Two grants supporting research on defects in the function of the immune system are leading to discoveries that could create gene therapies for systemic lupus erythematosus and stop tumor growth.
Both of these studies are taking place in the labs of Laura Conforti, PhD, associate professor in the department of internal medicine’s nephrology and hypertension division.
Delivery of Gene Therapies for Patients With Lupus
Conforti recently received a two-year, $395,000 grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to explore how nanotechnology could be used to deliver gene therapies in individuals with autoimmune diseases, particularly systemic lupus.
Autoimmunity is the failure of an organism to recognize its own makeup, resulting in an immune response—or fight—against its own cells and tissues. Lupus ultimately results in damage of multiple organs, including the kidney, brain and heart.
Conforti’s team, which also includes researchers associated with the College of Engineering and Applied Science, has found a defect in the behavior of certain ion channels—or proteins that control the functionality of immune cells—that may contribute to the hyperactivity of human T-lymphocytes in patients with systemic lupus.
T-lymphocytes, or T cells, are white blood cells that play a large role in the immune response.
Previous research has also shown that patients with lupus show defects in the response to antigens, or foreign molecules that trigger the immune system. A characteristic of these defects is an exaggerated calcium signaling.
"Calcium ions normally increase inside a T cell when it responds to an antigen,” she explains. "Calcium ions are critical for the functionality of the T cells, and any intervention that limits the build-up of calcium in the immune cells suppresses their function.
"The influx of calcium is controlled by ion channels which regulate the flux of ions in and out of the cells. In lupus, this process is out of control, and suppressing ion channel function could be used to inhibit the immune system in these patients.”
In this project, Conforti is using unique nanotechnology to produce tiny (nano) liposomes (bubbles) filled with therapeutic agents (immunosuppressive therapies) to send through the body to "knock out” the ion channel that causes the defects in calcium signaling and the progression of the illness.
These liposomes will also be constructed in such a way that they will be able to attack only specific T cells that are responsible for the disease, while the other immune cells needed to fight infections will still be able to work.
"This therapy will hopefully protect the body from the action of harmful T cells but will still leave the immune system able to function correctly to do its job,” she says. "Immunosuppressive therapies often have terrible side effects. If this therapy is proven to be beneficial, we are able to deliver treatment to a targeted cell and avoid undesirable effects for the patient.”
Lack of Oxygen and Ion Channels Affect Tumor Growth
Conforti’s laboratory is also funded by a National Institutes of Health R01 renewal grant for $1.2 million to continue looking at how lack of oxygen in tumors can lead to their progression.
"In autoimmune diseases, the immune system is overworking,” she says. "However, the opposite is true in tumors. We have found that low levels of oxygen in the tumors, otherwise known as hypoxia, suppresses ion channels and ultimately the ability of T cells to fight the tumor.
"In this study, we are trying to discover by which mechanisms hypoxia inhibits ion channel levels and ultimately T cell function to find out how we can manipulate them to maintain the T cell function and stop tumor growth.”
This topic, led by Ameet Chimote, PhD, a postdoctoral fellow in Conforti’s lab, is the focus of an article by this group in the Journal of Biological Chemistry.