From www.bloodjournal.org by guest on November 1, 2016. For personal use only.
The Journul of
BLOOD
VOL 79, NO 12
REVIEW ARTICLE
Interleukin-5, Eosinophils, and Disease
By Colin J. Sanderson
E OSINOPHIL production can be induced in vitro by
interleukin-3 (IL-3), granulocyte-macrophage colony-
stimulating factor (GM-CSF), and IL-5. Both IL-3 and
GM-CSF have activities on other hemopoietic lineages,
whereas IL-5 is specific for the eosinophil/basophil lineage.
The activity of IL-5 on basophils has been reviewed
recently' and will not be discussed here. There is now good
evidence that IL-5 is the major, and possibly the only,
cytokine involved in the production of specific eosinophilia.
Classically eosinophilia is observed in a restricted number
of diseases, most notably helminth infections and allergic
diseases. However, although the increase in eosinophil
numbers is less spectacular, there is increasing evidence for
an involvement of eosinophils in a wider spectrum of
diseases.
A study of experimental infection of volunteers by the
hookworm Necator americanus gave clear evidence for an
increase in eosinophils with no significant increase in other
blood leucocytes,2 and infection of mice with the cestode
Mesocestoides Corti causes a massive increase in blood and
peritoneal eosinophils with little effect on the number of
ne~trophils.~ This biologic specificity, the relatively re-
stricted disease profile of eosinophilia, and the requirement
for a functional T-lymphocyte ~ y s t e m suggested
~-~ that the
control of eosinophilia must be part of the immune re-
sponse and based on a subset of T celk7
Eosinophils are cytotoxic cells capable of killing hel-
minths, parasitic protozoa, chicken erythrocytes, and tumor
cells in vitro. For more general reviews and background see
Spry,8 Dexter et a1,9 Thompson,'O and Smith and Cook.ll
Time-lapse cinematography has shown that eosinophils
phagocytose and regurgitate red blood cells very rapidly.
This is in contrast to neutrophils and macrophages that
retain them until they have been broken down.12 This
explains why eosinophils appear to be less active in compar-
ison to neutrophils in classical phagocytosis assays using
yeast or bacteria. They do not retain the particles. It is
unclear what this implies for the killing ability of the
eosinophil, but it is possible that they are better adapted to
attach to large parasites13rather than to phagocytose small
particles.
IL-5 STRUCTURE
IL-5 is unusual among the T-cell-produced cytokines in
being a disulphide-linked homodimeric glycoprotein. It is
Blood, Vol79, No 12 (June 151,1992: pp 3101-3109
The American Society of Hematology
JUNE 15, 1992
highly homologous between species, as indicated by the
high sequence homology between mouse and human 1L-5
and the cross-reactivity of the protein across a variety of
mammalian species. Mature human IL-5 monomer com-
prises 115 amino acids (molecular weight [M,] of 12,000and
24,000 for the dimer). The secreted material has an M, of
40,000 to 45,000, and thus nearly half the native material
consists of carbohydrate, although this carbohydrate does
not appear to be necessary for biologic activity in vitro.14
Studies with mouse IL-5 indicate that the monomer has no
biologic activity and has no inhibitory activity, suggesting
that they do not form high-affinity interactions with the IL-5
receptor (IL-5R).IS The dimer exists in an antiparallel
(head to tail) c o n f i g u r a t i ~ n . ~ ~ - ~ ~
INTERACTION WITH IL-5 R
Binding studies of IL-3, IL-5, and GM-CSF to human
eosinophils showed cross-inhibition, suggesting some com-
mon components in the receptors for each cytokine.18J9
Murine eosinophils have been calculated to express approx-
imately 50 high-affinity receptors for IL-5 (kd in the range
of 4 to 6 x lo-'' mol/L) and approximately 5,000 low-
affinity rceptors (kd in the range of 0.3 to 2 x
mol/L).20Initial work on the human receptor used a clone
of the human promyelocytic leukemia cell line HL-60.*l
These cells express only a single population of high-affinity
IL-5 binding sites. Similarly, only a single high-affinity
receptor population (kd range, 3 to 6 x lo-" mol/L) has
been identified on human eosinophil^.^^-^^
Recent work has shown that each of these human
receptors consists of (at least) an a- and a P-chain. The
a-chains are unique to each cytokine and form a group of
homologous glycoproteins within the hematopoietin recep-
tor super family.25The a-chain forms a low-affinity bond
with the analogous cytokine. The P-chain is common to all
From the Searle Research Group, Department of Biochemistry,
Oxford, UK.
Submitted January 21,1992; accepted March 26,1992.
Address reprint requests to Colin J. Sanderson, ScD, Searle Re-
search Group, Dept. of Biochemistry, S Parks Rd, O.aford, OX1 3QU
UK.
0 1992 by The American Sociery of Hematology.
0006-4971I921 7912-0036$3.0010
3101
 From www.bloodjournal.org by guest on November 1, 2016. For personal use only.
3102
three receptors and in combination with the a-chain forms
the high-affinity r e c e p t ~ r . It~ ~seems
. ~ ~ likely that the cross
inhibition exhibited within the group is due to limiting
numbers of p-chains.28
Structure-function studies exploiting human-mouse hy-
brid molecules and the distinct cross-species reactivities
displayed by these molecules identified an important role
for the C-terminal region in the determination of both
biologic activity and receptor binding.29,30 There is an area
of sequence similarity, determined using Dayhoff mutation
indices, at the C-terminal region of a number of different
cytokines, including IL-5.31 The head-to-tail arrangement
of the dimer and the importance of the C-terminal regions
of the molecule imply that the configuration of the IL-5
molecule probably forms two receptor binding sites.
Experiments with GM-CSF suggest that the p-chain may
bind in the region of residue 2132 and a series of mouse-
human GM-CSF hybrids identified residue 20 as important
in the interaction with the p-chain. Furthermore, a hybrid
in which the N-terminal region of GM-CSF was substituted
by the analogous region from IL-5 showed strong biologic
activity. This very elegant approach showed that IL-5 uses
the same P-receptor subunit as GM-CSF, and implies an
interaction between the p-chain and the N-terminal region
of the cytokine molecule.33
The mouse receptors show some differences with the
human counterparts. Firstly, there is no demonstrable
cross-inhibition, possibly indicating that the p-chains are
present in excess. Secondly, the receptors show both high-
and low-affinity binding, whereas those in humans show a
single class of high-affinity binding. Thirdly, the counterpart
of the human IL-3 a-chain has not been identified. A
protein (AIC2A) binds to IL-3 with low affinity34and is
closely related to a protein (AIC2B) that is the P-chain for
the IL-5R.3SJ6 However, expression of the two proteins
(AIC2A) and AIC2B) does not reconstitute a high-affinity
receptor for IL-3, and so the structure of the high-affinity
I L 3 R is not yet clear. Finally, mouse B cells express
IL-5R37-39and the generation of IL-5-dependent murine
pro-B-cell lines has greatly facilitated the characterization
of IL-5R.37,40
An intriguing aspect of the cloning of the IL-5R was that
the most abundant transcript encoded a soluble form of the
receptor, lacking a transmembrane regi0n.2~9~~ This soluble
form was inhibitory in an eosinophil differentiation assay
with IL-5, raising the possibility that eosinophil production
may be regulated by switching between a membrane-bound
and a soluble form of the IL-5R.
