Cytokines’ steady march to labs
If cytokines labored under any slogan, it might well be the
popular political directive, "Think globally, act locally."
Taking the global perspective is easy. Pick a problem, and cytokines
are likely to be involved: Cancer. AIDS. Crohn’s disease. Rheumatoid
arthritis. Sepsis. Nosocomial infections. Diabetes. Asthma. Graft-versus-host
disease. Hypertension. Colitis. Postpartum anemia. And the list
Despite their far reach, however, cytokines appear to be most
successful clinically when they have a limited locus of operation.
Moreover, no one mechanism is likely to explain their function and
possible use. This is no field for dyed-in-the-wool absolutists.
Administering exogenous cytokines may be helpful in some casesand
in other cases can kill. Cytokines can be inhibited and replacedbut
in many cases should not be. Their presence may indicate spread
of diseaseor reveal absolutely nothing.
Confused yet? Hang onit’s only going to get worse.
"Never make an absolute in cytokine research," says Marion C. Cohen, PhD.
"Never," she repeats firmly.
Even the mere act of defining "cytokine" eludes simplicity. In
an interview with CAP TODAY as well as in a presentation given at
last year’s American Association for Clinical Chemistry annual meeting,
Dr. Cohen explained the ongoing puzzle that is cytokine nomenclature.
Cytokines were originally named for the activity they described,
which resulted in a plethora of three-, four-, and five-letter acronyms
and perpetual confusion as researchers deciphered cytokines’ complex
actions. "It was unclear whether each cytokine activity represented
a distinct cytokine or multiple activities of fewer cytokines. As
it turns out, it’s some of both," reports Dr. Cohen, associate professor
of pathology and laboratory medicine, UMDNJ-New Jersey Medical School,
Early definitions characterized cytokines as cell-derived, hormone-like
polypeptides that regulate cellular replication, differentiation,
or activation in processes relating to host defense and repair.
The next step in the definition evolution was this pronouncement:
Cytokines were cell-derived regulatory polypeptides involved in
the coordination of multicellular interactions. This was followed
by the view that cytokines were macromolecules that influence cellular
"Then it became ’a molecule with biologic effects,’ and, finally,
’a molecule,’" says Dr. Cohen, not entirely facetiously.
For sticklers who insist on a definition, the current generally
agreed-upon concept describes cytokines as simple polypeptides or
glycoproteins with molecular weights of usually less than 30 kd,
Dr. Cohen says. For many years cytokines were called hormone-like,
although the distinction is blurring, with growth hormones and prolactin
considered to be cytokinesat least by some.
Cytokine production is transient, and the action radius is typically
short. Cytokines create their actions by binding to specific high-affinity
cell surface receptors. Though individual cytokines can display
a broad and diverse range of actions, at least some actions of each
cytokine are targeted at hemopoietic cells. And while researchers
used to believe all cytokines were secreted, "We know today there
are at least some membrane-bound forms of some of the secreted cytokines,
and at least one chemokine that seems to be completely membrane
bound," Dr. Cohen says.
Manybut not allcytokines have multiple target cells
and actions. Redundancy is common with some groups of cytokines;
different groups may have similar actions. Synergy as well as antagonism
can occur. Simultaneous exposure of cells to multiple cytokines
can lead to qualitatively different responses; likewise, a cytokine
may increase, decrease, or otherwise affect production of another
cytokine or the expression of another cytokine’s receptors.
Classification of cytokines can be somewhat arbitrary as well.
In her AACC presentation, Dr. Cohen outlined the following categories:
- cytokines that mediate and regulate innate immunity, such as type 1 interferons; tumor necrosis factor-alpha; interleukin-1,
-6, -10, -12, and -15; and chemokines (although not everyone subscribes to the chemokines-are-cytokines theory).
- cytokines that in general mediate and regulate specific immunity, including IL-2, -4, -5, -13, -16, and -17; interferon-gamma; transforming growth factor-beta; and lymphotoxin (also known as tumor necrosis factor-beta).
