Originally published by UPMC Media Relations. Reposted with permission.
PITTSBURGH – Inspired by a tactic cancer cells use to evade the immune system, University of Pittsburgh researchers have engineered tiny particles that can trick the body into accepting transplanted tissue as its own.
that were treated with these cell-sized microparticles developed
permanent immune tolerance to grafts — including a whole limb — from a
donor rat, while keeping the rest of their immune system intact,
according to a paper published today in Science Advances.
“It’s like hacking into the immune system borrowing a strategy used
by one of humanity’s worst enemies to trick the body into accepting a
transplant,” said senior author Steven Little, Ph.D., William Kepler Whiteford Endowed Professor and Chair of chemical and petroleum engineering in the Swanson School of Engineering at Pitt. “And we do it synthetically.”
The advantage of a synthetic approach rather than cell-based therapy, which is currently in clinical trials, is that the treatment logistics are much simpler.
“Instead of isolating cells from a patient, growing them up in the
lab, injecting them back in and hoping they find the right location,
we’re packaging it all up in an engineered system that recruits these
naturally occurring cells right to the transplanted graft,” said lead
author James Fisher, M.D., Ph.D., a postdoctoral researcher in the Pitt School of Medicine.
The microparticles work by releasing a native protein secreted by
tumors, CCL22, which draws regulatory T cells (Treg cells) to the site
of the graft, where they tag the foreign tissue as “self” so that it
evades immune attack.
Microparticle-treated animals maintained healthy grafts for as long as they were monitored — a little under a year, equivalent to about 30 human years. All it took was two shots to effect seemingly permanent change.
In a companion paper published recently in PNAS, the researchers
showed that these engineered microparticles can train the immune system
of one strain of rat to accept a donor limb from a different strain.
This new paper shows that the effects are specific to the intended
donor. Skin grafts from a third strain were rapidly rejected.
Today, transplant patients take daily doses of immunosuppressant
drugs to avoid rejection, leaving them vulnerable to cancer, diabetes,
infectious diseases and a host of other ailments that come along with a
weakened immune system.
“These drugs hammer the immune system into submission so it can’t
attack the transplanted organ, but then it can’t protect the body
either,” said coauthor Stephen Balmert, Ph.D., a postdoctoral researcher
in the Pitt School of Medicine. “We’re trying to teach the immune
system to tolerate the limb, so that a transplant recipient can remain
The risks of lifelong immunosuppression are particularly
problematic when the transplant isn’t a life-saving procedure. Doctors
and patients have to consider whether the benefits outweigh the risks.
“The ability to induce transplant tolerance while avoiding systemic
immunosuppression, as demonstrated in these innovative studies, is
especially important in the context of vascularized composite
transplantation where patients receive quality-of-life transplants, such
as those of hands or face,” said coauthor Angus Thomson, Ph.D., professor of surgery and immunology in the Thomas E. Starzl Transplantation Institute at Pitt.
Additional authors on the study include Wensheng Zhang, Ph.D., Ali
Aral, M.D., Abhinav Acharya, Ph.D., Yalcin Kulahci, M.D., Jingjing Li,
M.D., Heth Turnquist, Ph.D., Mario Solari, M.D., all of Pitt; and Vijay
Gorantla, M.D., Ph.D., of the Wake Forest School of Medicine.
This research was supported by the National Institute of Allergy and Infectious Diseases (R01-AI118777 U19-AI131453, R01-HL122489, T32-AI074490), National Institute of Dental and Craniofacial Medicine (R01-DE021058), the Department of Defense (W81XWH-15-2-0027 and W81XWH-15-1-0244), The Camille & Henry Dreyfus Foundation and the National Cancer Institute (T32-CA175294).
Author: Erin Hare, Ph.D., Manager, Science Writing, 3/13/2020
Contact: Erin Hare, Ph.D.