Interleukin-2: Immune Boost,
or Bust?
by Bob Munk
Interleukin-2 (IL-2) is a
protein produced by the immune system. IL-2 is a cytokine,
a chemical messenger that plays an important role in mobilizing
the immune response to an invading germ. IL-2 stimulates CD4+
(T-helper) cells to multiply and mature, releasing additional
cytokines that stimulate other immune cells, including CD8+
(T-killer) cells and natural killer (NK) cells.
The activity of IL-2 was discovered
in 1976. The molecule was identified a few years later. Researchers
identified the gene that produces IL-2 and cloned it, which
allows the production of IL-2 for treatments. It has been
approved to treat some kinds of cancers, but it continues
to have ups and downs in studies for HIV disease.
IL-2 was used to stimulate
T-cells in people with HIV even before the development of
effective antiretroviral therapies. In the late 1980s, studies
used several different doses given by intravenous infusion.
CD4+ cell increases were not too large, and didn’t last
long. HIV viral loads increased after each cycle, returning
to baseline in about a month. In addition, the IL-2 infusions
caused fever and serious flu-like symptoms.
In the mid-1990s, with viral
load controlled by HAART, IL-2 made a comeback. It was again
tested using daily IV infusions. With HAART, there were no
measurable increases in viral load. A cycle of 5 days of IL-2
infusions using 12 to 18 million international units (MIU)
became the standard, with dose reductions as needed when side
effects were too severe.
Subcutaneous (just below the
skin) injections were tried as a way of reducing IL-2’s
side effects and making it possible for patients to treat
themselves at home. Doses of 5 to 9 MIU were studied, injected
twice a day during 5-day cycles. Overall, side effects were
reduced, although many patients had some irritation where
they injected the IL-2.
More T-cells, but how
good are they?
After several dosing
cycles, IL-2 produces T-cell counts 3 or 4 times as high as
baseline, or as high as 1,000, and a reduction in the abnormal
activation of T-cells. These benefits appear to be maintained
even with less frequent follow-up cycles.
Not all the news is good,
however. For one thing, IL-2 doesn’t fill any gaps in
the immune defenses. Cliff Lane, a key IL-2 researcher at
the National Institutes of Health (NIH), uses a “Scrabble”
analogy to describe T-cell repertoire. The full set of alphabet
tiles represents a normal immune system. As your T-cell count
goes down and you lose “tiles”, you might run out
of some letters. If you use IL-2, these “lost” letters
don’t come back, but you will have more copies of any
letters you still had. Another disappointment is that people
who start out with lower T-cell counts get less benefit from
IL-2, and have more serious side effects.
Researchers at the NIH also
thought that IL-2 could help them deal with “reservoirs”
of infection. Current antiviral drugs have no effect on these
reservoirs, where HIV can hide out and re-emerge quickly if
medications are stopped. The researchers thought that IL-2
could “flush out” these reservoirs by activating
the infected T-cells so that antiviral drugs would reach them.
Unfortunately, in late October they announced that their experiment
had failed. Even in patients with undetectable viral loads
using extremely sensitive tests, and even after using IL-2,
the viral load came back when medications were stopped.
Looking for clinical benefits
Although many studies confirm
IL-2’s ability to produce big increases in T-cells, no
one knows whether those counts will translate into fewer opportunistic
infections or longer life. Clinical trials had to be designed
to answer this question. Two major international studies of
IL-2 have been designed and are enrolling patients:
-
Chiron Corporation, which
manufactures IL-2, designed the “SILCAAT” study
for people with T-cell counts between 50 and 299 and viral
loads below 10,000 copies. The study will enroll 1,400
participants who will all receive regular antiviral therapy.
The treatment group will get IL-2; the control group will
not. Patients will be followed for up to 6 years.
-
The National Institutes of
Health is funding the international “Esprit”
study of IL-2 for people with more than 350 T-cells. This
$43 million study is the most expensive clinical trial
in history. It will enroll 4,000 participants at 210 research
sites in 18 countries and follow them for up to 6 years.
Again, all participants will receive antiviral therapy,
and the treatment group will also receive IL-2.
Both of these studies allow
physicians to freely change the antiviral therapy of patients
during the trial. IL-2 doses can be reduced for participants
with serious side effects or increased if there is not a significant
increase in CD4+ counts. Also, the timing of IL-2 cycles after
the first few can be extended as long as CD4+ counts are high
enough.
Are we on the right track?
The SILCAAT and Esprit studies
should eventually tell us whether using IL-2 results in clinical
benefit. But the discoverer of the IL-2 molecule thinks these
studies aren’t using IL-2 in the best possible way. In
an interview published in AIDS Treatment News, Dr. Kendall
Smith explained that daily low-dose injections of IL-2 were
enough to stimulate T-helper cells without “waking up”
too many natural killer cells. The T-helpers fight the HIV
infection, but the natural killer cells are responsible for
IL-2’s nasty side effects.
After a year or two of daily
low-dose injections, along with HAART, Dr. Smith’s patients
saw their CD4 counts return to the normal range. Then Dr.
Smith asked them to consider stopping their antiviral medications,
while continuing IL-2. So far, 9 patients have done so. As
expected, the virus came back and viral loads increased for
about two weeks. But then, the immune systems of every patient—with
help from their daily IL-2—kicked in and knocked out
about 90% of the virus. Their viral loads stabilized at lower
levels than before they started HAART. Five patients have
since re-started antiviral therapy, but 4 have been off drugs
for as long as 9 months.
ItĂs not nice to mess
with Mother Nature
IL-2 is a good example of
the challenges involved in using the body’s own chemical
defenses. Our immune systems represent a very complicated
balance and interaction of various types of cells and cytokines
like IL-2. When we take one of those elements out of context,
we have to do a lot of research to figure out the best way
to use it, or whether it even has benefits when used by itself.
|
