Platelets, tiny and relatively uncharted tenants of
the bloodstream known mostly for their role
in blood clotting, turn out to also rally sustained immune
system inflammatory responses that play a
critical role in organ transplant rejection, according to a
new report from Johns Hopkins scientists.
"Platelets potentially hold sway over many aspects of
transplant biology," said Craig Morrell, an
assistant professor of molecular and comparative
pathobiology at the Johns Hopkins University School
of Medicine. "Our data, as well as others', show a
surprising interplay of platelets and the immune
system, so it's time for the transplant world at large to
have platelets on its radar."
A self-described "platelet guy" transfixed by the
unexplored biology of these circulating
bodies, Morrell collaborated with clinicians in the fields
of transplant to write a comprehensive review
of platelets and transplant biology, published in the
January issue of American Journal of
"It all began with the observation that when
transplant tissue is rejected, platelets line up in
the interior of blood vessels feeding the tissue," Morrell
said. "It turns out they are not just
bystanders but have a role in driving that rejection."
As one of the most abundant cell types in the blood
— second only to the oxygen-carrying red
variety — platelets are ubiquitous but relatively
unexplored, Morrell said. "It's crazy how many
potentially active molecules are jam-packed in these small
cells and that we're only just beginning to
appreciate their pro-inflammatory qualities."
In fact, mounting evidence from Morrell and others
shows that platelets are part of a sustained
and general immune response that can trigger or exacerbate
organ rejection. Not only do they rush to
the scene of a wound and adhere to local blood vessels,
preventing fatal bleeding, they also dump out
granules that "talk to" immune system white blood cells,
Morrell said, recruiting them from far and
wide to stave off potential infections.
These are on the whole very good things for platelets
to do, Morrell said, but in the context of
organ transplants, their pro-inflammatory function gets out
of control and they do more bad than good
after contributing to initial wound healing.
Strategies using drugs or other means to keep
platelets quiet and noninflammatory might
benefit transplant patients in the long run because chronic
rejection — as contrasted with acute or
immediate organ rejection — is a major complication
for which there is little current treatment,
according to Hamid Rabb, medical director of Kidney
Transplantation and a professor of medicine at
the Johns Hopkins University School of Medicine.
In prior research using mice with skin transplants,
Morrell and his team noted that increased
platelet interactions led to increased and prolonged white
cell interactions with the inner lining of the
blood vessels and worsened transplant vessel damage.
"We watched platelets flowing through the blood
vessels of transplanted skin in mice with and
without platelets and determined tissue-platelet
interactions by comparing the speeds of those
flows," said Morrell, whose team ultimately demonstrated
that antibodies made in reaction to the
transplanted tissue sparked platelet activation and white
Studies on tissue from platelet-depleted mice helped
confirm the importance of platelets in
white cell activation and recruitment, strongly suggesting
that limiting the inflammatory response
might improve transplanted tissue survival.
Mounting evidence suggesting that platelets are
activated not only post-transplant but also
during organ harvest presents new opportunities for
attacking organ injury and rejection head on,
Rabb said. The traditional target of current anti-rejection
medicine is the so-called T lymphocyte, a
white blood cell believed to be the major orchestrator of
the immune response against any foreign
tissues, including transplants.
"The thought was that if we hit the general that
initiates acute rejection, it would put the
troops in disarray," Rabb said. "Traditional therapies
therefore inhibit or deplete T lymphocytes and
other white blood cell components of the immune system. The
newest kid on the block is the platelet,
and it represents an opportunity to target the effectors of
organ injury rather than only the general."
The authors of the review, who were supported by
National Institutes of Health grants, are
A.D. Kirk, of Emory University; W.M. Baldwin III, formerly
of Johns Hopkins and now at the Lerner
Research Institute; and Morrell, of Johns Hopkins.