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

Date:
March 31, 2022
Source:
Fred Hutchinson Cancer Research Center
Summary:
Zinc's immune-boosting properties are well-established, but
scientists haven't known exactly how it works. Scientists now
reveal two ways the mineral supports immunity and suggest how it
could 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 prompts regeneration of the thymus,
the immune organ that produces T cells.



FULL STORY ========================================================================== Zinc's immune-boosting properties are well-established, but scientists
haven't known exactly how it works. In a new study published online
March 25 in the journal Blood, Fred Hutchinson Cancer Research Center scientists reveal two ways the mineral supports immunity and suggest
how it could 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 prompts regeneration
of the thymus, the immune organ that produces T cells.

"This study adds to our knowledge of what zinc is actually doing in
the immune system and suggests a new therapeutic strategy for improving recovery of the immune system," said senior author Dr. Jarrod Dudakov,
an immunologist at Fred Hutch.

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

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

Thymic regeneration and immune function, and zinc Previously, Dudakov
and his team have outlined the molecular pathways and cell types that
govern how the immune system's thymus repairs itself after injury.

Such treatments could improve vaccine efficacy and hasten thymic
regeneration after stressors like chemotherapy, blood stem cell transplant
and radiation exposure.



========================================================================== Dudakov began studying zinc a few years ago when Dr. Lorenzo Iovino,
the study's first author and a research associate at Fred Hutch, joined Dudakov's lab. Since the scientists knew that low levels of zinc are
linked to fewer infection fighting T cells and a shrunken thymus, where
T cells develop, Dudakov and Iovino explored how to supplement with zinc
in mouse models where the immune system is damaged.

Iovino, who's also a blood stem cell transplant physician, had shown
in a previous study that zinc could boost immune recovery in patients undergoing stem-cell transplants for the blood cancer multiple myeloma.

But the study didn't explain why zinc was helping.

Zinc is critical for T-cell development and thymic regeneration As in
humans, Iovino and Dudakov found that the thymuses of mice deprived of
dietary zinc shrink and produce notably fewer mature T cells, even after
as little as three weeks of a no-zinc diet. Iovino was able to show that without zinc, T cells cannot fully mature.



==========================================================================
He also found that zinc deficiency slows recovery of T-cell numbers
after mice receive immune-destroying treatments akin to those given to
patients about to receive a blood stem cell transplant.

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

"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 didn't know how
exactly zinc was working." Iovino discovered that it was the change in
zinc levels around cells that release a key regenerative factor that
seemed to kick off the thymus' renewal processes. T cells accumulate
zinc as they develop, but release it after a damaging event -- like a
burst of radiation -- kills them off.

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 could also promote renewal
factor release and thymic regeneration.

"What we think is going on is, as you give zinc supplementation, that
gets accumulated within the developing T cells. It gets stored and
stored and stored, then the damage comes along and the zinc is released," Dudakov said.

"Now you have more zinc than you normally would, and it can instigate
this regenerative pathway. With the experimental compound we can just
directly target GPR39 and basically get the same effect without any
of that pretreatment." Getting to the clinic There's still a lot to
learn before they can turn their findings to therapeutic strategies,
the scientists said.

Transplant patients already receive mineral supplements, so if
extra zinc were to be incorporated into their treatment regimens,
it would be important to make sure that anyone receiving it is truly zinc-deficient. Iovino thinks many patients might be, but right now there
isn't a good test to assess this. He's currently working on developing
one, which would first be used to help researchers determine whether
patients' zinc status correlates with immune recovery after blood stem
cell transplant.

Dudakov will pursue GPR39-stimulating compounds as therapies to improve
thymic recovery after acute injuries like pre-transplant radiation. The
team is currently screening similar compounds to find any that may be
more effective.

He and Iovino are also working to determine whether such compounds
could help with thymic regeneration in other settings. Unfortunately,
our thymuses also slowly shrink and reduce their T-cell output as we
age. Dudakov and Iovino would also like to know whether this chronic degeneration could be slowed by boosting the organ's regenerative
processes.

"Our lab is continuing to piece together the molecular players that
contribute to thymus regrowth," Dudakov said. "Ultimately, we aim 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.


========================================================================== Story Source: Materials provided by
Fred_Hutchinson_Cancer_Research_Center. Original written by Sabrina
Richards. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Lorenzo Iovino, Kirsten Cooper, Paul deRoos, Sinead Kinsella, Cindy
Anggelica Evandy, Tamas Ugrai, Francesco Mazziotta, Kathleen
S. Ensbey, David Granadier, Kayla Hopwo, Colton W Smith, Alex
Gagnon, Sara Galimberti, Mario Petrini, Geoffrey R Hill, Jarrod A
Dudakov. Activation of the Zinc-sensing receptor GPR39 promotes
T cell reconstitution after hematopoietic cell transplant in
mice. Blood, 2022; DOI: 10.1182/ blood.2021013950 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220331185359.htm

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