is receiving blood and oxygen as if it were still being supported by a living body. The goal is to maintain the organ in a live state, despite its removal from a deceased person and transplantation into a patient.
Compared to the cold storage method of preserving organs, which has been an effective gold standard for 40 years, this new ex-vivo method currently being tested holds the potential to prevent damage that can occur because the organ does not receive oxygen. Another limiting factor of ice and cold preservation is that it can damage the cell membrane permeability, causing swelling and injury to the organ. For these reasons, marginal organs might not be considered for the transplantation process, Dr. Quintini says.
And today, donors are older and have organs that may be minimally damaged from health issues such as obesity, which directly affects the liver. “Organ scarcity continues to be the limiting factor in organ transplantation, and the mortality on the waiting list can reach as much as 20 to 25 percent around the country,” Dr. Quintini says. So this ex-vivo perfusion method could expand the pool of donors by providing the necessary organ protection during perfusion so those marginal organs can be utilized in a patient.
Currently, this alternative perfusion method is being tested on pigs, and, as of press time, Dr. Quintini performed the tenth liver perfusion. One notable advantage to the ex-vivo normothermic oxygenated perfusion is successful bile production, which can suffer under cold storage and damage the preserved liver. Bile production is a very sensitive marker of liver function and so far, “every single parameter we have been looking at so far shows that our machine is far superior to ice and cold storage,” Dr. Quintini says.
The next step is to test the process on human organs, and the goal is to begin a trial within the next two years. “It’s very exciting technology,” Dr. Quintini says, adding that technology in terms of the sophistication of the heart-lung machine used during the process has greatly improved in recent years, making this new perfusion process more feasible. “We’re testing a method we believe can preserve organs in a better way by keeping organs alive during the time of storage, ultimately revolutionizing the way we practice organ transplantation today,” he says.
Significant Developments In Cleveland Clinic Transplantation
It’s a transformative time in transplant care at Cleveland Clinic with innovation and greater access on the horizon. The addition of transplant surgeons, Kareem Abu-Elmagd, MD, PhD and Andreas Tzakis, MD, PhD, will drive further technology and innovation in this space. Meanwhile, Cleveland Clinic Florida has received approval for a transplant program to extend the reach of the established and reputable program at Cleveland Clinic in Ohio.
Kareem Abu-Elmagd to Lead Ohio Transplant Programs
Cleveland Clinic’s Digestive Disease and Surgery Institute continues to strengthen its transplant expertise with the addition of Dr. Abu-Elmagd. He has joined as Director of the Intestinal Transplant Program and will take on leadership of the Transplant Center in Ohio from John Fung, MD, PhD, Chairman of the Digestive Disease and Surgery Institute. “Dr. Abu-Elmagd is a world-class specialist who will bring exciting technology and expertise to Cleveland Clinic,” says Dr. Fung.
Dr. Abu-Elmagd has led the Intestinal Rehabilitation and Transplant Center at the University of Pittsburgh Medical Center (UPMC) since its establishment in 1999 and has earned an international reputation for clinical and technical contributions to the field of transplantation. He is current president of the Intestinal Transplantation Association.
Florida Receives Approval For Transplant Program
Cleveland Clinic Florida recently received approval of its applications for heart, liver, and kidney transplant services from the Agency for Health Care Administration (AHCA).
According to research, about 15 percent of patients have to travel out of the South Florida area for liver transplants, 23 percent for kidney transplants and 33 percent for heart transplants making it an ideal location to build an accessible transplant program.
The Florida program has the clinical expertise to support a comprehensive transplant program as a collaborative partner of Cleveland Clinic in Ohio, which has more than 50 years of experience and proven protocols in organ transplantation. “Cleveland Clinic is a recognized pioneer in the field of organ transplantation,” says Dr. Fung. “Our patient outcomes and survival rates have been at or above national standards. We will work closely with our nationally recognized colleagues in Florida to implement this model of success for providing high-quality, value-based transplant services.”
Andreas Tzakis, MD, PhD, has been appointed as Director of the Transplant Center for Cleveland Clinic Florida and will have a joint appointment at Cleveland Clinic in Ohio. He previously led the Abdominal Transplantation Program at the University of Miami School of Medicine where he was also Professor of Surgery.
Dr. Fung emphasizes the milestone of recruiting two internationally known leaders in transplant innovation and what this means for the future at Cleveland Clinic in Ohio and Florida. Dr. Fung says, “We have developed close relationships with Dr. Abu-Elmagd and Dr. Tzakis over the years and we look forward to what their collaborative experience will bring to Cleveland Clinic and the patients we serve.”
