In a mouse model of multiple sclerosis
(MS), researchers funded by the National Institutes of Health have
developed innovative technology to selectively inhibit the part of
the immune system responsible for attacking myelin—the insulating
material that encases nerve fibers and facilitates electrical
communication between brain cells.
Autoimmune disorders occur when
T-cells—a type of white blood cell within the immune system—mistake
the body’s own tissues for a foreign substance and attack them.
Current treatment for autoimmune disorders involves the use of
immunosuppressant drugs which tamp down the overall activity of the
immune system. However, these medications leave patients susceptible
to infections and increase their risk of cancer as the immune
system’s normal ability to identify and destroy aberrant cells
within the body is compromised.
Supported by the National Institute of
Biomedical Imaging and Bioengineering (NIBIB) at NIH, Drs. Stephen
Miller and Lonnie Shea at Northwestern University, Evanston, teamed
up with researchers at the University of Sydney, and the Myelin
Repair Foundation in Saratoga, Calif. to come up with a novel way of
repressing only the part of the immune system that causes autoimmune
disorders while leaving the rest of the system intact.
The new research takes advantage of a
natural safeguard employed by the body to prevent autoreactive
T-cells—which recognize and have the potential to attack the body’s
healthy tissues—from becoming active. They report their results in
the Nov. 18 online edition of Nature Biotechnology.
“We’re trying to do something that
interfaces with the natural processes in the body,” said Shea. “The
body has natural mechanisms for shutting down an immune response
that is inappropriate, and we’re really just looking to tap into
that.”
One of these natural mechanisms involves
the ongoing clearance of apoptotic, or dying, cells from the body.
When a cell dies, it releases chemicals that attract specific cells
of the immune system called macrophages. These macrophages gobble up
the dying cell and deliver it to the spleen where it presents
self-antigens—tiny portions of proteins from the dying cell—to a
pool of T-cells.
In order to prevent autoreactive T-cells from being activated,
macrophages initiate the repression of any T-cells capable of
binding to the self-antigens.
Dr. Miller was the first to demonstrate
that by coupling a specific self-antigen such as myelin to apoptotic
cells, one could tap into this natural mechanism to suppress T-cells
that would normally attack the myelin.
The lab spent decades demonstrating that they could generate
antigen-specific immune suppression in various animal models of
autoimmune diseases. Recently, they initiated a preliminary clinical
trial with collaborators in Germany to test the safety of injecting
the antigen-bound apoptotic cells into patients with MS.
While the trial successfully demonstrated that the injections were
safe, it also highlighted a key problem with using cells as a
vehicle for antigen delivery:
"Cellular therapy is extremely expensive
as it needs to be carried out in a large medical center that has the
capability to isolate patient’s white blood cells under sterile
conditions and to re-infuse those antigen-coupled cells back into
the patients," said Miller. "It’s a costly, difficult, and
time-consuming procedure."
Thus began a collaboration with Dr. Shea,
a bioengineer at Northwestern University, to discuss the possibility
of developing a surrogate for the apoptotic cells. After trying out
various formulations, his lab successfully linked the desired
antigens to microscopic, biodegradable particles which they
predicted would be taken up by circulating macrophages similar to
apoptotic cells.
Much to their amazement, when tested by
the Miller lab, the antigen-bound particles were just as good, if
not better, at inducing T-cell tolerance in animal models of
autoimmune disorders.
Using their myelin-bound particles, the
researchers were able to both prevent the initiation of MS in their
mouse model as well as inhibit its progression when injected
immediately following the first sign of clinical symptoms.
The research team is now hoping to begin
phase I clinical trials using this new technology. The material that
makes up the particles has already been approved by the U.S. Food
and Drug Administration and is currently used in resorbable sutures
as well as in clinical trials to deliver anti-cancer agents.
Miller believes that the proven safety record of these particles
along with their ability to be easily produced using good
manufacturing practices will make it easier to translate their
discovery into clinical use.
"I think we’ve come up with a very
potent way to induce tolerance that can be easily translated into
clinical practice. We’re doing everything we can now to take this
forward," said Miller.
In addition to its potential use for the
treatment of MS, the researchers have shown in the lab that their
therapy can induce tolerance for other autoimmune diseases such as
type I diabetes and specific food allergies. They also speculate
that transplant patients could benefit from the treatment which has
the potential to retract the body’s natural immune response against
a transplanted organ. Dr. Christine Kelley, NIBIB director of the
Division of Science and Technology, points to the unique
collaboration between scientists and engineers that made this
advance a reality.
"This discovery is testimony to the
importance of multidisciplinary research efforts in healthcare,"
said Kelley. "The combined expertise of these immunology and
bioengineering researchers has resulted in a valuable new
perspective on treating autoimmune disorders."
In addition to a grant from NIBIB
(R01-EB013198-02), the research was also supported by NIH’s National
Institute of Neurological Disorders and Stroke (NS026543), the
Myelin Repair Foundation, and the Juvenile Diabetes Research
Foundation (17-2011-343).
Form ore informations
http://www.nih.gov
(MDN) |