Increasing levels of a certain protein in blood stem cells so that the immune system stops attacking insulin cells in the pancreas could be a way to halt type 1 diabetes, according to a new study reported in Science Translational Medicine.
Researchers led by those at Harvard Medical School’s Boston Children’s Hospital in Massachusetts found that they could reverse hyperglycemia in diabetic mice by modifying their defective blood stem cells to increase production of a protein called PD-L1.
In type 1 diabetes, the pancreas fails to produce enough insulin. Without sufficient insulin, the body cannot convert blood sugar, or glucose, into energy for cells, with the result that it builds up in the bloodstream.
Over time, high blood sugar, or hyperglycemia, leads to serious complications such as vision problems and damage to blood vessels, nerves, and kidneys.
The body produces insulin in the pancreas, which is an organ that sits just behind the stomach. It contains insulin-producing beta cells that normally sense glucose levels in the blood and release just the right amount of insulin to keep sugar levels normal.
In type 1 diabetes, a fault in the immune system makes inflammatory T cells — which usually react to “foreign” material — attack beta cells in the pancreas. Nobody knows exactly how this comes about, but scientists suspect that a virus, or some other trigger in the environment, sets it off in people with certain inherited genes.
The “holy grail” of scientists seeking a cure for type 1 diabetes is to find a way to prevent or stop the immune attack on the beta cells.
Several approaches have been tried, including “cytostatic” drugs to halt cell activity, vaccines that try to alter the immune response, and treatments that use stem cells taken from umbilical cords.
‘Defective blood stem cells’
One approach that has shown more promise is the “autologous bone-marrow transplant,” which tries to “reboot” a person’s immune system using their own blood-forming stem cells. However, even this method has not proven to be as effective as doctors had hoped it would be.
Now, in the new study, the researchers — who were led by senior investigator Paolo Fiorina, an assistant professor of pediatrics at Harvard Medical School’s Boston Children’s Hospital — might have discovered why treatments that use the person’s own blood stem cells may not always work.
“We found that in diabetes,” explains Prof. Fiorina, “blood stem cells are defective, promoting inflammation and possibly leading to the onset of disease.”
The defect that they discovered is that the blood stem cells — that is, the progenitor cells that give rise to mature cells — do not produce enough of a protein called PD-L1 that reigns back attack by T cells.
They found this using gene expression profiling to discover which proteins blood stem cells make. They found that the genetic network of pathways that controls PD-L1 production is different in the blood stem cells of diabetic humans and mice. This difference is enough to stop PD-L1 being produced, even in the early stages of the disease.
‘Reshaping the immune system’
PD-L1 is an “immune-checkpoint” molecule that helps to keep the immune system in balance. When it plugs into another protein called PD-1 that sits on the surface of T cells, it inactivates them.
The scientists ran a number of experiments wherein they treated the blood stem cells so that they made more PD-L1 and then tested them on human and mouse cells. They found that the modified blood stem cells reduced the inflammatory immune reaction in both human and mouse cells.
When they injected diabetic mice with the modified stem cells, they found that the cells traveled to the animals’ pancreases and reversed their hyperglycemia in the short-term. In the longer-term, a third of the mice maintained normal levels of blood sugar for the rest of their lives.
“There’s really a reshaping of the immune system when you inject these cells,” notes Prof. Fiorina.
The researchers experimented with two ways of getting the blood stem cells to make more PD-L1: one that inserted a healthy gene for PD-L1, and another that modified the cells’ protein machinery with a “cocktail” of three small molecules. Both methods had the same diabetes-reversing effect.
“The beauty of this approach is the virtual lack of any adverse effects, since it would use the patients’ own cells.”
Prof. Paolo Fiorina
In the meantime, the researchers are working with a private company to improve the method that uses the cocktail of small molecules. They hope to launch a clinical trial of this approach as a treatment for type 1 diabetes.
https://en.shafaqna.com/wp-content/uploads/2017/11/diabetes-1.jpg240360Yahyahttps://en.shafaqna.com/wp-content/uploads/2018/02/new-logo-s-2.pngYahya2017-11-18 22:09:362017-11-18 22:09:36Curing type 1 diabetes by blood stem cells!