Autoimmune diseases are not only hard to diagnose, but are also challenging to prevent and manage appropriately. The overall morbidity and long-term complications due to diabetes type 1, multiple sclerosis, rheumatoid arthritis, and other autoimmune diseases is becoming a major concern throughout the world. Ongoing research by investigators of UC San Francisco is expected to help in combating the issue by manipulation of the human immune system.
The research team under immunologist Mark Anderson (who is also a professor at the UCSF Diabetes Center) suggested that certain immune cells (like eTAC) may help in modulation of immune response. The results of this remarkable discovery are published in the September issue of the peer reviewed journal Immunity.
Details of the study:
The experiments conducted in animal subjects concluded that eTAC is a normal immune component that is present in a variety of immune tissues like lymph nodes and the spleen. An investigational study suggested that manipulation of eTACs can stop the pancreatic destruction in the pancreas of a diabetic mouse.
The research team discovered that the phenomenon of ‘peripheral tolerance’ is responsible for autoimmunity within the body that can be tracked by using a key regulatory protein, AIRE, with the help of green fluorescent protein (GFP). Anderson discovered the functional and metabolic role of AIRE almost a decade ago while working on the specialized cells of thymus. AIRE contributes to the phenomena of central tolerance (the initial training in thymic tissue where immune cells learn to distinguish between self from non- self).
These immune cells are functionally dentritic cells that are a rather rare variety of immune cells (only 3% of all immune cells are eTACs). Anderson explained that eTACs are even rarer forms of dentritic cells. Multiple research projects are currently underway using dentritic cells for the management of cancers by boosting the production of complementary immune cells, also known as T cells. Unlike most microbial invaders, cancer cells (being the abnormal human cells) are mostly successful in evading host immune responses. However, when stimulated by dentritic cells, the T cells are better able to locate and destroy cancer cells.
Anderson’s team identified that eTACs can also manage autoimmunity by counteracting hyper-immune responses by the tissues by turning off the T- cells by demonstrating “self” molecules on normal tissues.
“The mouse model we are working with involves using T cells that normally attack the islet cells of the pancreas, specifically by recognizing a molecule called chromagranin A that is present on islet cells. But if the eTACs can get to the T cells first and display chromagranin A, they can prevent T cells from attacking the islets.”
Currently, Anderson is working at expanding the total number of eTACs outside the body. He said:
“We need to figure out how to grow a lot of these cells, to load them up with whatever molecule it is that we want to induce tolerance to, and then to load them back into a patient. Such a strategy could help selectively shut down an unwanted immune response, such as the anti-islet immune response in type 1 diabetes.”
Anderson explained that the mechanism of shutting down hyperactive immune system is simple. Once the eTACs comes in contact with a T cell, the aggressive T cell immune functions are shut-down (the activity is different when T cell come in contact with dentritic cells leading to activation of former to kill/ attack tissues where molecule is populated.
Why eTACs are so different in activity and functions than dentritic cells?
Anderson and his research team discovered that activation of T- cells is a two step process.
1. Display and recognition of foreign molecules
2. Activation of T-cells via B7-1 and B7-2 (the molecular arms that are present on dentritic cells but absent on eTACs)
The source of origin of eTACs is also bone marrow like other immune cells and blood cells.
Anderson’s Research Team:
Other UCSF researchers who contributed to this study are Jay Gardner, MD, PhD, and Todd Metzger; research associates Anna Krawisz, Wen Lu, and Kellsey Johannes; postdoctoral fellows Eileen McMahon, PhD, and Byron Au-Yeung PhD; and Arthur Weiss, MD, PhD, chief of rheumatology.
Contributors from National Institute of Diabetes and Digestive and Kidney Diseases include Jeffrey Price, MD and Kristin Tarbell, PhD
Researchers from Washington University in St. Louis, Ansuman Satpathy and Kenneth Murphy, MD, PhD, also participated in the research.
Photo from http://www.pennmedicine.org