CYTOKINE GENE CLUSTER
The genes encoding IL-3, IL-4, IL-5, and GM-CSF share
certain structural features and form a cluster on chromo-
some 5 in human^^^,^^ and on chromosome 11 in the
mouse.44This finding suggests that they are members of a
gene family and raises the possibility of common mecha-
nisms in the control of expression. Studies with T-cell
clones in vitro indicate that IL-4 and IL-5 are often
coexpressed in clones designated Th2.45 However, anti-
CD3 induces the expression of IL-4, IL-5, and GM-CSF
COLIN J. SANDERSON
messenger RNA (mRNA) in mouse T cells, whereas
treatment with IL-2 induced IL-5 mRNA expression but
did not induce detectable IL-4 or GM-CSF.& That eosino-
philia can occur without increases in other leukocytes
suggests an independent control for IL-5 expression, while
the association between high levels of IgE antibody and
eosinophilia suggests coordinate expression of IL-4 and IL-5
in these cases.
The molecular mechanism of the regulation of the genes
in this cytokine gene cluster is not understood, but it
appears likely that both common and independent control
mechanisms exist between IL-5 expression and the expres-
sion of the other genes.
PRODUCTION OF EOSINOPHILS IN VITRO
The first studies on the production of eosinophils in
vitro4 indicated that an eosinophil colony-stimulating activ-
ity was present in mouse spleen-conditioned medium.
However, with mouse marrow the eosinophil colony assay
has low sensitivity compared with simple liquid culture
~ y s t e m s , 4and
~ - ~ it~ was the development of a liquid assay
and quantification by assay for eosinophil peroxidase that
led to the identification of a murine cytokine called eosino-
phil differentiation factor and subsequently termed IL-
5.7,31,51,52Although the difference is not so marked with
human bone marrow cells, IL-5 performs poorly in colony
assays compared with IL-3 and GM-CSF, whereas in liquid
cultures the situation is reversed and IL-5 stimulates more
eosinophil production than the other c y t o k i n e ~ . ~ ~ ~ ~ ~ , ~ ~
Whereas IL-5 is specific for the production of eosinophils,
both GM-CSF and IL-3 induce the production of neutro-
phils, macrophages, and e o ~ i n o p h i l s . ~ ~ ~ ~ ~
A number of studies have suggested that IL-5 is a
late-acting factor for eosinophil production. The transient
production in vitro in both human and mouse culture
systems suggests that IL-5 is incapable of stimulating the
production of eosinophil precursor^.^,^^^^^,^^ Other studies
have suggested a network of cytokines is involved in the
production of eosinophil precursor^.^^^^^ Both IL-3 or GM-
CSF can induce a significant increase in eosinophil precur-
sors, as assessed by colony formation in semi-solid agar
cultures with IL-5,58-60which is consistent with the network
hypothesis. However, a network involving cytokines with
activities on other lineages is difficult to reconcile with the
biologic specificity of eosinophilia.
IL-5 ACTIVITY IN VIVO
In contrast to studies in vitro, experiments in vivo clearly
indicate the central role of IL-5 in eosinophilia and indicate
that experiments in vitro may be misleading, possibly
because the culture conditions do not accurately reproduce
the microenvironment of the bone marrow.
The administration of anti-IL-5 antibody to mice in-
fected with Nippostrongylus brasi1iensis:l Schistosoma man-
soni,62Heligmosomoidespolygylu~,~~ or Strongyloides venezu-
elensis@ totally blocked the development of eosinophilia.
These experiments show the essential role that IL-5 per-
forms in the control of eosinophilia in such parasite
infections. In addition, they show that the apparent redun-
 From www.bloodjournal.org by guest on November 1, 2016. For personal use only.
INTERLEUKIN-5, EOSINOPHILS, AND DISEASE
dancy seen in vitro, in which both IL-3 and GM-CSF are
also able to induce eosinophil production, does not operate
in these infections.
Two types of experiments have shown that expression of
the IL-5 gene in vivo is sufficient to induce eosinophilia.
Firstly, mice carrying hematopoietic cells infected with a
retrovirus carrying the IL-5 gene produced high-level eo-
sinophilia for at least 12 months.65 There were excess
numbers of eosinophils in the bone marrow, spleen, liver,
lung, and gut.
Secondly, transgenic mice that express IL-5 by two
different methods show long-lasting eosinophilia. Firstly,
the IL-5 gene was ligated to the human CD2 locus control
region (LCR) to give constitutive expression of IL-5 by all T
cells. Secondly, the IL-5 cDNA was ligated to the mouse
metallothionein promoter (MT-1) to give a low-level consti-
tutive production of IL-5 from spleen, liver, kidney, and
bone marrow.
Four lines of transgenic mice produced with the CD2-
IL-5 construct all showed high-level eosinophil production
proportional to the transgene copy number. These animals
have detectable levels of IL-5 in the serum, and show a
profound and lifelong eosinophilia, with large numbers of
eosinophils in the blood, spleen, bone marrow, lung, and
gut Of the two transgenic lines produced with the
MT-1-IL-5 construct, one carried about five copies of the
transgene and produced low and variable levels of eosino-
phils, but the other carried about 40 copies and gave
high-level eosinophilia in the spleen, peritoneum, liver, and
skeletal muscle.67
ACTIVITY OF IL-3 AND GM-CSF IN VIVO
To assess the relative importance of IL-5 in eosinophilia,
it is important to understand the activities of IL-3 and
GM-CSF that induce eosinophil production in vitro. Firstly,
the dose required for optimum eosinophil production in
vitro by IL-3 or GM-CSF is at least 10-fold higher than the
dose required to induce neutrophillmacrophage produc-
tion.68Secondly, in assessing increases in eosinophils num-
bers, it is important to note that the number of eosinophils
in normal animals is very low, and so even when the
numerical increase is not large, it can appear large when
expressed as a multiple. Clinical trials with IL-3 and
GM-CSF have shown that they both stimulate the produc-
tion of eosinophils, although the actual increase in eosino-
phils is relatively low compared with the effect on other
lineage^.^^.^^
Results in experimental animals also indicate a low
activity on eosinophils compared with other lineages. Injec-
tions of IL-3 into mice induced an increase of about 3 x lo6
eosinophils in the peritoneum compared with an increase of
about 14 X lo6 macrophage^,^^ whereas GM-CSF induced
about 4 x lo6 eosinophils compared with about 25 x lo6
macrophages.72
Mice reconstituted with bone marrow cells that express
GM-CSF had very high levels of serum GM-CSF and high
levels of neutrophils and macrophages. Although the num-
ber of eosinophils was increased ninefold over controls, this
was a very small fraction of the total cell increase.73
3103
Similary, mice that express high levels of IL-3 had increased
numbers of neutrophils, but the increase in eosinophils
represented less than 5% of the total cells.74Transgenic
mice expressing GM-CSF developed a massive myeloid
response, but eosinophils represented less than 5% of the
total in one line and in another less than l%.75
As high levels of either IL-3 or GM-CSF result in
relatively low production of eosinophils in vivo, it is unlikely
that these cytokines play a significant role in eosinophilia
under conditions in which their levels are low or undetect-
able, as occurs in most pathologic conditions.
