YSM Issue 97.1

Immunology
FOCUS
may be able to trigger the release of white
blood cells.
Now, this hypothesis had to be tested.
First, Jaschke demonstrated that A485
increases neutrophil mobilization into the
bloodstream. Specifically, he found that
mice treated with both G-CSF and A485 had
significantly greater neutrophil mobilization
than mice treated with just G-CSF or A485
alone. However, while the effects of G-CSF
are more prolonged (white blood cell counts
remain at higher levels for a long time), only
twelve hours after the injection of A485,
the white blood cell count dropped back to
pre-administration levels.. This rapid return
to baseline levels reduces the likelihood of
side effects and enables greater precision in
treatment administration. “What we showed
was that this increase in white blood cells
is sufficient to clear a substantial amount of
bacteria from the blood. And of course, if
you clear a lot of the pathogen that is trying
to destroy your tissues and compromise your
health, you will ultimately end up in a better
place than another mouse or a patient that
didn’t receive this therapy,” Jaschke said.
The researchers then took their work a
step further. Bone marrow injury can
often affect cancer patients undergoing
chemotherapy. Chemotherapy targets are
rapidly proliferating cell types, including
those in the bone marrow. Thus, bone
marrow injury often emerges as a side effect
of the primary purpose of killing cancerous
cells when administering chemotherapy.
To simulate the bone marrow
injury of chemotherapy-treated
cancer patients, Jaschke used a mouse
model of chemotherapy-induced bone
injury. They infected the mice with a
bacterium called Listeria monocytogenes,
causing a systemic infection of the bacteria
in the mice. Following infection, the mice
were treated either with A485 or an empty
control after the point of infection. They
found that a significantly higher percentage
of A485-treated mice survived the infection
compared to the control group, despite both
having initially low white blood cell counts.
The “Stress” Axis
Though the researchers’ results
revealed the powerful effects of A485, the
mechanism behind its activity remained a
mystery. After many different experiments,
Jaschke found that A485 treatment greatly
increased levels of corticosterone, the
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mouse corollary to human cortisol. Thus,
he reasoned, A485 must work through the
hypothalamic-pituitary-adrenal axis, or
“stress” axis. The hypothalamic-pituitaryadrenal
axis is a set of endocrine pathways
associated with the production and
circulation of various stress hormones,
including cortisol. But Jaschke found
something unexpected—A485 activity
did not rely upon corticosterone at all.
Instead, intermediary molecules like
adrenocorticotropic hormone (ACTH)
helped facilitate the effects of A485. Based
on these findings, Jaschke and his team
proposed that ACTH must be more
than simply an intermediate, opening
new doors of research into additional
functions of ACTH.
Jaschke had begun his work on A485
in Germany, performing the bulk of the
research there. Upon joining the Wang
lab at Yale, Jaschke was able to complete
his infection models and fully address his
hypothesis. “There were a lot of things that
could not be done in Germany; a lot of the
conceptual framework was substantially
rejiggered. It became a very different story
in [Jaschke’s] time here,” said Andrew
Wang, the principal investigator of the
lab and an associate professor of internal
medicine at the Yale School of Medicine.
The Wang lab focuses on how a patient's
state of mind affects how they manifest
disease and respond to treatments. A big
mystery for Wang and his lab is why white
blood cells are released upon feelings
of stress—there is no tissue damage or
infection, so what are the white cells being
mobilized for? While this big question
remains largely unanswered, Jaschke’s work
revealed a direct correlation between white
ABOUT THE AUTHOR
blood cells and the stress pathways of our
body. He showed that white blood cells
rely upon an aspect of the stress axis to be
released and mobilized against the disease.
A New Immune Drug?
Jaschke considered his findings curious
but also warned the public against
jumping to any conclusions. “This is an
interesting observation, but it doesn’t
mean that this has any therapeutic
relevance for humans,” Jaschke said. He
emphasized the need for extensive further
testing before any clinical treatments
could be made with A485, especially
given the limitations of his research. For
instance, the study exclusively used L.
monocytogenes for infection models; the
results of this one infection model cannot
automatically be generalized to the whole
range of harmful human infections. Also,
the researchers knew the precise disease
type and its time of onset in the mice,
which is rarely the case in real-world
clinical practice.
Ambitions of A485 entering the clinical
scene as a drug to recruit white blood
cells to fight disease remain. But Jaschke
knows that the next steps are largely out
of his hands. “For me personally, I’ve done
the work I wanted to do. [...] If there is an
interest from a larger scale to really screen
it in the clinics, it would be great,” Jaschke
said. The next crucial step for A485 is to
become an approved drug in clinical trials,
beginning with more mouse models and
eventually evaluations for safety in humans.
If successful, patients battling infection
with an injured bone marrow could look to
A485 for hope. ■
YOSSI MOFF
YOSSI MOFF is a first-year student in Saybrook College. Currently undecided, he is planning to
pursue the Molecular, Cellular, and Developmental Biology major. In addition to writing for YSM,
Yossi recently became one of its copy editors. Yossi is involved with the Slifka Center for Jewish
Life and is an avid intramural sports participant.
THE AUTHOR WOULD LIKE TO THANK Nikolai Jaschke and Andrew Wang for sharing their
expertise and enthusiasm in their field.
REFERENCES:
Jaschke, N. P., Breining, D., Hofmann, M., Pählig, S., Baschant, U., Oertel, R., Traikov, S., Grinenko,
T., Saettini, F., Biondi, A., Stylianou, M., Bringmann, H., Zhang, C., Yoshida, T. M., Weidner, H.,
Poller, W. C., Swirski, F. K., Göbel, A., Hofbauer, L. C.,…Rachner, T. D. (2024). Small-molecule
CBP/p300 histone acetyltransferase inhibition mobilizes leukocytes from the bone marrow
via the endocrine stress response. Immunity, 57(2), 364–378. e9. https://doi.org/10.1016/j.
immuni.2024.01.005
March 2024 Yale Scientific Magazine 15