Natural Born
Killers to the Rescue
Evan David Rosen, M.D., Ph.D.
Assistant Professor of Medicine,
Harvard Medical School
The
immune system is amazingly complex and only partially understood.
The primary job of the immune system, of course, is to rid the
body of foreign invaders, be they bacteria, viruses, parasites,
or even cancer cells. One of the most enduring mysteries in
immunology is how the body learns to tell the good guys from
the bad guys, or “self” from “non-self”.
Our desire to understand this phenomenon is made more urgent
by the existence of conditions where the immune system gets
it wrong—by failing to discriminate between things that
belong and those that don’t, an immune attack can be launched
against an otherwise healthy organ. The term for this is “autoimmunity”,
and the result is tissue death by friendly fire. If the target
organ is the pancreas, specifically the insulin-producing beta
cells within the pancreas, the condition shows up as type 1
(juvenile) diabetes.
Scientists have spent years trying
to figure out how this process occurs, with an eye on halting
the autoimmune attack and potentially reversing the damage to
the beta cells. One of the best tools they have in this struggle
is a rodent called the NOD mouse, which stands for non-obese
diabetic. These mice develop diabetes at a young age, and many
if not most aspects of their illness look remarkably like what
occurs in type 1-diabetes in humans. Recently, several studies
have appeared demonstrating remarkable success in preventing
or reversing diabetes in NOD mice, raising hope that some of
these advances will work in people as well.
Two new papers in the journal
Nature Medicine illustrate what I’m talking about, but
in order to understand what they tell us we need to back up
and talk a little about some of the complicated ways the immune
system works.
In type 1 diabetes, the attack
on the beta cells of the pancreas is spearheaded by certain
immune cells called T cells; specifically a subclass of T cells
called Th1 cells. Normally, Th1 cells play a role in protecting
us from disease, but in autoimmune conditions like type 1 diabetes,
too many Th1 cells can be bad news. Fortunately, there is another
type of T cell called the Th2 cell, and Th2 cells can protect
against the mischief caused by Th1 cells run amok. So far, so
good, you’re thinking. All we need to do is make fewer
Th1 cells and more Th2 cells. Well, there is still another type
of T cell that controls how many of these cells are created
and how active they’ll be—the natural killer T cell,
or NKT cell. NKT cells release special hormones that regulate
the Th1 and Th2 cells, and studies have shown that NOD mice
and people with type 1-diabetes have fewer NKT cells. Furthermore,
the NKT cells they do have don’t secrete the right hormones,
and generally do a very poor job of running the show.
Well, as it turns out, there’s
a chemical called alpha-galactosylceramide (alpha-GalCer) that
both induces the formation of more NKT cells as well as instructs
them to make the right hormones. These two new papers show that
giving alpha-GalCer to NOD mice can greatly reduce the likelihood
that they will develop diabetes. Furthermore, experiments were
done with NOD mice that had already become diabetic and that
had been given grafts of pancreatic beta cells. If you follow
the latest developments on diabetes (and if you’re reading
this, you probably do), you know that there are very encouraging
data on islet cell transplantation in humans with type 1-diabetes.
The problem is that the autoimmune attack that knocked out the
patient’s original beta cells will try to destroy the
new islets as well. This necessitates a lifetime of immunosuppression;
powerful drugs that keep the immune system in check allowing
the graft to survive, but predisposing the patient to infections
and other nasty side effects. In the diabetic NOD mice, the
alpha-GalCer acted to let the grafts in the NOD mice survive.
However, because this drug has very specific effects on the
immune system, the animals did not seem to suffer from the sort
of general immunosuppression caused by the types of drugs in
current use. This exciting result opens the possibility of selective
immunosuppression in pancreatic graft recipients, which could
dramatically reduce the morbidity of that procedure.
There are potential drawbacks--
alpha-GalCer is toxic to the liver in mice, although by a stroke
of luck it appears humans don’t have the same problem.
There is also the problem that bedevils all drugs designed to
prevent type 1-diabetes. Because we can’t say for sure
who will get type 1-diabetes and who will not, one would have
to give alpha-GalCer to a lot of people who would never develop
the disease in order to stop the process in those who will.
But I have to say that I’m encouraged by the effects on
the islet cell grafts given to NOD mice. I hope that this will
be a productive line of inquiry for many academic labs and drug
companies, and in the event that things pan out it will probably
be some chemically modified cousin of alpha-GalCer that makes
it to the bedside. I am rooting for this therapy also because
I enjoy the irony of conquering a deadly disease by unleashing
the killers within.
References:
1. S Hong, M T Wilson, I Serizawa,
L Wu, N Singh, O V Naidenko, T Miura, T Haba, D C Scherer, J
Wei, M Kronenberg, Y Koezuka & L Van Kaer. The natural killer
T-cell ligand alpha-galactosylceramide prevents autoimmune diabetes
in non-obese diabetic mice. Nature Medicine. 7:1052, 2001
2. S Sharif, G A Arreaza, P Zucker,
Q -S Mi, J Sondhi, O V Naidenko, M Kronenberg, Y Koezuka, T
L Delovitch, J -M Gombert, M Leite-de-Moraes, C Gouarin, R Zhu,
A Hameg, T Nakayama, M Taniguchi, F Lepault, A Lehuen, J -F
Bach & A Herbelin. Activation of natural killer T cells
by alpha-galactosylceramide treatment prevents the onset and
recurrence of autoimmune Type 1 diabetes. Nature Medicine 7:
1057, 2001.
Written by Evan D. Rosen, M.D.,
Ph.D.
Content created 09/10/2001
Content last reviewed September
12, 2001
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