148
Cytokines: Interleukins
outcome. When IL-6 is expressed under
the control of the human Ig heavy chain
promoter in B cells, the result is IgG1 plas-
macytosis and inFltration of plasma cells
into lung, spleen, and kidney. If, however,
IL-6 is expressed under the control of the
human keratin (K14) promoter in skin and
tongue, there is growth retardation, poor
hair growth, and epidermal scaliness (tail,
paws), but no changes typical of psoria-
sis. By contrast, if bone marrow cells are
infected with an IL-6-expressing recombi-
nant retrovirus, a fatal myeloproliferative
disease with massive neutrophil inFltra-
tion of lungs, liver, and lymph nodes
develops within four weeks of engraft-
ment, but no plasmacytosis occurs. As a
further example of the diverse outcomes
of constitutive interleukin expression, it
has been found that IL-4 expression in
the thymus and T cells results in thymic
hypoplasia, inflammatory ocular lesions
(blepharitis), and raised IgE and IgG1 lev-
els, whereas IL-4 expression in B cells
results in raised IgE and IgG1, but no
thymic hypoplasia or blepharitis. Such dif-
ferences indicate an importance of where
or in which cells an interleukin is ex-
pressed, together with the quantitative and
temporal elements, on the outcome.
7
Clinical Uses of Interleukins
The biological activities of interleukins
have suggested that some may be of clin-
ical use as therapeutic agents in human
diseases as shown in Table 6. ±or exam-
ple, the stimulating activity of IL-2 on
the cytotoxic function of NK and LAK
cells against tumor cells
in vitro
suggested
that IL-2 had potential as an anticancer
agent. Thus, once adequate amounts of
recombinant IL-2 (rIL-2) became avail-
able, clinical trials to evaluate rIL-2 in
different human malignancies were car-
ried out. It was quickly established that
high-dose IL-2 therapy caused severe side
effects, for example, hypotension, olig-
uria, fluid retention, breathing difFculties,
heart problems, with the dose-limiting side
effect being the so-called
vascular leak syn-
drome
. In the latter, fluid extravasation and
subsequent edema (swelling) takes place in
the pleural and peritoneal cavities. The un-
derlyingcauseappearstobetheadherence
of IL-2-activated lymphocytes to vascular
endothelial sites, that is, the linings of
blood vessels, resulting in holes in the en-
dothelial cell layer being produced through
which fluids leak. Despite these severe side
effects, some tumor responses were found
in a limited number of malignancies, in-
cluding renal cell carcinoma, melanoma,
and non-Hodgkins lymphoma. However,
overall response rates with IL-2 as a single
agent have been disappointingly low. New
strategies involving combinations of IL-2
with other cytokines (e.g. I±N
α
,TN±
α
), an-
titumor monoclonal antibodies, cytotoxic
d
ru
g
s
,o
rLAKc
e
l
l
sr
em
o
v
edb
yl
eu
k
o
-
pheresis, activated by IL-2 and grown
ex
vivo
before reinfusing back into the patient,
have or are being tested in order to improve
efFcacy. The most ‘‘successful’’ approach
has been that of adoptive cellular therapy
where activated LAK cells are combined
with high doses of IL-2. However, this
is a highly aggressive antitumor therapy,
which has serious complications for pa-
tients, with major life-threatening side ef-
fects. Despite initial tumor regressions fol-
lowing this therapy in ‘‘hard-to-treat’’ can-
cers such as colorectal cancer and malig-
nant melanoma, in most instances remis-
sions were not durable. A more sophisti-
cated approach in which tumor-inFltrating
lymphocytes
(TIL)
are
obtained,
IL-2
previous page 1468 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 1470 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off