EFFECT OF OVERPRODUCTION OF IL-5
Animals reconstituted with hematopoietic cells that con-
stitutively express IL-3,74GM-CSF,73 and IL-565have been
reported. The animals reconstituted with cells expressing
IL-3 or GM-CSF survived only a few weeks due to massive
tissue infiltration by myeloid cells. In contrast, the IL-5
mice developed eosinophilia but remained healthy.65Simi-
larly, despite the massive, life-long eosinophilia in both
models of IL-5 transgenic mice, they remained apparently
n ~ r m a l . This
~ , ~ finding
~ is in contrast to transgenic mice
expressing GM-CSF that develop a myeloid response result-
ing in blindness and a fatal syndrome of tissue damage.76
These observations illustrate that increased numbers of
eosinophils are not themselves harmful, or that a control
mechanism exists to prevent the production of eosinophils
to toxic levels.
Infection of the CD2-IL-5 transgenic mice with M Corti,
itself a potent inducer of eosinophilia, increased serum IL-5
from about 40 U to over 1,000 U. However, the number of
eosinophils in the blood, bone marrow, and spleen de-
creased during the period corresponding to high-level
serum IL-5. This was shown to be due to a decrease in
eosinophil precursors. This also suggests that some form of
control is operating to prevent the overproduction of
eosinophil^.^^
ASSOCIATION BETWEEN IL-5 AND EOSINOPHILIA
The development of eosinophilia in mice infected with T
canis is accompanied by the appearance of IL-5 mRNA in
the A comparison of the production of cytokines
by normal individuals and by eosinophilic patients infected
with the filarial parasite Loa loa gave interesting results. It
was found that both groups produced similar levels of IL-3
and GM-CSF, but whereas the normals gave relatively little
IL-5, the cells from infected patients produced high levels
of IL-5.79
Significant levels of IL-5 were also detected in the serum
of patients with idiopathic hypereosinophilia80 and in pa-
tients with the eosinophilic-myalgia syndrome resulting
from the ingestion of L-tryptophane.81Patients with eosino-
philia associated with Hodgkins disease were found to have
IL-5 mRNA in the tumor cells,82 and a patient with
angiolymphoid hyperplasia with eosinophilia (Kimuras
disease) was found to have constitutive expression of IL-5
mRNA in lymph node tissue.83
Asthma is associated with an inflammatory reaction
involving the infiltration of eosinophils, and in situ hybrid-
 From www.bloodjournal.org by guest on November 1, 2016. For personal use only.
3104
ization on mucosal bronchial biopsies indicates local expres-
sion of IL-5, which correlated with the number of infil-
trating eosinophil^.^^
These studies are part of an expanding body of evidence
linking IL-5 expression with eosinophilia in a wide variety
of diseases.
EOSINOPHIL LOCALIZATION
Eosinophil infiltration of the tissues frequently occurs
independently of other blood leukocytes. This suggests that
a mechanism must exist for the specific extravasation of
eosinophils. The different tissue distribution of eosinophils
in the two transgenic systems (discussed above) probably
results from the different tissue expression of IL-5. Using
the MT-1 promoter, transgene expression was shown in the
liver and skeletal muscle, and eosinophils were observed in
these tissues. In contrast, the CD2-IL-5 mice with IL-5
expression in T cells did not have eosinophils in the liver or
skeletal muscle. This suggests that eosinophils migrate into
tissues in which IL-5 is expressed. While IL-5 is reported to
be chemotactic for eosinophil^,^^^^^ the activity is relatively
weak, and it is not clear what role that could play in vivo.
An alternative mechanism of extravasation of eosinophils
is suggested by experiments in which IL-5 has been shown
to upregulate adhesion molecules. Thus, it was shown that
IL-5 increased the expression of the integrin C D l l b on
human eosinophil^,^^ and this increased expression was
accompanied by an increased adhesion to endothelial
cells.86 Adhesion was inhibited by antibody to C D l l b or
CD18 suggesting that the integrins are involved in eosino-
phil adhesion to endothelial cells.86More recently, it has
been shown that eosinophils can use the integrin very late
antigen-4 (VLA-4) (CD49d/CD29) in adherence to endo-
thelial cells. In this case, the ligand is vascular cell adhesion
molecule-1 (VCAM-1). In contrast, neutrophils do not
express VLA-4 and do not use this adherance me~hanism.~
While none of these adhesion molecules are restricted to
eosinophils, these results suggest a possible pathway for the
specific localization of eosinophils. The activation of T cells
as part of the immune response in the tissues presumably
leads to the production of IL-5 and one or more of the
cytokines influencing endothelial cell expression of adhe-
sion molecules. The IL-5 increases the expression of adhe-
sion molecules on the circulating eosinophils. The total
effect is to increase the adhesion of eosinophils to the vessel
walls in the inflamed tissue. Clearly, the production of
cytokines such as IL-3 and GM-CSF that upregulate adhe-
sion molecules on monocytes and neutrophils would cause
these cells to comigrate with the eosinophils.
The potential for blocking eosinophil adhesion as a
therapeutic approach to asthma has been shown in a
primate asthma model. It was first shown that antibody to
intracellular adhesion molecule-1 (ICAM-1) inhibited the
adhesion of eosinophils to endothelial cells in vitro. When
the antibody was administered to the animals, eosinophil
migration into the lung was decreased and the asthmatic
reaction significantly reduced.88
COLIN J. SANDERSON
EOSINOPHILS AND HELMINTHS
While the association between eosinophils and infections
by helminths has been well documented, it has been more
difficult to show that the eosinophils were involved in
parasite rejection. The observations that eosinophils in
vitro could kill schistosomula of Schistosoma mansoni l3
have been followed by many similar descriptions with
different parasites. The association between eosinophilia
and resistance to schistosomiasis in two studies in Africa
remain the best evidence that eosinophils are involved in
immunity to parasite^.^^^^ Bearing in mind the high conser-
vation of the IL-5 sequence and the high exposure to
parasites in nature, it is possible that resistance to parasitic
infections has provided the selective pressure for the
evolution of IL-5.
