Cytokines: Putting Body Mechanics to Work
by Marian Segal

     The human body is a remarkable self-service center, open 24
hours a day, including weekends. It provides routine maintenance
and repair free of charge, with no wait and no hassle. Most of us
have no idea what makes us run, yet our own bodies are our best
mechanics.
     Our cells are microscopic specialists that tend to our daily
upkeep, leaving us free to pursue other important--or frivolous--
matters. They are dispatchers, sentries, soldiers, builders,
destroyers, and mechanics. They also manufacture products to help
with their chores. Among these products are cytokines.
     "Cytokines are hormone-like proteins that act as communicators
between cells," says Theresa Gerrard, Ph.D., acting director of
FDA's division of cytokine biology. "They're made by one cell and
act on another, relaying a message telling that cell to grow, stop
growing, move to a trouble spot, or otherwise somehow modify its
function."
     An explosion in cytokine research has occurred in the last
decade. Using genetic engineering techniques, researchers are
producing large quantities of these human proteins and testing them
for possible medical applications.
     Developing biological products--naturally occurring
substances--for medicine is not a new concept. Doctors have long
used whole blood and blood products to replace blood lost due to
injury or during surgery, for example, and to treat anemia and
hemophilia.
     Gerrard describes cytokines as "new era" biologics, explaining
that even though they originally derived from human cells, they're
mostly manufactured using recombinant DNA technology. They may even
be chemically altered to achieve a desired characteristic, such as
greater activity, thus becoming more like drugs than the "old-time
biologicals," she says.
     Developing cytokines for medical treatment can be a tricky
business. Some are very specific, and their effects are
predictable. Others, however, can produce a variety of effects
depending on the type of cell they're acting on. Because of this,
cytokine research often takes somewhat of a "shotgun" approach.
     "Even though you may not know exactly how the cytokine will
act in the body, information from laboratory experiments or animal
studies may provide a good indication," Gerrard says. "If a
particular cytokine modulates immune function, for example, it can
affect countless things, and you might try it in cancer, infectious
diseases, or various other things."

Interferons
     That was the case with interferons, for example. Interferon
alfa (Intron-A, Roferon-A) was the first cytokine FDA licensed. In
June 1986, it was approved to treat hairy cell leukemia--a rare
cancer primarily affecting adults. Since then, it has been licensed
for Kaposi's sarcoma (a type of cancer mostly affecting people with
AIDS), genital warts, hepatitis C, and hepatitis B.
     Interferon gamma (Actimmune) was licensed in 1990 to treat 
chronic granulomatous disease, a hereditary disease that strikes
primarily young boys. These children have a defect in a certain
type of white blood cell, so that the cells can ingest bacteria,
but can't kill them. The patients suffer repeated bouts of life-
threatening infections from common organisms that normally wouldn't
present serious problems. Children treated with Actimmune have
fewer serious infections.
     The most recent cytokine to be licensed is another interferon.
In 1993, FDA approved interferon beta (Betaseron) for multiple
sclerosis, after studies showed it helped prevent flare-ups of the
disease. (See "Multiple Sclerosis: New Treatment Reduces Relapses"
in the June 1994 FDA Consumer.)
     Scientists don't know exactly how interferons work to produce
the desired effects in any of these diseases. All interferons have
anti-viral activity, Gerrard says, but that's about all they have
in common. In some cases, the substance may act directly on tumor
cells; in others, it may enhance an immune response, or perhaps
subdue it.
     Most patients have not had serious side effects from the
interferons licensed so far. The most common adverse effects are
flu-like symptoms, including fatigue, fever, chills, and headache.
Less frequent side effects include abnormal liver function and
severe depression.
     Other classes of cytokines commanding considerable interest
among researchers are wound-healing factors, neurotrophic factors,
inflammatory and anti-inflammatory factors, and hematopoietic
growth factors. Scientists working with cytokines expect to
eventually develop products in all these categories. So far,
however, only interferons and hematopoietic growth factors have
been shown safe and effective for certain conditions.