- cytokines that stimulate hematopoiesis, which include IL-3, -7, -9, and -11; and the colony-stimulating factors.
Cytokines can also be grouped on the basis of their receptors, according
to the sequence homology of the receptors to which they bind, Dr.
Cohen says. Families of receptor proteins include the immunoglobulin
superfamily; cytokine receptor 1 and 2, or the hematopoietins; the
TNF receptor family; and the family of receptors involved in chemokines.
Not surprisingly, the families are often further divided into subfamilies.
All this might be a matter of interest only to chemistry genealogists
if some general rules of behavior could be applied to cytokines.
They can’t. Thus, anyone who wants to understand the function and
possible clinical utility of a particular cytokine better be prepared
to give that cytokine fairly close scrutiny.
"The only thing you can say with any assurance about cytokines
is that the old notion we hadthat you can identify a specific
cytokine as having a specific function physiologically or a specific
pathologydoesn’t seem to happen. What you have is a smorgasbord
of cytokines and a given reaction that you have to study," says
Stanley Cohen, MD, who is credited with minting the word "cytokine"
as well as being the first to describe cytokine function (Cohen
S, et al. Cell Immunol. 1974;12:150 and Cohen S, et al. Mechanisms
of Cell-Mediated Immunity. New York: Wiley; 1974:331-358).
Measuring cytokines presents pathologists with an ample melange
of choices as well. "We’ll probably never have a situation where if
you have one single value it absolutely says you have this one single
disease," says Daniel Remick, MD, professor of pathology, University
of Michigan, Ann Arbor. "It’s always going to be a complicated matter,
because so many dynamic interactions take place, on so many different
Yet Dr. Remick and others are convinced clinical laboratories
will be called on to measure cytokines for their clinical colleagues.
Understandably, they just don’t know when. Or how. Or why. At least
"I see a really, really big role for pathologyat some point,"
says Dr. Stanley Cohen, who chairs the Department of Pathology at
UMDNJ-New Jersey Medical School, Newark.
"We’re going to be asked to do this for a number of reasons,"
says Dr. Remick, who also spoke about cytokines at the AACC meeting.
Cytokines and their inhibitors are slowly but surely creeping into
the clinical setting, he notes. At the same time, as researchers
further unravel the link between cytokines and various diseases,
measuring cytokines undoubtedly will assist clinicians with differential
In fact, Dr. Remick reports, his laboratory has already begun
fielding requests from clinical colleagues to test for cytokines.
Predictablygiven cytokines’ omnipresencethe requisitions
come from all over. "We hear from rheumatologists and cancer specialists,"
Dr. Remick says. "People doing clinical trials. Trauma burn surgeons.
Gastroenterologists. You name it."
Reading about cytokine research in the literature seems to prompt
many of the requests, Dr. Remick says. "They read about a study
in a journal and say, ’Oh, if I could measure this, then I could
determine what to do next.’"
Likewise, says Dr. Marion Cohen, the word about cytokines is beginning
to leak into the popular press. "A few weeks ago I saw an article
about medical treatments in New York magazine, of all places,
and it talked about cytokines. I said to my husband [who happens
to be Dr. Stanley Cohen], ’Look, cytokines are entering prime time
for the public.’
"On the other hand," she’s quick to add, "they’re certainly not
ready for prime time for most treatments and certainly not for most
How soon might cytokine testing take center stage? It’s hard to
say, experts agree.
"We’re closer than we were," says Monica L-S Tsang, PhD, vice
president of research at R&D Systems, which manufactures research
reagent kits for measuring cytokines. "But we are still far away.
It’s simply a matter of time before measurements of certain cytokines
will be useful for certain diagnoses, but we don’t know how long
that will be. Maybe years."