EOSINOPHILS AND ASTHMA
Although the potential role of the eosinophil in the
production of tissue damage in asthma has been evolving
for some years,91 the central role of the eosinophil as
possibly the most important inflammatory cells in asthma is
becoming more widely a ~ c e p t e d . ~ ~ - ~ ~
Antigen challenge of asthmatic patients results in the
accumulation of eosinophils in the and the number
of eosinophils correlates with the severity of the late
asthmatic reaction?6 The accumulation of eosinophils was
found to be selective after specific allergen inhalation,
because the numbers of macrophages, neutrophils, and
lymphocytes were not significantly increased. Patients with
a late response showed a significant increase in eosinophils
by 4 hours with higher numbers at 24 hours.97Experimental
asthma in guinea pigs is accompanied by large numbers of
eosinophils in the peribronchial vessels, the mucosa, and
the airways.98Similarly, inhalation of antigen in sensitized
primates (Macacafasiculurk) resulted in a prolonged inflam-
matory reaction characterized by a large increase in bronchi-
alveolar eosinophil^.^^
Evidence that eosinophils are producing tissue damage in
the asthmatic lung is based on the demonstration of
eosinophil major basic protein and eosinophil-derived neu-
rotoxin, indicating degranulation at sites of injury. Further-
more, the concentrations of these toxic products in asth-
matic sputum is similar to the concentrations that are
cytotoxic in
These types of data have caused a reappraisal of the
etiology of the late-phase asthmatic reaction from a disease
mediated by mast cells and IgE to a disease that is primarily
a T-cell response (delayed-type hypersensitivity reaction)
accompanied by e o ~ i n o p h i l i a . ~ ~ , ~ ~ . ~ ~ , ~ ~ ~
EOSINOPHILS AND GRAFT REJECTION
Eosinophilia was noted 1 to 4 days before the develop-
ment of inflammation after renal transplantation,lo2 and
this was shown to be an adverse prognostic factor for graft
s ~ r v i v a I . Eosinophils
~ ~ ~ J ~ in liver grafts were reported to be
a sensitive and specific indicator for acute rejection.105
Experimental lung allograft in the rat causes eosinophil
 From www.bloodjournal.org by guest on November 1, 2016. For personal use only.
INTERLEUKIN-5, EOSINOPHILS, AND DISEASE
infiltration, representing up to 20% of the cell infiltration 2
to 4 days after implantation.lM
It is not clear from these observations whether the
eosinophils are involved in graft rejection or whether they
simply represent a marker for an active T-cell response.
EOSINOPHILS AND TUMORS
Approximately half of the patients receiving abdominal
irradiation as curative therapy for tumors developed eosino-
philia as a consequence of the irradiation. This was found to
be an important prognostic factor, independent of other
parameters indicative of cell-mediated immunity. Those
who developed eosinophilia had double the median survival
time of those who did
The presence of eosinophils in association with tumors
has been noted for many years.8J08In a histologic study of
the cellular infiltration of tumors, it was observed that in
oral, gastric, and breast carcinomas only a small proportion
of cases had eosinophils and these occurred as an insignifi-
cant part of the infiltrate. However, in carcinoma of the
cervix, eosinophils were observed in one-third of the cases
(43 of 134) and there was a positive correlation between
eosinophils and survival rates.lW In a study of 72 operable
primary lung cancers, 37 (50%) showed a strong local
infiltration of eosinophils. Follow-up studies indicated that
this was associated with a good prognosis, while absence of
eosinophils indicated a poor prognosis.l1 In a prospective
study of 647 cases of gastric carcinoma in Japan, 157 (24%)
showed eosinophil infiltration in the resected tumor. This
was found to have a marked positive prognostic signifi-
cance."' In a study of 67 patients with colonic carcinoma,
18-month survival was higher in the group with high
eosinophil infiltration.lI2
In Hodgkin's disease, a selective blood eosinophilia,
without a general leukocytosis, occurred in 95 of 1,260cases
(7.5%). This was associated with a clear selective advan-
tage,lI3 and appears to be caused by IL-5 production by the
tumor cells.82An extensive deposition of eosinophil peroxi-
dase in a proportion of biopsies indicated eosinophil
degranulation and suggested a cytotoxic effect may be
o~curring."~ An intriguing experimental system designed to
assess the role of cytokines in tumor rejection uses tumor
cells transfected with an expression vector containing the
cDNA sequence of a cytokine. The tumor cells produce the
cytokine constitutively. When tumor cells secreting IL-4115
or IL-2116 were introduced into mice, they were rejected
faster than the parent tumor cells. In both cases the tumors
were infiltrated with eosinophils, possibly (but not proven)
because the animal's T cells were stimulated to produce
IL-5.
Patients receiving IL-2 as an antitumor treatment fre-
quently develop eosinophilia. This appears to be because
IL-2 induces the production of IL-5 by T cells.l17 In view of
the observations (discussed above) that eosinophils corre-
late with a positive prognosis, it may be useful to analyze
the number and distribution of eosinophils for a correlation
with the antitumor activity of IL-2.
3105
CONCLUSION
Most cytokines appear to be pleitropic and as they have
become more widely available the range of their biologic
activities has increased. On the other hand, the availability
of human IL-5 has narrowed our concepts of its biologic
role. Mouse IL-5 has well-characterized activities on B cells
in vitro and activities on T cells have been reported, but in
humans IL-5 appears not to act on B cells1ls and no
activities have been reported on T cells. Thus, in humans
IL-5 activity appears to be restricted to the eosinophil/
basophil lineages.
Studies in vitro suggested that IL-5 was a late-acting
factor in a cytokine network in which IL-3 and GM-CSF
played a key role in controlling eosinophilia. However, the
complete inhibition of eosinophil production by anti-IL-5
antibody and the development of eosinophilia in transgenic
mice expressing only IL-5 suggests that studies in vitro may
be misleading. Furthermore, the association of eosinophilia
with the production of IL-5 in a wide spectrum of human
eosinophilic diseases all indicate a unique role for IL-5 in
the regulation of eosinophilia.
In view of the potential for eosinophils to cause tissue
damage, it is interesting that constitutive expression of IL-5
in mice induced long-lasting eosinophilia without apparent
ill effects. This suggests that additional factors, such as
antibody-antigen complexes, are required to induce the
cytotoxic effect of eosinophils. Expression of very high
levels of IL-5 appears to suppress the production of
eosinophils, possibly indicating some form of control to
prevent their over production. The soluble IL-5R inhibits
IL-5 activity, suggesting the possibility that high levels of
IL-5 lead to expression of the soluble form (rather than the
membrane form) of the IL-SR, thus regulating the produc-
tion of eosinophils.
The unique role of IL-5 in the production, activation, and
localization of eosinophils makes it a prime target for
therapeutic intervention in asthma and other eosinophilic
diseases. On the other hand, eosinophils have been shown
to be a positive prognostic indicator in a variety of human
tumors.
The studies of eosinophils in tumors do not directly
implicate eosinophils as the effector cells in tumor rejec-
tion. However, they represent a remarkable positive prog-
nostic indicator, and raise the possibility that manipulation
of eosinophil numbers might be used in tumor therapy.
Systemic administration of IL-5 may induce eosinophilia,
but will not provide the eosinophil infiltration that will
probably be necessary. A possible approach would be to use
IL-5 to increase eosinophils in those patients known to have
infiltrating eosinophils in their tumors. This would be based
on the assumption that the tumors were producing the
stimulus causing the eosinophils to localize. While experi-
ments in animals suggest that eosinophil induction may not
be harmful, this may not be an indicator of the effects in
humans. It is possible that subclinical allergic disease may
be exacerbated by an increase in eosinophils, and this
provides a daunting barrier for the clinical application of
IL-5.