Preview DDI International Education Week 2013
An innovative format and world-renowned faculty have made the Digestive Disease and Surgery Institute’s (DDSI) International Interdisciplinary Education Week symposium one of the most well-attended meetings for specialists in all digestive disciplines. “Ours is one of few opportunities where you can obtain the latest updates on the treatment of GI disorders from around the world in a week to 10 days,” says Cleveland Clinic colorectal surgeon Feza H. Remzi, MD, who co-chairs the colorectal disease symposium with his Cleveland Clinic Florida colleague, Steven D. Wexner, MD.
More than a course, DDSI International Education Week is an academic meeting based on the Digestive Disease Week model. “We provide a highly interactive experience, with hands-on workshops and live surgeries. It’s definitely cutting-edge,” says Dr. Wexner.
To register, please visit www.ClevelandClinicFloridaCME.org.
The three meetings that comprise DDSI International Education Week 2013 will be held as follows:
- February 12-17, 2013: ACDS 2013 (24th David G. Jagelman/34th Rupert B. Turnbull International Colorectal Disease Symposium), Marriott Harbor Beach Hotel, Fort Lauderdale, Florida
- February 14-16, 2013: 2nd Annual Gastroenterology and Hepatology Symposium, Marriott Harbor Beach Hotel, Fort Lauderdale, Florida
- February 17-20, 2013: 12th Annual Surgery of the Foregut Symposium, Biltmore Hotel, Coral Gables, Florida
Highlights for colorectal surgeons
The ACDS symposium combines the experience, ideas and contacts of the Cleveland Clinic in Ohio and Florida to provide a powerhouse of national and international expertise.
Attendees will be treated to numerous live cases streamed from operating rooms in Florida and Ohio. All cases will be different; all will be complex and challenging. Also offered will be a live course in advanced transanal surgery. This will be paired with the opportunity for participants to try minimally invasive, transanal equipment on inanimate trainers.
Additionally, a free paper session will take place. Anyone may submit an abstract in advance, which will be blinded and peer-reviewed. The presenters will share exciting and innovative information about cutting edge techniques and approaches prior to general dissemination of these concepts.
Key courses for gastroenterologists and hepatologists
The gastroenterology and colorectal symposium overlap to encourage cross-pollination of ideas and common interests. Three complex IBD cases will be presented for discussion by a panel of national and international experts in gastroenterology, colorectal surgery and pathology.
Another highlight is a half-day capsule endoscopy practicum designed to help gastroenterologists learn how to optimize the procedure in their own practices. Participants will be taught how to read through up to eight hours of recordings and spot findings. Hepatology topics will also be covered.
CME for foregut surgeons
Sessions on laparoscopic and open surgery, transplantation and surgery for malignancies of the liver, stomach and esophagus are scheduled for February 17 and 18. Other sessions will include discussions on surgical management of gastric cancer, medical and surgical management of gastroparesis, and a special feature on pancreatic islet cell transplantation for chronic pancreatitis.
A separate session will be devoted to bariatric and metabolic surgery. Obesity surgery pioneer Walter Porris, MD, will attend his named lecture, which will be devoted to the management of complications and reoperations.
Finally, a series of live surgeries will be televised from Cleveland Clinic Florida and Ohio and from the European School of Laparoscopic Surgery in Belgium.
How to register or for more information
More details and registration forms are available on www.ClevelandClinicFloridaCME.org.
Digestive Disease Clinical Trials
Highlights of the actively enrolling clinical trials in both Cleveland and Florida:
|Trial name ||Site principal investigator |
|A Randomized Controlled Trial to Compare the Functional Outcome and Quality of Life in Patients with Low Rectal Cancer Who Undergo a J Pouch or a Side-to-End Coloanal Anastomosis ||Massarat Zutshi, MD (Cleveland) |
Steven Wexner, MD (Florida)
|A Pain Relief Study Utilizing the Infiltration of a Multivesicular Liposome Formulation of Bupivacaine, EXPAREL: A Phase 4 Health Economic Study in Adult Patients Undergoing Ileostomy Reversal (IMPROVE — Ileostomy Reversal) ||Jon Vogel, MD (Cleveland) |
Steven Wexner, MD (Florida)
|A Multicenter, Double-Blind, Randomized, Phase 3 Study to Compare the Efficacy and Safety of Intravenous CXA-201 with that of Meropenem in Complicated Intra-abdominal Infections ||Giovanna da Silva, MD (Florida) |
|ACOSOG Z6051: A Phase 3 Prospective Randomized Trial Comparing Laparoscopic-Assisted Resection Versus Open Resection for Rectal Cancer ||Luca Stocchi, MD (Cleveland) |
Steven Wexner, MD (Florida)
|An Investigation of the Treatment of Fecal Incontinence Using the TOPAS Sling System for Women (TRANSFORM) ||Massarat Zutshi, MD (Cleveland) |
Dana Sands, MD (Florida)
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