Or maybe not. Says Lance Fors, PhD, president and CEO of Third
Wave Technologies: "There’s a tremendous amount of interesting information
that will be coming out in the literature in the next six months
that will help drive the initial utilities of this into the clinical
situation." Though he declined to be more specific, given that the
studies were pending publication, he noted his predictions were
based on his company’s collaborations with researchers propelling
the need for cytokine assays.
"We’re out there in the field and are a lot closer to new developments
than most people," he says. "So there’s no doubt in my mind cytokines
are moving toward the lab, and it’s coming much, much faster than
most people realize. There’s some exciting discovery work going
on, and it’s pretty late-stage. And it’s going to drive what happens
in the clinical labs."
Researchers have unveiled scores of new findings related
to cytokines, some, all, or none of which may beat a path to the
laboratory and clinical settings. Picking the likely winners requires
beating odds that would make most bookies smile greedily.
"It’s hard," admits Dr. Marion Cohen. "Everybody’s got their favorite
She gives the nod to chemokines. "There seems to be a lot of effort
expended in this area right now," she says, particularly with regard
to the role chemokine homologues or chemokine receptor homologues
play in certain viral diseases. "We also know HIV uses some chemokine
receptors as cofactors for entering cells," she adds, "so this is
an important area for HIV research."
Among other favorites, Dr. Stanley Cohen says he’s intrigued by
the potential impact of cytokines in embryogenesis differentiation.
"This is going to be tremendously interesting," he predicts. "Many
of the factors involved in influencing and controlling this are
regulated by cytokines, which may make their appearance very early
in immunologic development."
A by no means exhaustive (though possibly exhausting) overview
of promising cytokine developments includes the following.
Cancer. One current hope is that cytokines will be useful
at least as an adjunct therapy for cancer, by modifying them and
delivering them in what Dr. Remick calls "industrial-strength doses."
Interleukin-2 and tumor necrosis factor are among the most widely
used cytokines for cancer therapy and have met with varying success,
Dr. Remick reports. Originally used by itself, IL-2 now is primarily
used in conjunction with lymphokine-activated killer cells or tumor-infiltrating
lymphocytes. IL-2 has been used extensively in treating patients
with renal cell carcinoma, with the first clinical trialssome
of which also involved interferonbeing done in patients with
advanced or widely metastatic disease. Response rates run between
20 and 30 percent, he reports, "which doesn’t sound great until
you remember that these were patients who failed everything else."
IL-2 has also been used in patients with advanced or widely metastatic
melanoma; response rates again range between 20 and 30 percent.
TNF embodies the ignominy of cytokine failure as well as the promise
of success. "We originally thought TNF-alpha would possibly be capable
of killing tumor cells and under certain conditions would be the
treatment of choice," Dr. Marion Cohen says. "But by and large that
hasn’t panned out." Ironically, one reason for TNF’s failure has
been its own importance, which has made it difficult to pin down
for clinical use. "It does so many things, and it has proved to
be such a critical cytokine, capable of causing good as well as
harm under various circumstances," she says. "That’s one of the
biggest problems with cytokines."
The dose-limiting toxicities of TNF have also stunted its application,
although it can be used in isolated limb perfusion to avoid amputation
in patients with widely metastatic disease. In this setting, surgeons
isolate the endangered limb with a tourniquet, cannulate the appropriate
artery and vein, and administer high-dose TNF in addition to chemotherapeutic
agents. "Clinically the response is spectacular," says Dr. Remick.
Toxicity has plagued other cytokines as well. IL-12 given systematically
as a recombinant protein caused severe toxicity (including two reported
fatalities) in a phase II clinical trial, for example, which halted
further clinical development despite its intense antitumor activities.
Yet researchers have suggested at least one possibility for circumventing
that problem. In a recently published study (Narvaiza I, et al.
J Immunol. 2000;164:3112-3122), a Spanish team found that
adenoviral vectors expressing the chemokine interferon-gamma-inducible
protein-10, or IP-10, and suboptimal doses of IL-12 extinguished
tumors in a mouse model of colorectal cancer.
