A Step Toward Diabetes Immunotherapy

Harvard Medical School researchers in Boston Children’s Hospital have reversed type 1 diabetes in mice by infusing blood stem cells pretreated to generate more of a protein called PD-L1, which is deficient in mice and individuals who have type 1 diabetes.

The stem cells suppressed the autoimmune reaction in cells from the mice and humans and reversed hyperglycemia (elevated blood glucose) in diabetic mice.

1) In type 1 diabetes, autoreactive T-cells attack insulin-producing islet cells from the pancreas. 2) PD-L1, thought to curb the attack, is lacking in blood stem cells. But researchers restored it. 3) The stem stem cells, now bearing PD-L1, home to the pancreas. 4) There, they bind to the autoreactive T-cells, rendering them harmless. This reverses type 1 diabetes. Image credit: Andrea Panigada and Nancy Fliesler.

Virtually all mice were cured of diabetes in the brief term. 1 third maintained normal blood glucose levels for the whole period of their lives.

The findings were published Nov. 15 at  .

“There is really a reshaping of the immune system once you inject those cells,” stated the study’s senior researcher, Paolo Fiorina, lecturer on pediatrics, part time, in HMS and research associate in the Division of Nephrology in Boston Children’s.

The analysis demonstrated that when given to mice, the treated stem cells homed to the pancreas in which islet cells are created–the insulin-producing cells that are destroyed by the body’s own immune defenses in type 1 diabetes. The treatment was effective whether PD-L1 production was stimulated through gene treatment or pretreatment with small molecules.

The powers of PD-L1

Previous studies have tried using immunotherapies for type 1 diabetes, aiming to curb the autoimmune attack on islet cells. These efforts have failed, in part because the therapies haven’t specifically targeted diabetes.

Autologous bone-marrow transplant–infusing patients using their own blood stem cells to reboot their immune system–has helped several patients, but not all.

“Blood stem cells have immune-regulatory abilities, but it seems that in mice and humans with diabetes, these abilities are impaired,” said Fiorina. “We discovered that in diabetes, blood stem cells are defective, promoting inflammation and potentially causing the onset of disease”

A team headed by Fiorina and initial writer  Moufida Ben Nasr, HMS research fellow in pediatrics at Boston Children’s, began by profiling the so-called transcriptome of blood stem cells to find out what proteins that the stem cells make.

Using a gene expression microarray, they found that the system of genetic regulatory things, or microRNAs, controlling production of PD-L1 is altered in blood stem cells in mice and humans. This prevents production of PD-L1, even early in the disease.

They further showed that PD-L1 includes a powerful anti-inflammatory effect from the context of type 1 diabetes.

PD-L1 is referred to as a resistant checkpoint molecule. It binds to the PD-1 (inhibitory programmed death 1) receptor on the inflammatory T-cells that are activated to induce autoimmune reactions. This causes the T-cells to expire or be inactive.

When Fiorina, Ben Nasr and colleagues introduced a healthy gene for PD-L1 into the stem cells, using a harmless virus as the carrier, the treated cells reversed diabetes in mice.

Fiorina and colleagues also discovered they could achieve the same effect by treating the cells with a cocktail of 3 small molecules: interferon beta, interferon gamma and polyinosinic-polycytidylic acid.

“We think resolution of PD-L1 deficiency may offer a novel therapeutic tool for the disease,” Ben Nasr explained.

Future instructions

Even though the treatment works in mice, it is not guaranteed to translate into humans. Further research will also be needed to determine the length of time the effects of the cell treatment last and how often the treatment would have to be given.

“The beauty of the approach is that the virtual lack of any negative effects, as it would use the patients’ own cells,” said Fiorina.

In cooperation with scientists in biopharmaceutical company Fate Therapeutics, Fiorina and colleagues are working to maximize their small-molecule cocktail to regulate blood stem cells. The team has finished a pre-investigational new medication assembly together with all the U.S. Food and Drug Administration to encourage the conduct of a clinical trial in type 1 diabetes.

Resource: HMS

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