In millions of people worldwide, the pancreas is under attack! Damage to cells in the pancreas leads to type 1 diabetes, this destruction has largely been hidden from view – until now. Investigators at the La Jolla Institute for Allergy & Immunology have produced the first cellular movies demonstrating the destruction underlying type 1 diabetes in real-time mouse models, providing the worldwide scientific community with insights into this disease process as never before possible. This detailed, dynamic view might greatly affect the directions in diabetes type 1 R&D.
Matthias von Herrath, M.D. one of the world’s leading type 1 diabetes experts, and director of the Diabetes Research Center at the La Jolla Institute for Allergy & Immunology, explained:
“We are presenting the first images at cellular resolution of type 1 diabetes as-it-unfolds. Being able to view these insulin-producing cells while they interact in the pancreas, rather than in a static state under the microscope, will greatly enhance our ability – and that of the broader scientific community – to find interventions for type 1 diabetes.”
A report on the scientific findings of the study, in conjunction with the cellular movies taken by the scientists, are published online in the Journal of Clinical Investigation. The movies are freely available and can be viewed at the end of the article. Ken Coppieters, Ph.D., formerly of the La Jolla Institute and now at Ghent University, Belgium, is first author on the investigation. Dr. von Herrath is senior author.
George Eisenbarth, M.D., Ph.D., a prominent type 1 diabetes researcher and executive director of the Barbara Davis Center for Childhood Diabetes in Colorado, stated:
“This live imaging of the white blood cells that cause diabetes is quite remarkable. These images provide critical information about the disease process, in particular showing us the reasons why the beta cell destruction (underlying type 1 diabetes) occurs very slowly over time. Such information may enable new approaches to stop the destruction process, with the ultimate goal being prevention.”
This research is a shining light on cell processes that previously had to be concluded from lab experiments, photos, or computer modeling.
According to Bart Roep, M.D., Ph.D, a diabetes expert and professor at Leiden University Medical Center in the Netherlands, the work was a technological breakthrough.
Dr. Roep said:
“I thought this was unfeasible (in vivo imaging of type 1 diabetes). But thankfully, they proved me wrong. These videos show the cellular interactions in the incredible detail, things are moving. The information they have found thus far is amazing and this is just the beginning of the knowledge that can be gained through this technology.”
Dr. Coppieters explains that the movies have provided numerous remarkable insights:
“We have drawn several scientific conclusions from these studies in mice that we believe will influence future therapeutic directions. We are continuing our studies and hope that other researchers will also find these movies valuable in enhancing their research efforts.”
In the movies, immune system T cells (the body’s cellular soldiers) can be seen frantically dashing about looking for insulin-producing beta cells. The T cells wrongly attack and destroy the insulin-producing beta cells, eventually leading to type 1 diabetes.
The revolutionary investigations were enabled through the use of a two-photon microscope and a novel procedure created by Dr. von Herrath that allowed the microscope’s use in the pancreas. The pancreas is a small, soft, and difficult organ to access, that has long presented scientists with significant challenges. To date, researchers have used the two-photon to examine the liver, lymph nodes and other organs in vivo, but has never been used to examine the pancreas.
Dr. von Herrath, said:
“The two-photon microscope enables researchers to “see” into living tissues at a much greater depth than conventional imaging methods. It uses intense pulses of light that enable us to monitor interactions of cells without destroying them.”
Significant funding for the two-photon microscope was provided by The Brehm Coalition, a unique type 1 diabetes research collaboration. The Juvenile Diabetes Research Foundation (JDRF) was a major contributor to the research investigations. Richard Insel, M.D., the JDRF’s chief scientific officer, noting the award targets high-risk, high-reward endeavors, explained:
“Dr. von Herrath was one of a very limited, select group of scientists chosen to receive funding through the JDRF Scholar Award program. We are thrilled that Dr. von Herrath’s research has provided new insights into the pathogenesis of type 1 diabetes that could lead to novel therapeutic approaches. This is just the kind of pioneering research that the Scholar Award was designed to encourage.”
According to Dr. Coppieters, the movies show the exact behaviors of various cells:
“We’re able to see how the beta cells eventually die and how the immune T cells access the pancreas from the blood stream.” Among the several insights the investigators obtained, they were able to distinguish the exact blood vessels where the T cells (usually these cells do not live in the pancreas) enter the pancreas, as well as how the T cells launch an attack and the time sequence of events.
Furthermore, the movies highlight intriguing data about the beta cell destruction process. Dr. Coppieters said: “The T cells move randomly throughout the pancreas until they encounter the beta cells, where they slow down and release toxic substances that eventually kill the beta cells. What was more surprising is that this “kiss of death” takes quite a while, elaborate calculations indicated a timeline in the order of hours (to kill a few beta cells).”
In addition, the team discovered that a significant number of T cells are required in the mice – tens of millions – to produce massive beta cell destruction.
Dr. von Herrath said:
“These factors may help explain the long pre-clinical stage in type 1 diabetes, since T cell numbers in the human pancreas are thought to be significantly lower than in mice. This means that the autoimmune attack is already ongoing for years before the number of beta cells drops below a critical threshold, resulting in clinical diagnosis.” Dr. von Herrath notes that 90% of beta cells are killed in humans prior to the disease being diagnosed. “From a therapeutic perspective, these studies suggest that we may need to find a way to prevent the T cells from accessing the pancreas in the first place, since once they do, they have the ability to destroy several beta cells at a time.”
Written by Grace Rattue