"Our results are very encouraging because of the potency of the
antitumor activity that we observe even at very low levels of IL-12
gene transfer," says Ignacio Melero, MD, PhD, of the University
of Navarra School of Medicine, Pamplona, Spain. "The overall synergistic
effects were able to eradicate large established murine tumor nodules."
The team is now preparing for several clinical trials, one of
which will use a human version of a recombinant adenovirus encoding
for IL-12 genes. "The clinical setting for our studies is very challenging,
for there is not current treatment for such malignancies at those
advanced stages," Dr. Melero says, adding that U.S. groups plan
to use similar gene transfer technology in other tumors, such as
melanoma, that traditionally have been more responsive to immunotherapy.
Granulocyte colony-stimulating factor and IL-11 are among other
cancer-related cytokine success stories, according to Dr. Remick.
IL-11 reduces the need for platelet transfusions following chemotherapy,
in addition to reducing the time needed to recover from thrombocytopenia.
G-CSF, which increases and enhances the number of circulating neutrophils,
has been indicated for use in chemotherapy, bone marrow transplantation,
inducing progenitor cells, and radiation therapy, as well as for
treating febrile neutropenia and for some nonneutropenic settings.
Inhibiting cytokines related to angiogenesis is another "hot area
of research right now," says Dr. Stanley Cohen.
At the same time, researchers recently have demonstrated that,
when elevated in plasma, two angiogenesis-related cytokinesvascular
endothelial growth factor and hepatocyte growth factormay
indicate the presence of a tumor.
The investigators tested plasma levels of five cytokines, including
VEGF and HGF, in 75 patients with a variety of solid tumors. Statistically
significant differences in VEGF and HGF levels were found in subjects
who had local disease compared with those who had metastatic disease.
"In the case of VEGF, this is likely to reflect the increase in
angiogenesis that accompanies tumor growth," explains Michael S.
Pepper, MD, PhD, one of the researchers involved in the study, which
was published earlier this year (Fuhrmann-Benzakein E, et al. Int
J Cancer. 2000;85:40-45). "In the case of HGF, this is likely
to reflect the increase in tumor bulkmany of the tumors were
carcinomas, which are epithelial in nature, and in which HGF is
likely to be an important tumor cell growth factor." Therefore,
he adds, "I would think that measuring both is optimal."
Dr. Pepper, senior lecturer in the Department of Morphology, University
of Geneva Medical Center, Switzerland, notes the timing of blood
sampling was critical. He and his colleagues observed an augmentation
in plasma concentrations in the early postoperative period for VEGF
in breast and ovarian carcinomas, and for HGF in ovarian and hepatocellular
carcinomas, followed by a decrease when measurements were made on
samples collected two weeks later. The early increase, they suggest,
may be associated with normal wound healing. The researchers are
now setting their sights on a more in-depth prospective study of
selected common tumorslung, colon, breastusing serial
Congestive heart failure. Compelling evidence exists that inhibiting
TNF may be useful in treating congestive heart failure in patients
with high plasma levels of TNF. Phase II and phase III trials are
underway and appear promising, says Dr. Remick. "It’s too early to
say, of course, but it may offer a whole new class of agents for treating
One caveat, he cautions, is that patients with
Crohn’s disease or rheumatoid arthritis, who also respond well to
TNF inhibitors, do not have elevated TNF levels. Those diseases
may be driven by local concentrations of TNF, rather than plasma
levels. "It may be a little bit easier with congestive heart failure,
because the heart is pumping the blood, giving you a better chance
of having access to the local levels that are causing the congestive
Transplantation. Cytokines are associated with disregulations
as well as disease. Polymorphisms in the promoter regions of various
cytokines may be predictors of clinical response to liver transplantation,
for example. "If this turns out to be a common pattern, molecular
diagnostic labs will be looking for cytokine polymorphisms," predicts
Dr. Stanley Cohen.
