Dr. Pandelakis Koni, immunologist, has developed a conditional knockout mouse in which cellular communication that triggers the immune response to an invader can be selectively stopped. His mouse is featured in a special February issue of Genesis: The Journal of Genetics and Development, which contains 43 papers documenting the development of new animal models available for use by researchers across the world.
Dr. Koni is studying a type of surveillance cell called dendritic cells that stand on patrol throughout the body looking for invaders. "If you have an infection or some foreign agent in your body, dendritic cells detect it and are very good at picking it up and delivering it to the right place to switch on your immune system," he said. "They literally eat up bacteria, put them inside their vesicles, where a lot of acids and digestive enzymes chop them up. Eventually, a small piece of protein from the bacteria makes its way to the surface of the dendritic cell," he explained.
This is where Dr. Koni interrupts the process. Dendritic cells have on their surface major histocompatibility complex molecules, or MHC molecules, that take up these pieces of protein and literally hold them up for another immune system cell called T cells. "The T cell comes along with its own surface protein which is designed so it can survey that surface." Those T cell receptors lock onto the MHC molecule on the dendritic cell. The T cell then switches on, begins to proliferate and determines what other immune components it needs to summon.
"The conditional knockout we made enables us to eliminate the MHC molecule from different types of dendritic cells," Dr. Koni said. The four general types of dendritic cells are Langerhans' cells primarily found in the skin, myeloid dendritic cells found throughout most solid body tissue, plasma cytoid dendritic cells thought to be involved in clearing viral infections and lymphoid tissue dendritic cells found in the lymph nodes and spleen.
He's most interested in the plasma cytoid and lymphoid tissue types not only because of their role in natural immunity, but because they are thought to have an important role in preventing autoimmune disease.
"We think they might also be involved in controlling your immune system so you don't attack yourself," Dr. Koni said. "We want to be able to get rid of the MHC molecule to see not only what happens to your ability to fight viral infections or bacterial infections, but to see what happens to your ability to protect yourself from autoimmunity."
He's genetically engineered a mouse by inserting DNA recognition signals called loxP on either side of the gene that makes the MHC molecule involved in signaling T-cells. This mouse can be bred with others called CRE mice; CRE is a bacterial enzyme whose natural function is to recognize loxP, remove it and whatever is in between. So the offspring of these two mice will have the MHC molecule selectively removed from the varying types of dendritic cells. Right now Dr. Koni is working on developing CRE mice that remove the molecules from the plasma cytoid and lymphoid tissue dendritic cells. "I'm relying on the mice that we make to study autoimmune disease," he said.
Multiple sclerosis occurs when the immune system attacks the insulation of nerves called myelin, ultimately resulting in loss of motor and sensory function. "Some people say it's a virus that triggers (the attack). But whatever triggers it, you start to attack your cells with immune-based weapons that rely on the whole system being switched on. In that situation, we would like to be able to switch it off again," he said.
In type 1 diabetes, pancreatic islet cells undergo similar attack, resulting in insulin deprivation and a myriad of related problems. "We don't know what kicks (the immune system) off or how you can prevent it from continuing. You need to know how to do that, how you can stop the autoimmune disease from continuing," Dr. Koni said.
He's interested as well is understanding basic immunology. "How do dendritic cells talk to T cells and how can that whole network of regulation and keeping everything under control fail? What are the molecules involved in how normal works and how it goes wrong when you have autoimmune diabetes?"
Dr. Koni's research is funded by the National Institutes of Health.