“It's A Bargain” Thrift Shop - Orthopaedic Hospital

ally stimulates the immune response.
One thing we’ve never understood is exactly
how that piece of plastic activates the human
immune response. We’ve never been able to
determine the connection between this particle
of plastic and the macrophage, which is the cell
that initiates the immune response.
People have discovered things called pattern-recognition
receptors on the surfaces of
cells. These pattern-recognition receptors recognize
the shape of molecules that are outside
of the macrophage. If the shape is particularly
disturbing to that cell, that receptor will bind
that thing and it will activate that receptor.
When that receptor gets activated, it turns on
what we call the innate immune response,
which tells that macrophage to make every
effort to get rid of that piece of plastic.
We made a discovery with regard to the
immune response — in our case, we used
tuberculosis as a model organism system to
stimulate that cell — and published the results
in Science in 2006.
When a human macrophage gets activated,
a number of genes turn on in that cell. Lo and
behold, a couple of these genes are ones that we
know from the bone field. They are the vitamin
D receptor — a major factor that increases the
number of bone-forming cells.
As it turns out, the macrophage is capable
of responding to the active vitamin D hormone
by expressing the receptor when it’s activated.
At the same time, it expresses the enzyme that
makes the active vitamin D hormones from
its precursor mode, from its substrate. With
the substrate molecules floating around in
the blood, the macrophage now becomes a
factory to take that substrate and convert it
to the active vitamin D hormone inside the
cell. That active vitamin D hormone then can
interact with this vitamin D receptor, which is
the signaling molecule to tell the genes in the
nucleus of the cell to start transcribing genes
— in this case, genes that encode an antibiotic.
This antibiotic then gets transported into these
little vesicles where the tuberculosis organism
is being killed.
So, if you don’t have enough vitamin D in
research
your circulation, you can’t generate enough of
the active hormone inside that cell. You can’t
then engage the vitamin D. You can’t then turn
on that gene that makes the antibiotic and so
you don’t have enough antibiotic to kill this
invading organism — therefore you’re infected.
Essentially that’s failure of the innate immune
response.
Well, we’re looking at the same thing with
these particles. These particles actually activate
the same pathways in much the same way. If
somebody is deficient in vitamin D, and they
have an implant that’s shedding particles, they
can’t generate enough of the kinds of things to
take care of that insult.
motion: So the human immune response is
hijacked?
Dr. Adams: Exactly. It just keeps reacting and
reacting and reacting. These macrophages then
make these cytokines that stimulate other lymphocytes
in the area: “Come on in, guys, we’ve
got a real problem here. We need to get to this
joint and take care of this infecting agent.” But
they can never really do it. They can’t get rid of
the offending agent and they just continue to
make more and more inflammation.
Our idea is if you can allow that macrophage
to more effectively deal with that
offending agent, there are ways that you can
destroy these things and coat them so that they
don’t stimulate the host immune response.
If you do that by making that a more competent
macrophage — by making it vitamin
D sufficient — then you have a much better
chance of dealing with an immune response to
some sort of rare particle.
In this project, there are people like me who
know about bone and bone cells. I have a number
of colleagues who are immunologists. They
are trying to figure out exactly what signals are
being made by the macrophage and how the
lymphocytes are being turned on.
Of course, again, we have a biomaterials
person who’s responsible for making a better
biomaterial that doesn’t shed. And that’s happened.
We also have an orthopaedic surgeon
who has to be involved to recognize which
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