 From www.bloodjournal.org by guest on November 1, 2016. For personal use only.
3106
REFERENCES
1. Denburg JA: Basophil and mast cell lineages in vitro and in
vivo. Blood 795346,1992
2. Maxwell C, Hussian R, Nutman TB, Poindexter RW, Little
MD, Schad GA, Ottesen EA: The clinical and immunologic
responses of normal human volunteers to low dose hookworm
(Necatoramericanus) infection. Am J Trop Med Hyg 37:126,1987
3. Strath M, Sanderson CJ: Detection of eosinophil differentia-
tion factor and its relationship to eosinophilia in Mesocestoides
Corti-infectedmice. Exp Hematol 14:16,1986
4. Basten A, Beeson PB: Mechanism of eosinophilia. 11. Role of
the lymphocyte. J Exp Med 131:1288,1970
5. Nielsen K, Fogh L, Andersen S: Eosinophil response to
migrating A s c a mum
~ larvae in normal and congenitally thymus-
less mice. Acta Path Microbiol Immunol Scand 82:919,1974
6. Hsu CK, Hsu SH, Whitney RA, Hansen CT:Immunopathol-
ogy of schistosomiasis in athymic mice. Nature 262:397,1976
7. Sanderson CJ: Interleukin-5, Thomson AW (ed): Immunol-
ogy and Molecular Biology of Cytokines. London, UK, Academic,
1991, p 149
8. Spry CJF: Eosinophils: A Comprehensive Review, and Guide
to the Scientific and Medical Literature. Oxford, UK, Oxford
University, 1988
9. Dexter TM, Garland JM, Testa NG (eds): Colony-Stimulat-
ing Factors: Molecular and Cellular Biology. New York, NY,
Dekker, 1990
10. Thompson AW (ed): The Cytokine Handbook. London,
UK, Academic, 1991
11. Smith H, Cook R (eds): Immunopharmacology of Eosino-
phils. London, UK, Academic (in press)
12. Sanderson CJ, Thomas J A A comparison between the
cytotoxic activity of eosinophils and other cells by 51Crrelease and
time lapse microcinematography. Immunology 34:771,1978
13. Butterworth A E Cell-mediated damage to helminths. Adv
Parasitol23:144,1984
14. Tominaga A, Takahashi T, Kikuchi Y, Mita S, Noami S,
Harada N, Yamaguchi N, Takatsu K Role of carbohydrate moiety
of IL5: Effect of tunicamycin on the glycosylation of IL5 and the
biologic activity of deglycosylated IL5. J Immunol 144: 1345, 1990
15. McKenzie ANJ, Ely B, Sanderson CJ: Mutated interleukin-5
monomers are biologically inactive. Mol Immunol28:155,1991
16. Minamitake Y, Kodama S, Katayama T, Adachi H, Tanaka
S, Tsujimoto M: Structure of recombinant human interleukin 5
produced by Chinese hamster ovary cells. J Biochem (Tokyo)
107:292, 1990
17. Proudfoot AE, Davies JG, Turcatti G, Wingfield P T Human
interleukin-5 expressed in Escherichia coli: Assignment of the
disulfide bridges of the purified unglycosylated protein. FEBS Lett
283:61, 1991
18. Lopez AF, Eglinton JM, Lyons AB, Tapley PM, To LB, Park
LS, Clark SC, Vadas MA: Human interleukin-3 inhibits the
binding of granulocyte-macrophage colony-stimulating factor and
interleukin-5 to basophils and strongly enhances their functional
activity. J Cell Physiol145:69,1990
19. Lopez AF, Eglinton JM, Gillis D, Park LS,Clark S, Vadas
M A Reciprocal inhibition of binding between interleukin 3 and
granulocyte-macrophage colony-stimulatingfactor to human eosino-
phils. Proc Natl Acad Sci USA 86:7022,1989
20. Barry SC, McKenzie AN, Strath M, Sanderson CJ: Analysis
of interleukin 5 receptors on murine eosinophils: A comparison
with receptors on B13 cells. Cytokine 3:339,1991
21. Plaetinck G, der Heyden JV, Tavernier J, Fache I, Tuypens
T, Fischkoff S, Fiers W, Devos R: Characterization of interleukin 5
COLIN J. SANDERSON
receptors on eosinophilic sublines from human promyelocytic
leukemia (HL-60) cells. J Exp Med 172683,1990
22. Migita M, Yamaguchi N, Mita S, Higuchi S, Hitoshi Y,
Yoshida Y, Tominaga M, Matsuda F, Tominaga A, Takatsu K
Characterization of the human IL-5 receptors on eosinophils. Cell
Immunol133:484,1991
23. Ingley E, Young IG: Characterization of a receptor for
interleukin-5 on human eosinophils and the myeloid leukemia line
HL-60. Blood 78:339,1991
24. Lopez AF, Vadas MA, Woodcock JM, Milton SE, Lewis A,
Elliott MJ, Gillis D, Ireland R, Olwell E, Park LS: Interleukin-5,
interleukin-3, and granulocyte-macrophage colony-stimulating fac-
tor cross-compete for binding to cell surface receptors on human
eosinophils. J Biol Chem 266:24741,1991
25. Bazan J F Structural design and molecular evolution of a
cytokine receptor superfamily. Proc Natl Acad Sci USA 87:6934,
1990
26. Tavernier J, Devos R, Cornelis S, Tuypens T, Van der
Heyden J, Fiers W, Plaetinck G: A human high affinity interleu-
kin-5 receptor (IL5R) is composed of an IL5-specific a-chain and a
P-chain shared with the receptor for GM-CSF. Cell 66:1175,1991
27. Tominaga A, Takaki S, Koyama N, Katoh S, Matsumoto R,
Migata M, Hitoshi Y, Hosoya Y, Yamauchi S, Kanai Y, Miyazaki
J-I, Usuku G, Yamamura K-I, Takatsu K: Transgenic mice express-
ing a B cell growth and differentiation factor gene (interleukin 5 )
develop eosinophilia and autoantibody production. J Exp Med
173:429,1991
28. Nicola NA, Metcalf D: Subunit promiscuity among hemopoi-
etic growth factor receptors. Cell 67:1,1991
29. McKenzie ANJ, Barry SC, Strath M, Sanderson CJ: Struc-
ture-function analysis of interleukin-5 utilizing mouse/human
chimeric molecules. EMBO J 101193,1991
30. Kodama S, Tsuruoka N, Tsujimoto M: Role of the C-termi-
nus in the biological activity of human interleukin 5. Biochem
Biophys Res Commun 178:514,1991
31. Sanderson CJ, Campbell HD, Young IC: Molecular and
cellular biology of eosinophil differentiation factor (interleukin-5)
and its effects of human and mouse B cells. Immunol Rev 102:29,
1988
32. Lopez AF, Shannon MF, Hercus T, Nicola NA, Camareri B,
Dottore M, Layton MJ, Eglinton L, Vadas M A Residue 21 of
human granulocyte-macrophage colony-stimulating factor is criti-
cal for biological activity and for high but not low affinity binding.
