The La Jolla Institute provides world-class
immunological expertise in a multitude of autoimmune and viral diseases as well
as cancer. Located in the UC
San Diego Science Research Park, the La Jolla Institute provides the scientists
of the Center for Type 1 Diabetes Research with essential state of the art core
facilities such as the novel 2-photon microscope with imaging capability that
has been used to successfully track live destruction of beta cells.
COMBINING IMMUNOLOGY AND BETA-CELL AUGMENTATION RESEARCH - A KEY LINK
The synergy between scientists in the two essential disciplines of
immunology and beta-cell augmentation /regeneration is timely and
highly desirable, because intricate links between the immune system and
the beta cell need to be explored and better understood. Beta cell
replacement will not become a cure without keeping the autoimmune
response in check and immune modulators alone will not be effective in
patients who lost most beta cells. In addition, the side effects from
long-term immune suppression constitute an intolerable risk for type 1
diabetes patients. Therefore, a strong translational research focus of
this center is the development of combination therapies. These will
consist of a reduced course of systemic immunomodulation, agents that
foster beta cell survival or replenishment and, most importantly,
approaches that establish long-term beta-cell specific tolerance. The
research on the induction of beta-cell specific immune tolerance
(involving DNA vaccinations to induce regulatory T cells and similar
approaches) is being conducted at the La Jolla Institute for Allergy
& Immunology, and carried out by a team led by Dr. Matthias von Herrath.
Close collaborations with some of the companies that
bring such approaches to the clinic (Novocell, Bayhill Therapeutics and
Genentech) have been established.
REAL-TIME IMAGING OF THE PANCREAS DURING DEVELOPMENT OF DIABETES
Our principal aim is to visualize islet antigen-specific T cell trafficking in the pancreas to understand the kinetics of diabetes development.
Ken Coppetiers, Ph.D.
There is a broad consensus among investigators on the fact that particular cell types of our immune system are responsible for the destruction of beta cells in type 1 diabetes. Numerous reports indicate that these cells, which are somehow aberrantly activated against the body's own beta cells, accumulate around the islets and cause them to die. The traditional way to study the principal cell type involved, namely 'T cells', is either to make sections of pancreas tissue (see picture 1) or to analyze the cells present in blood drawn from patients at diagnosis.
Unfortunately, in both cases the information that can be derived from such samples has limitations. Given the relative inaccessibility of pancreas tissue, most studies have to be done on organs from deceased patients and these may represent only the final stage of the disease process. When analyzing the blood, one can easily imagine that it remains questionable as to how relevant the cells are to the disease process that's actually going on around the pancreatic islets. In addition, both approaches only yield insight into how cells look like at a given time point, while the dynamics of their interactions remain elusive.
In order to unveil how the aberrant immune response looks like 'in real-time', while it is occurring, we have developed a model system in mice that allows us to track the movements of individual cell types, known to contribute to type 1 diabetes development. Essentially, we have acquired a highly sophisticated microscope that enables us to look inside the pancreas and the pancreatic lymph nodes (where many of the destructive T cells are activated) to see what is happening in these intact organs in living animals.
We are, to our knowledge, the first in the world looking at the dynamics of T cells in the pancreas of living animals during type 1 diabetes development.
The pancreatic islets can be seen in green, while the vasculature is stained magenta. Our approach allows for the detection of cellular interactions in great detail.
HISTOLOGICAL ASSESSMENT OF TYPE 1 DIABETES
Our principal aim is to characterize the cellular events causing type 1 diabetes in patients
Although our knowledge on the various aspects of diabetes development in the NOD mouse model is substantial and keeps expanding at dramatic pace, the dataset on histopathologic features of type 1 diabetes in patients remains largely stagnant. Detailed histological study of the disease is of course hampered by the inherent inaccessibility of the target organ, and as a consequence most of what we know is derived from retrospective collections of formalin-fixed, paraffin embedded autopsy pancreases. One of the most promising initiatives is the recent establishment of the Network for Pancreatic Organ Donors with Diabetes (nPOD, www.jdrfnpod.org), a collaborative effort sponsored by the Juvenile Diabetes Research Foundation (JDRF) which aims to support the scientific community by the optimal procurement of pancreas specimens and distribution to nearly 25 type 1 diabetes-focused scientific institutions around the world, including the von Herrath lab.
LEFT: CD8 T cells (red) can be seen attacking the beta cells (green)
RIGHT: The CD8 T cells 'recognize' the beta cells (here in yellow) owing to the expression of MHC I (red). The latter molecule is aberrantly upregulated in recent-onset diabetic individuals, although it is unclear what causes this.
