How 'Blood' 'Zinc' Works to Boost Immunity

Zinc's immune-boosting properties have been recognized, but we're still figuring out how it works

Research has also shown that an experimental compound that mimics zinc's actions in this organ works even better than the natural mineral in promoting immune recovery and possible therapeutic potential in people receiving blood stem cell transplants as a treatment for advanced leukemia or another serious blood disorder

Zinc supports the immune system

The link between zinc and optimal immune function has a long history

When chemotherapy and radiation do not cure a patient's blood cancer, they undergo a blood stem cell transplant (also called a bone marrow transplant) to receive new, healthy blood stem cells that will replace the cancer blood cells and become infection-fighting white blood cells , oxygen-carrying red blood cells and wound-healing platelets

He said: "I started to think that maybe these [blood stem cell transplant patients] populations are at risk for [low zinc]

A pilot study by Iovino in patients undergoing autologous stem cell transplants for the blood cancer multiple myeloma showed that zinc may promote immune recovery

But it doesn't explain why

Thymus regeneration and immune function

Dudakov is the world's expert on the study of the thymus gland, especially the regeneration process of the thymus gland after injury

Although the thymus gland is the core of our defense against infection, it is quite fragile

But the thymus is also elastic

After a devastating chemotherapy regimen before transplantation, it can take months or even years for the thymus to return to its original T-cell production levels

Zinc is essential for T cell development and thymus regeneration

As in humans, Iovino and Dudakov found that the thymus shrank and the production of mature T cells was significantly reduced in mice on a zinc-deficient diet, even after just three weeks on a zinc-free diet

He also found that zinc deficiency slowed the recovery of T-cell numbers after mice received an immune-system-destroying treatment similar to what is done in patients who are about to receive blood stem cell transplants

Conversely, extra zinc can speed up immune recovery

Previous work by Dudakov and others in his lab revealed that there is a special set of cells in the thymus that release factors that drive T cells to support cell repair and regeneration

Iovino first investigated whether zinc could directly stimulate the growth of these cells, but found no effect
.
He then investigated whether zinc could affect the regeneration process by affecting the release of a repair factor called BMP4
.

He found that the levels of BMP4 in the thymus of zinc-deficient mice were lower after radiation therapy than mice on a standard diet
.
But levels of BMP4 were even higher in the thymus of mice that received extra zinc in the weeks before radiation therapy
.
These findings suggest that zinc is involved in a Bmp4-dependent regeneration pathway
.
But how?

"At that moment, we were furious because zinc interacts with about 300 proteins, and probably indirectly," Dudakov said
.

There are more than a dozen molecules that transport zinc into cells, and another 10 molecules that transport zinc outside cells -- but Iovino was able to exclude them
.
Dudakov's previous work revealed which cells in the thymus make BMP4
.
The researchers wondered: Would altering zinc levels in these cells increase BMP4? The answer was no
.

In contrast, Iovino found that zinc levels outside the cells increased after thymus damage, suggesting that changes in zinc levels around cells that release BMP4 appear to be the key
.
T cells accumulate zinc during development but release it after a damaging event, such as a radiation burst, killing them
.
When BMP4-releasing cells sense changes in external zinc levels, the massive release of zinc activates the renewal pathway, implying mass death of T cells
.

Cells use a molecule called GPR39 to sense changes in external zinc
.
Iovino found that GPR39 levels in BMPR-releasing cells increased after radiation injury
.
He then boosted BMP4 release and thymic regeneration with an experimental compound that mimics the rise in external zinc levels by stimulating GPR39
.

"We think when you supplement zinc, it builds up in developing T cells
.
It's stored, stored, stored again, and then the destruction comes and the zinc is released
.
Now you have more zinc in your body than normal.
To be more, that triggers this regeneration pathway
.
But (with the experimental compound) we can target the receptor directly and get the same effect without basically any pretreatment
.
"

The researchers caution that while their work sheds light on why zinc is so important for immunity, starting a high dose of the mineral is not a good thing
.

"We're not saying zinc is a panacea," Iovino said
.
"Severe reactions are possible due to intoxication and accumulation
.
We do not recommend taking zinc indiscriminately
.
"

He and Dudakov are further exploring the clinical potential of a compound that can recapitulate the immune-boosting effects of zinc after acute immune injury, and whether the treatment could also help suppress the chronic immune decline that occurs with age
.

go to the clinic

The scientists say there is still a lot to learn before translating their findings into therapeutic strategies
.

Transplant patients already receive mineral supplements, so if additional zinc is to be added to their regimen, it is important to ensure that the person receiving zinc supplementation is truly zinc deficient
.
Iovino thinks many patients may be, but there is currently no good test to assess this
.
He is currently developing a vaccine that will first be used to help researchers determine whether a patient's zinc status is associated with immune recovery after a blood stem cell transplant
.

Dudakov is excited to investigate GPR39-stimulating compounds as a way to improve thymic recovery after acute injury, such as pre-transplant radiation
.
The team is currently screening similar compounds to find any that might be more effective
.
There is also evidence that thymus damage may play a role in graft damage to the thymus
.
-Host disease, a sometimes debilitating and even fatal transplant complication in which transplanted donor immune cells attack the patient's healthy tissue
.
Dudakov hopes a treatment that helps heal the thymus gland will also help ease the condition, which affects 70 percent of patients who receive donated stem cells
.

He and Iovino are also investigating whether the compound could help regenerate the thymus in other conditions
.
Unfortunately, as we age, our thymus also slowly shrinks and reduces T cell output
.
Dudakov and Iovino also wondered if this chronic degeneration could be slowed down by promoting the organ's regeneration process
.
(Dudakov argues that ingesting extra zinc is unlikely to prevent long-term thymic decline, since this decline is not caused by a single disruptive event, which also raises extracellular zinc levels
.
)

"I'm very excited about (activating GPR39) as a potential therapeutic strategy
.
It's really, really good," Dudakov said
.

Lorenzo Iovino et al, High-dose zinc oral supplementation after stem cell transplantation causes an increase of TRECs and CD4+ na?ve lymphocytes and prevents TTV reactivation, Leukemia Research (2018).
  DOI: 10.
1016/j.
leukres.
2018.
04.
016