EMBO J 11:909,1992
33. Scanafelt AB, Miyajima A, Kitamura T, Kastelelein R A
The amino-terminal helix of GM-CSF and IL-5 governs high
affinity binding to their receptors. EMBO J 104105,1991
34. Ogorochi T, Hara T, Wang H-M, Maruyama K, Miyajima A
Monoclonal antibodies specific for low-affinity interleukin-3 (IL-3)
binding protein AIC2A Evidence at AIC2A is a component of a
high-affinityIL-3 receptor. Blood 79:895,1992
35. Devos R, Plaetinck G, Van der Heyden J, Cornelis S,
Vandekerckhove J, Fiers W, Tavernier J: Molecular basis of a high
affinity murine interleukin-5 receptor. EMBO J 10:2133,1991
36. Takaki S, Mita S, Kitamura T, Yonehara S, Yamaguchi N,
Tominaga A, Miyajima A, Takatsu K Identification of the second
subunit of the murine interleukin-5 receptor: Interleukin-3 receptor-
like protein, AIC2B is a component of the high affinity interleu-
kin-5 receptor. EMBO J 10:2883, 1991
37. Rolink AG, Melchers F, Palacios R: Monoclonal antibodies
reactive with the mouse interleukin 5 receptor. J Exp Med
169:1693,1989
 From www.bloodjournal.org by guest on November 1, 2016. For personal use only.
INTERLEUKIN-5, EOSINOPHILS, AND DISEASE
38. Tsuruoka N, Funakoshi K, Kodama S, Tsujimoto M: Interac-
tion of interleukin-5 with its receptors on murine leukaemic BCL 1
cells and its implication in biological activity. Cell Immunol
125:354,1990
39. Hitoshi Y, Yamaguchi N, Mita S, Sonoda E, Takaki S,
Tominaga A, Takatsu K Distribution of IL-5 receptor-positive B
cells. Expression of IL-5 receptor on Ly-l(CDS)+ B cells. J
Immunol144:4218,1990
40. Takaki S, Tominaga A, Hitoshi Y, Mita S, Sonoda E,
Yamaguchi N, Takatsu K Molecular cloning and expression of the
murine interleukin-5 receptor. EMBO J 9:4367,1990
41. Murata Y, Takaki S, Migita M, Kikuchi Y, Tominaga A,
Takatsu K Molecular cloning and expression of the human
interleukin-5 receptor. J Exp Med 175:341,1992
42. van-Leeuwen BH, Martinson ME, Webb GC, Young I G
Molecular organization of the cytokine gene cluster, involving the
human IL-3, IL-4, IL-5, and GM-CSF genes, on human chromo-
some. Blood 73:1142,1989
43. Chandrasekharappa SC, Rebelsky MS, Firak TA, Le Beau
MM, Westbrook C A A long-range restriction map of the interleu-
kin-4 and interleukin-5 group on chromosome 5. Genomics 6:94,
1990
44. Lee JS, Campbell HD, Kozak CA, Young IG: The IL-4 and
IL-5 genes are closely linked and are part of a cytokine gene cluster
on mouse chromosome 11.Somat Cell Genet 15:143,1989
45. Coffman RL, Seymour BWP, Lebman DA, Hiraki DD,
Christiansen JA, Shrader B, Cherwinski HM, Savelkoul HFJ,
Finkelman FD, Bond MW, Mosmann TR: The role of helper T cell
products in mouse B cell differentiation and isotype regulation.
Immunol Rev 102:5,1988
46. Bohjanen PR, Okajima M, Hodes RJ: Differential regula-
tion of interleukin 4 and interleukin 5 gene expression: A compari-
son of T-cell induction by antLCD3 antibody or by exogenous
lymphokines. Proc Natl Acad Sci USA 875283,1990
47. Metcalf D, Parker JW, Chester HM, Kincade PW: Forma-
tion of eosinophilic-like granulocytic colonies by mouse bone
marrow cells in vitro. J Cell Physiol84:275,1974
48. Strath M, Warren DJ, Sanderson CJ: Detection of eosino-
phils using an eosinophil peroxidase assay. Its use as an assay for
eosinophil differentiation factors. J Immunol Methods 83:209,1985
49. Strath M, Clutterbuck EJ, Sanderson CJ: Production of
human and murine eosinophils in vitro and assay for eosinophil
differentiation factors, in Pollard JW, Walker JM (eds): Methods
in Molecular Biology, Vol 5. Animal Cell Culture. Clifton, NJ,
Humana, 361,1990
50. Ruscetti FW,Cypess RH, Chervenick P A Specific release of
neutrophilic- and eosinophilic-stimulating factors from sensitized
lymphocytes. Blood 47:757,1976
51. Sanderson CJ, Warren DJ, Strath M: Identification of a
lymphokine that stimulates eosinophil differentiation in vitro. Its
relationship to IL3, and functional properties of eosinophils
produced in cultures. J Exp Med 162:60,1985
52. Sanderson CJ: Eosinophil differentiation factor (interleukin-
5), in Dexter TM, Garland JM, Testa NG (eds): Colony Stimulat-
ing Factors: Molecular and Cellular Biology. New York, NY,
Dekker, 1990, p 231
53. Lopez AF, Begley CG, Williamson DJ, Warren DJ, Vadas
MA, Sanderson CJ: Murine eosinophil differentiation factor: A n
eosinophil-specific colony stimulating factor with activity for hu-
man cells. J Exp Med 163:1085,1986
54. Clutterbuck EJ, Sanderson CJ: Human eosinophil hemato-
poiesis studied in vitro by means of murine eosinophil differentia-
tion factor (IL-5): Production of functionally active eosinophils
from normal human bone marrow. Blood 71:646,1988
3107
55. Campbell HD, Sanderson CJ, Wang Y, Hort Y, Martinson
ME, Tucker WQ, Stellwagen A, Strath M, Young IG: Isolation,
structure and expression of cDNA and genomic clones for murine
eosinophil differentiation factor. Comparison with other eosino-
philopoietic lymphokines and identity with interleukin-5. Eur J
Biochem 174:345,1988
56. Yamaguchi Y, Suda T, Suda J, Eguchi M, Miura Y, Harada
N, Tominaga A, Takatsu K Purified interleukin 5 supports the
terminal differentiation and proliferation of murine eosinophilic
precursors. J Exp Med 167:43,1988
57. Warren DJ, Moore M A Synergism among interleukin 1,
interleukin 3, and interleukin 5 in the production of eosinophils
from primitive hemopoietic stem cells. J Immunol140:94, 1988
58. Clutterbuck EJ, Sanderson CJ: The regulation of human
eosinophil precursor production by cytokines: A comparison of
rhIL-1, rhIL-3, rhIL-4, rhIL-6, and GM-CSF. Blood 75:1774, 1990
59. Lu L, Lin ZH, Shen RN, Warren DJ, Leemhuis T, Brox-
meyer H E Influence of interleukins 3, 5, and 6 on the growth of
eosinophil progenitors in highly enriched human bone marrow in
the absence of serum. Exp Hematol18:1180,1990