Hematopoietic Growth Factors
     flHematopoieticfl refers to blood cell formation. Hematopoietic
growth factors are cytokines that stimulate blood cells to
proliferate. Three have been licensed. Like most cytokines, they
have long names and short acronyms. Erythropoietin (EPO), normally
made by the kidneys in tiny amounts, accelerates red blood cell
production.
     Epoetin alfa, the genetically engineered form of EPO, was
licensed in 1989 under the brand name Epogen to treat severe anemia
in patients with chronic kidney failure. These patients may have as
little as half the normal count of red blood cells and require
frequent blood transfusions. But repeated transfusions put patients
at risk of developing antibodies that would make it more difficult
to match them with a donor for eventual kidney transplantation, or
even for more transfusions. Patients might also develop a
potentially harmful iron buildup. And, although blood is screened
for viral contamination, repeated transfusions increase the risk of
infection.
     Studies in the United States and Europe of 1,200 patients with
chronic renal disease treated with epoetin alfa showed that more
than 95 percent had increased red blood cell counts. In patients
who required them, the need for transfusions was reduced tenfold
within three months, and most patients no longer required them at
all.
     EPO was licensed for a second use in 1991--to treat patients
with AIDS who develop severe anemia as a side effect of treatment
with Retrovir (zidovudine, or AZT). In a study of 118 such
patients, there was a 40 percent reduction in transfusions during
a three-month period of treatment with Epogen, with very few
adverse reactions--mostly fever, headaches and fatigue.
     Two white-cell stimulating growth factors are also licensed:
Granulocyte-colony stimulating factor, or G-CSF (marketed as
Neupogen) and granulocyte-macrophage-colony stimulating factor, or
GM-CSF (sold under the names Leukine and Prokine). Licensed within
a month of each other in 1991, both are used to boost white cell
counts depleted by cancer treatments.
     GM-CSF is approved only for autologous bone marrow transplants
in people with non-Hodgkin's lymphoma, Hodgkin's disease, and acute
lymphoblastic leukemia. G-CSF, originally licensed for use in
conjunction with chemotherapy for solid tumors, was recently
licensed for use with bone marrow transplants also. The products
are for use only with treatment regimens that cause a significant
loss of white cells.
     Bone marrow transplantation is such a treatment, done in
patients with little or no hope of recovery using conventional
chemotherapy alone. The patient's marrow is removed and checked for
cancer cells. If malignant cells are found, the marrow is "purged"-
-treated with chemotherapy to kill the cancer cells.
     The patients also receive very high doses of chemotherapy,
leaving them with virtually no white cells, red cells, or
platelets. Their marrow is then returned, and they again begin to
manufacture their own blood cells. It is a slow process, however,
and until white cell counts rise sufficiently, the patients are at
significant risk of death from infection. Normally, it takes three
to four weeks after transplantation for marrow to begin producing
white cells.
     G-CSF and GM-CSF speed up this production. Although the body
makes its own cytokines, they are produced in very small
quantities. "By adding more cytokines, you're hurrying Mother
Nature along," Gerrard says, "reducing the window of vulnerability
by one-half to two-thirds."
     Studies supporting licensing of both these cytokines showed
that treated patients had significantly fewer infections, less need
for intravenous antibiotics, and, in some cases, a shortened
hospital stay, all contributing to improved quality of life.
     GM-CSF causes relatively mild side effects, including fever,
diarrhea, skin rash, and weakness. The most common adverse reaction
of G-CSF is mild to moderate bone pain, usually controlled with
acetaminophen.