Dr. Fors adds that a number of studies suggest a donor’s specific
expression pattern or specific polymorphism for a given cytokine
could be as valuable as HLA tissue typing for predicting transplant
In other work, researchers have shown that an antibody targeted
against the gamma-chain common to the five known T cell growth factor
receptorsIL-2, -4, -7, -9, and -15allows stable engraftment
of pancreatic islet transplants by inducing apoptosis of activated
Reporting in a recent issue of The Journal of Immunology
(Li XC, et al. 2000;164:1193-1199), Xian Chang Li, MD, PhD, and
colleagues hypothesized that blocking the signaling component represses
T-cell activation, permitting long-term engraftment.
"Most people have thought that in order for the graft to survive,
the only thing you need to do is turn off the immune system with
a potent immune suppression," says Dr. Li, assistant professor of
medicine at Harvard Medical School, Cambridge, Mass. "This is what
we practice in the clinic: We give a patient as many drugs as we
can to suppress the immune system, and then we hope the graft will
That may not be the best approach, he suggests. "Immune tolerance
is a learned process," he postulates, one that requires new T-cell
activation. This requires engagement between the foreign antigen
expressed on the graft and the host T cell; once it occurs, only
T cells activated by the graft will be allowed to die, creating
a very selective tolerance.
In the study done by Dr. Li and colleagues, mice treated with
a control antibody rejected the allografts within 17 days; 75 percent
of those treated with the common gamma-chain antibody had graft
survival beyond 150 days.
Use of the antibody against the gamma-chain has a significant
drawback: Its low affinity may be unable to compete with the high-affinity
cytokines for binding. Instead, the better approach might be to
block the signaling process mediated by the common gamma-chain,
using, for example, a JAK3 inhibitor to bypass the competing antibody
and cytokines. It’s an approach that has already caught the eyeand
presumably dollarsof a number of major pharmaceutical companies,
Diabetes. Another mouse model has explicated the role of
cytokines in the pathogenesis of autoimmune diabetes.
Pere Santamaria, MD, PhD, and colleagues recently published a
study in The Journal of Clinical Investigation (2000;105:459-468)
that suggests proinflammatory cytokines promote diabetogenesis by
marking pancreatic beta cells for Fas-dependent destruction by highly
pathogenic, autoreactive CD4-positive T lymphocytes. However, beta
cells in the animals normally do not express Fas at sufficiently
high levels to be detected by lymphocytes. "So something else had
to be happening," says Dr. Santamaria, associate professor, Department
of Microbiology and Infectious Diseases, University of Calgary,
The missing piece of the puzzle "turned out to be some cytokines,"
he says, namely interferon-gamma, TNF-alpha, IL-1-alpha, and IL-1-beta.
When the cytokines are secreted at the site of inflammationin
this case the pancreasthey stimulate the pancreatic beta cells
to express higher levels of Fas on the surface. This permits the
lymphocytes to engage Fas and trigger apoptosis. "It’s as if they
paint the beta cells for death," Dr. Santamaria says. Evidence from
human tissue studies suggests Fas may be implicated in the destruction
of human pancreatic beta cells as well, he adds.
Inhibiting the expression of these cytokines early on may delay
onset of diabetes, he suggests. "Obviously there are exceptions,
but in general terms, interfering with the expression of interferon-gamma
or TNF can delay or prevent onset of the disease in animal models."
However, blocking only one cytokine is not sufficient. "If you
impede one, the others will still upregulate Fas expression on the
beta cellyou have to figure out how to suppress them all to
achieve a complete effect. And that’s difficult to do."
Rheumatoid arthritis and Crohn’s disease. Soluble receptors
for TNF are considered to be a major therapeutic advance in treating
rheumatoid arthritis. In 1998 they were given the green light by
the Food and Drug Administration for treating this disease in adults;
they’re presently on the FDA fast track to be approved for juvenile
rheumatoid arthritis, Dr. Remick reports. The receptors appear to
be most effective when given in conjunction with methotrexate, and
recipients of this therapy show a significant decrease in the number
of swollen and tender joints.