60. Ema H, Suda T, Nagayoshi K, Miura Y, Civin CI, Nakauchi
H: Target cells for granulocyte colony-stimulating factor, interleu-
kin-3, and interleukin-5 in differentiation pathways of neutrophils
and eosinophils. Blood 76:1956,1990
61. Coffman RL, Seymour BW, Hudak S, Jackson J, Rennick D:
Antibody to interleukin-5 inhibits helminth-induced eosinophilia
in mice. Science 245:308,1989
62. Sher A, Coffman RL, Hieny S, Scott P, Cheever AW:
Interleukin 5 is required for the blood and tissue eosinophilia but
not granuloma formation induced by infection with Schistosoma
mansoni. Proc Natl Acad Sci USA 87:61,1990
63. Urban J F Jr, Katona IM, Paul WE, Finkelman FD: Interleu-
kin 4 is important in protective immunity to a gastrointestinal
nematode infection in mice. Proc Natl Acad Sci USA 885513,1991
64. Korenaga M, Hitoshi Y, Yamaguchi N, Sato Y, Takatsu K,
Tada I: The role of interleukin-5 in protective immunity to
Strongyloides venezuelensis infection in mice. Immunology 72502,
1991
65. Vaux DL, Lalor PA, Cory S, Johnson G R In vivo expression
of interleukin 5 induces an eosinophilia and expanded Ly-1B
lineage populations. Int Immunol2:965,1990
66. Dent LA, Strath M, Mellor AL, Sanderson CJ: Eosinophilia
in transgenic mice expressing interleukin 5 . J Exp Med 172:1425,
1990
67. Murata Y, Takaki S, Migita M, Kikuchi Y, Tominaga A,
Takatsu K Molecular cloning and expression of the human
interleukin 5 receptor. J Exp Med 175:341,1992
68. Clutterbuck EJ, Hirst EM, Sanderson CJ: Human interleu-
kin-5 (IL-5) regulates the production of eosinophils in human bone
marrow cultures: Comparison and interaction with IL-1, IL-3, IL-6,
and GM-CSF. Blood 73:1504,1989
69. Ganser A, Lindemann A, Seipelt G, Ottmann OG,
Herrmann F, Eder M, Frisch J, Schulz G, Mertelsmann R, Hoelzer
D: Effects of recombinant human interleukin-3 in patients with
normal hematopoiesis and in patients with bone marrow failure.
Blood 76:666,1990
70. Ottmann OG, Ganser A, Seipelt G, Eder M, Schulz G,
Hoelzer D: Effects of recombinant human interleukin-3 on human
hematopoietic progenitor and precursor cells in vivo. Blood 76:
1494,1990
71. Metcalf D, Begley CG, Nicola NA, Johnson GR: Quantita-
tive responsiveness of murine hemopoietic populations in vitro and
in vivo to recombinant multi-CSF (IL3). Exp Hematol 15:288,1987
72. Metcalf D, Begley CG, Williamson DJ, Nice EC, De
Lamater J, Mermod JJ, Thatcher D, Schmidt A Hemopoietic
 From www.bloodjournal.org by guest on November 1, 2016. For personal use only.
3108
responses in mice injected with purified recombinant murine
GM-CSF. Exp Hematol 15:1, 1987
73. Johnson GR, Gonda TJ, Metcalf D, Hariharan IK, Cory S: A
lethal myeloproliferative syndrome in mice transplanted with bone
marrow cells infected with a retrovirus expressing granulocyte-
macrophage colony stimulating factor. EMBO J 8:441,1989
74. Chang JM, Metcalf D, Lang RA, Gonda TJ, Johnson GR:
Nonneoplastic hematopoietic myeloproliferative syndrome in-
duced by dysregulated multi-CSF (IL-3) expression. Blood 73:
1487,1989
75. Metcalf D, Moore JG: Divergent disease patterns in granulo-
cyte-macrophage colony-stimulating factor transgenic mice associ-
ated with different transgene inserting sites. Proc Natl Acad Sci
USA 85:7767,1988
76. Lang RA, Metcalf D, Cuthbertson RA, Lyons I, Stanley E,
Kelso A, Kannourakis G, Williamson DJ, Klintworth GK, Gonda
TJ, Dunn AR: Transgenic mice expressing a hemopoietic growth
factor gene (GM-CSF) develop accumulations of macrophages,
blindness, and a fatal syndrome of tissue damage. Cell 51:675,1987
77. Strath M, Dent LA, Sanderson CJ: Infection of IL5 trans-
genic mice with Mesocestoides Corti induces very high levels of IL5
but depressed production of eosinophils. Exp Hematol 20:229,
1992
78. Yamaguchi Y, Matsui T, Kasahara T, Etoh S, Tominaga A,
Takatsu K, Miura Y, Suda T In vivo changes of hemopoietic
progenitors and the expression of the interleukin 5 gene in
eosinophilic mice infected with Toxocara canis. Exp Hematol
18:1152,1990
79. Limaye AP, Abrams JS, Silver JE, Ottesen EA, Nutman TB:
Regulation of parasite-induced eosinophilia: Selectively increased
interleukin 5 production in helminth-infected patients. J Exp Med
172399,1990
80. Owen WF, Rothenberg ME, Petersen J, Weller PF, Silber-
stein D, Sheffer AL, Stevens RL, Soberman RJ, Austen KF:
Interleukin 5 and phenotypically altered eosinophils in the blood of
patients with the idiopathic hypereosinophilic syndrome. J Exp
Med 170:343,1989
81. Owen WFJ, Petersen J, Sheff DM, Folkerth RD, Anderson
RJ, Corson JM, Sheffer AL, Auster KF: Hypodense eosinophils
and interleukin 5 activity in the blood of patients with the
eosinophilia-myalgia syndrome. Proc Natl Acad Sci USA 8723647,
1990
82. Samoszuk M, Nansen L Detection of interleukin-5 messen-
ger RNA in Reed Sternberg cells of Hodgkins disease with
eosinophilia. Blood 75:13,1990
83. Inoue C, Ichikawa A, Hotta T, Saito H: Constitutive gene
expression of interleukin-5 in kimuras disease. Br J Haematol
76554, 1990
84. Hamid Q, Azzawi M, Ying S, Moqbel R, Wardlaw AJ,
Corrigan CJ, Bradley B, Durham SR, Collins JV, Jeffery PK, Quint
J, Kay AS: Expression of mRNA for interleukin-5 in mucosal
bronchia biopsies from asthma. J Clin Invest 87:1541,1991
85. Wang JM, Rambaldi A, Biondi A, Chen ZG, Sanderson CJ,
Mantovani A Recombinant human interleukin 5 is a selective
eosinophil chemoattractant. Eur J Immunol19:701,1989
86. Walsh GM, Hartnell A, Wardlaw AJ,Kurihara K, Sander-
son CJ, Kay AB: IL-5 enhances the in vitro adhesion of human
eosinophils, but not neutrophils, in a leucocyte integrin (CD11/18)-
dependent manner. Immunology 71:258,1990
87. Walsh GM, Mermod J-J, Hartnell A, Kay AB, Wardlaw AJ:
Human eosinophil, but not neutrophil, adherence to IL-1-
stimulated human umbilical vascular endothelial cells is a431(very
