Burst of accumulated zinc shows how the mineral boosts immune function, suggesting ways to improve health: In mice, zinc helps thymus of the immune system regrow and immune-cell recovery after bone marrow transplant

Zinc’s immune-boosting properties are well established, but researchers have not known exactly how it works. In a new study published online March 25 in the journal Blood, Researchers from the Fred Hutchinson Cancer Research Center reveal two ways that the mineral supports immunity and suggest how it can be used to improve health.

Using mice, the team discovered that zinc is needed for the development of disease-fighting immune cells called T cells and causes the regeneration of the thymus, the immune organ that produces T cells.

“This study adds to our knowledge of what zinc actually does in the immune system and proposes a new therapeutic strategy to improve the recovery of the immune system,” said senior author Dr. Jarrod Dudakov, an immunologist at Fred Hutch.

The study also showed that an experimental compound that mimics the action of zinc in this organ works even better than the natural mineral to promote immune recovery.

“We are now investigating how zinc may fit into our other discoveries of how the immune system repairs itself and may eventually lead to therapies to improve immune function for people who receive a blood stem cell transplant for a blood cancer or people with a chronic immune system. Decline that accompanies aging, “said Dudakov.

Thymus regeneration and immune function, and zinc

Earlier, Dudakov and his team described the molecular pathways and cell types that govern how the thymus of the immune system repairs itself after injury. Such treatments may improve the efficacy of the vaccine and accelerate thymic regeneration following stressors such as chemotherapy, blood stem cell transplantation, and radiation exposure.

Dudakov began studying zinc a few years ago when Dr. Lorenzo Iovino, the study’s first author and a research assistant at Fred Hutch, joined Dudakov’s lab. Because the researchers knew that low levels of zinc are linked to fewer anti-infective T cells and a shrinking thymus, where T cells develop, Dudakov and Iovino investigated how to supplement with zinc in mouse models where the immune system is damaged.

Iovino, who is also a doctor for blood stem cell transplantation, had shown in a previous study that zinc can increase immune recovery in patients undergoing stem cell transplants for multiple myeloma in the blood.

But the study did not explain why zinc helped.

Zinc is essential for T cell development and thymic regeneration

As in humans, Iovino and Dudakov found that the braces of mice deprived of zinc in their diet shrank and produced significantly fewer mature T cells, even after as little as a three-week diet without zinc. Iovino was able to show that without zinc, T cells cannot mature completely.

He also found that zinc deficiency slows the recovery of the number of T cells after mice have received immunosuppressive treatments similar to those given to patients who are to receive a blood stem cell transplant.

Conversely, extra zinc accelerates this process, and T cells recover faster than normal. The team saw a similar result in a mouse model of blood stem cell transplantation.

“So we had a consistent result of a better reconstitution of the thymus and also a better reconstitution of T cells in the peripheral blood after zinc supplementation,” Iovino said. “But we still did not know exactly how zinc worked.”

Iovino discovered that it was the change in zinc levels around cells that release an important regenerative factor that seemed to start the regeneration processes of the thymus. T cells accumulate zinc as they develop, but release it after a harmful event – such as radiation – kills them.

Cells use a molecule called GPR39 to sense a change in external zinc, and Iovino found that an experimental compound that mimics rising external zinc levels by stimulating GPR39 can also promote the release of renewal factors and thymic regeneration.

“What we think is going on is, when you give zinc supplements, which accumulate in the developing T cells. It is stored and stored and stored, then the damage and the zinc will be released,” Dudakov said. “Now you have more zinc than you normally would, and it can start this regenerative path. With the experimental compound, we can only target GPR39 directly and basically get the same effect without any of that pretreatment.”

Getting to the clinic

There is still a lot to learn before they can turn their results into therapeutic strategies, the researchers said.

Transplant patients are already receiving mineral supplements, so if extra zinc were to be incorporated into their treatment regimens, it would be important to ensure that everyone who receives it really has a zinc deficiency. Iovino believes that many patients can be, but right now there is no good test to assess this. He is currently working on developing one that would first be used to help researchers determine if patients’ zinc status correlates with immune recovery after blood stem cell transplantation.

Dudakov will continue to use GPR39-stimulating compounds as therapies to improve thymic recovery after acute injury such as pre-transplant radiation. The team is currently screening similar associations to find someone who can be more effective.

He and Iovino also work to determine if such compounds can help with thymic regeneration in other environments. Unfortunately, our thymus also shrinks slowly and reduces its T-cell production as we age. Dudakov and Iovino would also like to know if this chronic degeneration could be slowed down by increasing the body’s regenerative processes.

“Our lab continues to put together the molecular players that contribute to the regrowth of the braces,” said Dudakov. “Ultimately, we strive to develop therapies that trigger natural regeneration and restore immune health.”

The study was funded by the National Institutes of Health, the American Society of Hematology and The Rotary Foundation.


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