Also in use for treating rheumatoid arthritisusually in
conjunction with other therapiesare monoclonal antibodies
that bind to and inactivate TNF. "Patients exhibit a significant
decrease in the number of tender joints and in the pain score, and
a significant decrease in C-reactive protein," Dr. Remick says.
Anti-TNF is establishing a strong track record in treating Crohn’s
disease as well. In one study, patients who failed high-dose steroids,
cyclosporine, combination therapy, and other conventional treatments
exhibited an 80 percent response rate when treated with anti-TNF,
with significant drops in their Crohn’s disease activity index as
well as CRP levels.
Anemia. Erythropoietin has been "a real success story"
for the treatment of anemia secondary to chronic renal failure,
Dr. Remick says. Some 95 percent of patients with chronic renal
failure respond to erythropoietinwhich boosts the number of
red blood cells in the peripheral blood by stimulating progenitor
cells in bone marrowwith an increase in their hematocrit.
Following two months of treatment, virtually all patients are transfusion
This cytokine also appears to effectively treat anemia secondary
to AZT therapy for human immuno-deficiency virus. One study showed
it reduced the cumulative number of transfused blood units by 40
percent. And when administered to surgical patients two weeks prior
to surgery, erythropoietin may reduce the need for packed red blood
transfusions, maintain hematocrit levels, and speed recovery.
Hypertension. High levels of transforming growth factor-beta-1
in African-Americans may explain their higher risk of hypertension
and related complications, according to a recently published report.
(Suthanthiran M, et al. Proc Natl Acad Sci U S A. 2000;97:3479-3484).
Researchers measured TGF-beta-1 protein levels and TGF-beta-1
mRNA levels in peripheral blood mononuclear cells; they also performed
TGF-beta-1 codon 10 genotyping in Caucasian and African-American
hypertensive and normal subjects.
TGF-beta-1 protein levels were higher in hypertensive subjects
(261 ng/mL) than in normal subjects (188 ng/mL), and highest in
African-American hypertensives (322 ng/mL). Among normotensives,
TGF-beta-1 protein levels were also higher in blacks (221 ng/mL)
than in whites (165 ng/mL). A similar pattern occurred in TGF-beta-1
mRNA levels, although the racial differences were not statistically
significant. The researchers hypothesize that TGF-beta-1 along with
other growth factors may directly cause high blood pressure and/or
endothelial fibrosis and vascular injury.
How might clinical laboratory tests fit into these various scenarios?
Take your pick. It could be as simple as an ELISA, or as complicated
as PCR. Or a bit of both.
R&D Systems’ Dr. Tsang, also a speaker at the AACC meeting,
outlines several methods for measuring cytokines. At the protein
level, approaches include:
- bioassays, which measure the biologically active molecule.
- immunoassays, which detect not only the biologically active molecule but the denatured inactive cytokine and cytokine precursors,
- functional immunoassays, which can use the extracellular domain of a cytokine receptor, which in turn binds only to the active
- receptor-binding assays, which are another form of functional assays and which use cell fragments, rather than a living cell,
for the binding study.
Immunoassays and functional immunoassays are by far the most specific
and sensitive, can be done quickly, are cost-effective, and are amenable
to automation and high-throughput applications, Dr. Tsang notes. Because
immunoassays measure active and inactive cytokine fragments and precursors,
manufacturers often substitute receptor bodiesbasically recombinant
proteinsfor antibodies in both competitive and noncompetitive
ELISA formats. These bind to the biologically relevant active form
of the cytokine but not to precursors or fragments.
The majority of available cytokine immunoassays and functional immunoassays are
primarily for research use. Because many of them are still in development,
they’re not widely standardized. "It’s not like getting a glucose,
where you know what it means coming from any hospital in the country,"
says Dr. Remick. Cytokine levels can vary depending on the reagents
used, how the assay is performed, the presence of reagents or proteins
in human plasma, interference from soluble receptors, complex structure,
and so on. That makes it "a little hard to use a value from the
literature for making therapeutic decisions, because it’s hard to
know what your value is compared to what the literature value is,"
Serum plasma samples are especially problematic because of their
many interfering substances. Dr. Pepper points to the significance
of measuring plasma values versus serum values in his study of VEGF
and HGF in cancer patients, which used R&D’s sandwich ELISAs to
assess the cytokine levels.