Progress, But No Miracles
     Many cytokine researchers are excited about future prospects
for these versatile substances, but they temper their optimism with
caution.
     Donald Price, M.D., a neurologist-neurobiologist at Johns
Hopkins University School of Medicine in Baltimore, is looking at
neurotrophic factors that may be helpful in certain neurological
diseases. He is enthusiastic about their potential for treatment,
but cautious about applying them to humans prematurely.
     "I think in the future, cytokines have enormous promise, but
there needs to be more basic science work and work with animal
models before taking these things into the clinic," he says.
     Price is testing in animals the effectiveness of nerve growth
factor (NGF) for Alzheimer's disease and brain-derived neurotrophic
factor (BDNF) for amyotrophic lateral sclerosis (ALS). In ALS,
motor neurons (nerve cells) degenerate, causing paralysis. In
Alzheimer's disease, patients suffer dementia because the neurons
governing cognition and memory are lost. Because neurons can't
regenerate, the hope for cytokine treatment is that growth factors
might act on these cells to prolong their function and viability.
     Gerrard compares research on neurotrophic factors today with
interferon research 10 years ago: "We don't know the precise
effects of these neurotrophic factors, but we do know from
laboratory study that they affect neurons--maybe preventing their
death or promoting their biological activity. So we try them in
diseases where we think this is important, such as Alzheimer's or
ALS."
     But, Gerrard explains, scientists don't understand the exact
pathology of these diseases, either, so use of neurotrophic
factors, again, takes a sort of shotgun approach.
     "Since these are tragic diseases with not terribly good
therapies," she says, "the idea is to try something that--even
though we don't know exactly how it works--may show promise." But
like Price, Gerrard counsels caution in clinical trials. John
DiGiovanna, M.D., a dermatologist with the National Cancer
Institute in Bethesda, Md., sees limited success so far in the use
of interferons for various skin conditions.
     "The anti-proliferative and cell-differentiating effects of
interferon might be useful in destroying some types of skin tumors,
for example, replacing the need for surgery," he says, "but the
question of how well it actually does work is still somewhat
controversial."
     Even for approved uses, cytokine therapies--like many others--
are not free of drawbacks. For example, he says, "Injections of
alfa interferon three times a week for three weeks to treat genital
warts can be expensive, awkward, painful, and the treatment doesn't
have a very high cure rate." Nevertheless, DiGiovanna says, many
conditions lack very effective treatments, and "it's always useful
to have another avenue to try when others can't be used any more or
don't work any more."

Wound-Healing Factors
     On the other hand, Anita Roberts, Ph.D., optimistically
envisions a host of future applications for another class of
cytokines--wound-healing factors--that help orchestrate healing.
Researchers are studying how these factors, given in larger
quantities than those produced naturally, might speed the healing
process.
     Roberts, a cell biologist with the National Cancer Institute,
is particularly interested in transforming growth factor beta (TGF-
beta). Whenever wounding occurs, TGF-beta and another cytokine,
platelet-derived growth factor (PDGF), are released. They attract
to the site of the injury various cells needed to combat infection,
cause clotting, and close the wound.
     The mending abilities of TGF-beta are being studied in venous
stasis ulcers (ulcers that develop in the leg because of
insufficient blood flow), and to speed healing from eye surgery to
repair macular holes. (The macula is the central part of the
retina.) In topical form, the substance is applied directly to the
wound.
     "I think, even more important than these applications is the
potential use of TGF-beta in normal wound healing," Roberts says,
pointing to a study in rats, reported in the December 1993 Journal
of Clinical Investigation, whose normal healing was suppressed by
steroids.
     In that study, a single intravenous injection of TGF-beta
significantly improved healing in rats whether it was given at the
time of wounding, four hours after wounding, or even 24 hours
before wounding. Roberts suggests the cytokine might enhance
healing in patients with a known impaired healing capacity, such as
those undergoing high-dose radiation therapy or chemotherapy, or in
elderly adults with impaired healing. She proposes it may also
prove useful given before surgery in elective procedures to speed
postoperative healing.
     PDGF is being studied in humans for possible use in
accelerating healing in chronic wounds, specifically diabetic foot
ulcers, which are fairly well managed. If it proves effective for
this type of sore, researchers may then try it in more serious
wounds. Its effectiveness is also being tested in periodontal (gum)
disease, where it is applied during surgery to help speed healing.

Is More Better?
     Cytokines may be a case of "if a little is good, more must be
better"--within reason, of course. These multipurpose proteins
produced naturally by the body in tiny quantities may, in larger
amounts, prove key to development of myriad new or improved medical
treatments.
     Cytokine research is still in its toddler-hood. Many more of
these "messengers" besides the ones mentioned here are now being
examined, and many more doubtless await scientists' future
identification and scrutiny. 

Marian Segal is a member of FDA's public affairs staff.