late antigen-4) dependent. J Immunol146:3419,1991
COLIN J. SANDERSON
88. Wegner CD, Gundel RH, Reilly P, Haynes N, Letts LG,
Rothlein R: Intercellular adhesion molecule-1 (ICAM-1) in the
pathogenesis of asthma. Science 247:456,1990
89. Sturrock RF, Kimani R, Cottrell BJ, Butterworth AE, Seitz
HM, Siongok TK, Houba V: Observations on possible immunity to
reinfection among Kenyan schoolchildren after treatment for
Schistosoma mansoni. Trans R SOCTrop Med Hyg 77:363,1983
90. Hagan P, Wilkins HA, Blumenthal UJ, Hayes RJ, Green-
wood BM: Eosinophilia and resistance to Shistosoma haematobium
in man. Parasite Immunol7:625,1985
91. Gleich GJ, Adolphson CR: The eosinophilic leukocyte:
Structure and function. Adv Immunol39:117,1986
92. Ackerman SJ: The new gestalt: Asthma as a chronic inflam-
matory disease. J Asthma 26:331, 1989
93. Kay AB: Inflammatory cells in bronchial asthma. J Asthma
26:335, 1989
94. Hoidal J R The eosinophil and acute lung injury. Am Rev
Respir Dis 142:1245,1990
95. DeMonchy JG, Kauffman HF, Venge P, Koeter GH, Jansen
HM, Sluiter HJ, De Vries K: Bronchoalveolar eosinophils during
allergen-induced late asthmatic reactions. Am Rev Respir Dis
131:373, 1985
96. Bousquet J, Chanez P, Lacoste JY, Barneon G, Ghavanian
N, Enander I, Venge P, Ahlstedt S, Simony Lafontaine J, Godard
P, Francois-Bernard M: Eosinophilic inflammation in asthma. N
Engl J Med 323:1033,1990
97. Rossi GA, Crimi E, Lantero S, Gianiorio P, Oddera S, Crimi
P, Brusasco V: Late-phase asthmatic reaction to inhaled allergen is
associated with early recruitment of eosinophils in the airways. Am
Rev Respir Dis 144:379,1991
98. Kallos P, Kallos L Experimental asthma in guinea pigs
revisited. Int Arch Allergy Appl Immunol73:77, 1984
99. Gundel RH, Gerritsen ME, Gleich GJ, Wegner CD: Re-
peated antigen inhalation results in a prolonged airway eosino-
philia and airway hyperresponsiveness in primates. J Appl Physiol
68:779,1990
100. Gleich GJ: The eosinophil in asthma, in Morley J, Colditz I
(eds): Eosinophils in Asthma. London, UK, Academic, 1989, p 259
101. Venge P, Carlson M: Eosinophil granule proteins in bron-
chial asthma, in Kay AB (ed): Eosinophils, Allergy and Asthma.
Oxford, UK, Blackwell Scientific, 1990, p 96
102. Lautenschlager I, Von Willibrand E, Hayry P: Blood
eosinophilia, steroids and rejection. Transplantation 40354,1985
103. Weir MR, Hall-Crags M, Shen SY, Posner JN, Alongi SV,
Dagher FJ, Sadler JH: The prognostic value of the eosinophil in
acute renal allograft rejection. Transplantation 41:709,1986
104. Kormendi F, Amend WJC: The importance of eosinophil
cells in kidney allograft rejection. Transplantation 45:537,1988
105. Foser PF, Sankary HN, Hart M, Ashmann M, Williams,
J W Blood and graft eosinophilia as predictors of rejection in
human liver transplantation. Transplantation 47:72,1989
106. Kondo T, Marchevsky AM, Jordan SC, Koerner SK,
Matloff JM, Waters P F Vascular rejection and graft eosinophilia
in rat lung allografts. J Surg Res 51:310,1991
107. Ghossein NA, Bosworth JL, Stacey P, Muggia FM, Krish-
naswamy V: Radiation-related eosinophilia. Radiology 117:413,
1975
108. Lowe D, Jorizzo J, Hutt MSR: Tumour-associated eosino-
philia: A review. J Clin Pathol34:1343, 1981
109. Pasternak A, Jansa P: Local eosinophilia in stroma of
tumors related to prognosis. Neoplasma 31:323,1984
110. Kolb E, Muller E: Local responses in primary and second-
ary human lung cancers. 11. Clinical correlations. Br J Cancer
40410,1979
 From www.bloodjournal.org by guest on November 1, 2016. For personal use only.
INTERLEUKIN-5, EOSINOPHILS, AND DISEASE
111. Iwasaki K, Torisu M, Fujimura T Malignant tumor and
eosinophils. Cancer 58: 1321,1986
112. Pretlow TP, Keith EF, Cryar AK, Bartolucci AA, Pitts AM,
Pretlow TGII, Kimball PM, Boohaker E A Eosinophil infiltration
of human colonic carcinomas as a prognostic indicator. Cancer Res
43:2997,1983
113. Vaughan Hudson B, Linch DC, Macintyre EA, Bennett
MH, MacLennan KA, Vaughan Hudson G, Jelliffe AM: Selective
peripheral blood eosinophilia associated with survival advantage in
Hodgkins disease (BNLI Report No 31). J Clin Pathol 40: 247,
1987
114. Samoszuk Michael K, Nathwani BN, Lukes RJ: Extensive
deposition of eosinophil peroxidase in Hodgkins and non-
Hodgkins lymphomas. Am J Pathol 125426,1986
3109
115. Tepper RI, Pattengale PK, Leder P: Murine interleukin-4
displays potent anti-tumor activity in vivo. Cell 57503,1989
116. Fearon ER, Pardoll DM, Itaya T, Golumbek P, Levitsky
HI, Simons JW, Karasuyama H, Vogelstein B, Frost P: Interleu-
kin-2 production by tumor cells bypasses T helper function in the
generation of an antitumor response. Cell 60:397,1990
117. Macdonald D, Gordon AA, Kajitani H, Enokihara H,
Barrett AJ: Interleukin-2 treatment-associated eosinophilia is
mediated by interleukin-5 production. Br J Haematol76:168, 1990
118. Clutterbuck E, Shields JG, Gordon J, Smith SH, Boyd A,
Callard RE, Campbell HD, Young IG, Sanderson CJ: Recombi-
nant human interleukin-5 is an eosinophil differentiation factor but
has no activity in standard human B cell growth factor assays. Eur J
Immunol17:1743,1987
 From www.bloodjournal.org by guest on November 1, 2016. For personal use only.

1992 79: 3101-3109

Interleukin-5, eosinophils, and disease

CJ Sanderson

Updated information and services can be found at:

http://www.bloodjournal.org/content/79/12/3101.citation.full.html
Articles on similar topics can be found in the following Blood collections

Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests

Information about ordering reprints may be found online at:

http://www.bloodjournal.org/site/misc/rights.xhtml#reprints

Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml

Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American
Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.