"Many reports prior to our own used serum for their measurements,"
he says. "However, platelets contain large quantities of VEGF, and
serum values are therefore unlikely to be a true reflection of circulating
levels of VEGF." The same does not appear to hold true for HGF,
Because cytokines rarely act alone, measuring panels of cytokines
on multiplex systems may be the most reasonable approach, says Dr.
Tsang. "Yet when you’re trying to measure many cytokines simultaneously,
you don’t know whether conditions for one assay may interfere with
the other, so we suspect it will work for some combinations but
R&D primarily continues to develop kits for single cytokine
measurements, she reports, but some clients have begun requesting
panels for multiple, custom cytokines. R&D also manufactures
what it calls RNA quantikine kits, which measure levels of cytokine
In addition to other applications, Third Wave has used its Invader
platform to look at cytokine gene expression as well as cytokine
polymorphisms, says Dr. Fors. "We’re developing a full panel that
will probably encompass up to a hundred cytokines and chemokines
for quantitative gene expression analysis." The company currently
has a panel of cytokine assays, about 15 of which are available
to pharmaceutical partners.
Dr. Melero, of the University of Navarra, foresees any number
of possible roles for laboratories should cytokine gene therapy
move beyond the research realm.
"Biopsies of tumors will be informative to assess whether an immunological
reaction is taking placefor instance, taking a look at the
inflammatory infiltrate at the treated solid tumors," he says. "Genetic
and immunohistology analysis of tumor cells can disclose if escape
variants of the tumors are being selected out. Traditional blood
tests will monitor the patients in order to detect adverse effects."
The possibilities for therapeutic drug monitoring are not so clear,
Dr. Remick says. "Intuitively it makes sense that you’d want to
monitor therapy. On the other hand, usually optimum doses are determined
by dose-ranging studies. Having said that, though, there are a number
of situations where there may be an optimal window for delivering
cytokine inhibitors, so it’s quite possible that testing of this
sort may evolve, similar to measuring cyclosporine levels or trough
Moreover, testing cytokine levels prior to starting a therapy
"is probably worthless, at least right now," he ventures, in part
because the correlation between plasma levels and disease activity
is not necessarily a strong one, particularly if disease activity
is localized, as is the case with rheumatoid arthritis, Crohn’s
disease, and diabetes.
Given the multiple variables involved in any cytokine equation,
it’s understandable why testing possibilities remain vague. Even
in situations where a cytokine level clearly corresponds to a disease
state, testing may not be worthwhile. High levels of IL-6, for example,
invariably indicate sepsis. "But most clinicians don’t need a blood
value to make a decision about whether the patient is septic or
notthey can tell by looking at the patient. And they probably
wouldn’t treat on the basis of that individual value," says Dr.
Yet hope for cytokine testing springs eternal. While attending
a medical meeting in Munich in March, Dr. Remick says he learned
neonatologists in Europe are routinely using plasma IL-8 levels
in lieu of neutrophil counts to determine the presence of nosocomial
infections in their patients. "It’s exciting, because clinicians
are using IL-8 numbers to make a decision about whether to give
antibiotics or not."
Perhaps such actions represent a solid step forward for cytokines
after multiple false starts. "There’s been a lot of disappointment
in cytokine research, but I think we’ve bottomed out and are finally
on the upward side of the curvealthough I’m sure others may
disagree," says Dr. Marion Cohen.
If nothing else, researchers have learned one sure lesson, she
says. "The easy things didn’t work. Now we’ve got to work a little
Karen Titus is CAP TODAY contributing editor and co-managing editor.