People with Type 1 diabetes must adhere to their insulin regimens consistently every day, taking injections of the hormone via syringe, insulin pump, or other devices. This course of treatment is a life sentence in the absence of suitable long-term remedies.

When blood sugar levels change, pancreatic islets control insulin production, and in Type 1 diabetes, the body’s immune system targets and destroys these insulin-producing cells. Over the last few decades, islet transplantation has gained popularity as a potential therapy for Type 1 diabetes.

Type 1 diabetes patients may no longer require insulin injections if healthy transplanted islets are found, but transplantation attempts have hit snags as the immune system continues to reject new islets. Immunosuppressive medications now on the market provide insufficient protection for transplanted cells and tissues, as well as a slew of unpleasant side effects.

Now, a group of Northwestern University researchers has discovered a method for making immunomodulation more effective. The approach re-engineers the commonly used immunosuppressant rapamycin using nanocarriers. The researchers created a new type of immunosuppression using these rapamycin-loaded nanocarriers that can target specific cells relevant to the transplant while not inhibiting broader immune responses.

Rapamycin is a well-studied and widely used immunosuppressant that has a wide range of impacts on numerous cell types throughout the body throughout various types of treatment and transplants. Rapamycin is usually given orally, but the dosage must be carefully managed to avoid harmful consequences. However, in circumstances like islet transplantation, it is ineffective at lower doses.

The team wanted to see how the drug could be improved by putting it in a nanoparticle and “controlling where it goes within the body.”

“To avoid the broad effects of rapamycin during treatment, the drug is typically given at low dosages and via specific routes of administration, mainly orally,” says Evan Scott, one of team leader. “But in the case of a transplant, you have to give enough rapamycin to systemically suppress T cells, which can have significant side effects like hair loss, mouth sores and an overall weakened immune system.”

After a transplant, immune cells known as T cells will reject newly introduced foreign cells and tissues. Immunosuppressants are used to counteract this effect, but they can also compromise the body’s ability to fight other infections by shutting down T cells across the body. However, the researchers designed the nanocarrier and medication combo to have a more targeted effect. Rather than directly influencing T cells, which is rapamycin’s most common therapeutic target, the nanoparticle would be designed to target and modulate antigen presentation cells (APCs), allowing for more targeted, controlled immunosuppression.

Using nanoparticles also allowed the team to give rapamycin by subcutaneous injection, which they discovered employs a distinct metabolic pathway to minimize substantial drug loss in the liver after oral treatment. To be effective, this route of delivery necessitates a much lower amount of rapamycin — around half the normal dose.

“We wondered, can rapamycin be re-engineered to avoid non-specific suppression of T cells and instead stimulate a tolerogenic pathway by delivering the drug to different types of immune cells?” Scott adds. “By changing the cell types that are targeted, we actually changed the way that immunosuppression was achieved.”

The researchers used mice to test their idea, giving them diabetes and then treating them with a combination of islet transplantation and rapamycin administered by the usual Rapamune® oral regimen and their nanocarrier formulation. Mice were given injections of the changed medication starting the day before transplantation and continuing every three days for two weeks.

A 100-day trial showed that mice with diabetes were completely cured, but the treatment is expected to endure as long as the organ is in place. The researchers also found that animals treated with the nano-delivered medicine showed a “robust immunological response” when compared to mice given normal pharmacological treatments.

The idea of using nanodelivery to improve and regulate drug side effects isn’t new, according to Scott.

“But here we’re not enhancing an effect, we are changing it – by repurposing the biochemical pathway of a drug, in this case mTOR inhibition by rapamycin, we are generating a totally different cellular response.”

The discoveries made by the scientists could have far-reaching consequences.

“This approach can be applied to other transplanted tissues and organs, opening up new research areas and options for patients,” adds Guillermo Ameer, one of the study lead authors. “We are now working on taking these very exciting results one step closer to clinical use.”

Jacqueline Burke, the study’s lead author, said she couldn’t believe her readings when she saw the mice’s blood sugar drop from very diabetic to normal levels. She kept checking to make sure it wasn’t a one-time occurrence, but the number remained consistent over months.

They consider this study a breakthrough and say it could have far-reaching ramifications for diabetes research in the future.

Source: 10.1038/s41565-021-01048-2

Image Credit: Getty

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