Copyright ®ERS Journals Ud 1993
European Respira!Oiy Journal
ISSN 0900- 1006
Eur Respir J, 1993, 6, 1239-1242
Pr1nled in UK - a1 rights reselved
EDITORIAL
Adhesion molecule antagonists: future therapies for allergic diseases?
M. W&.n, B.S. Bochner
In Ire piS!: 20 yrs. substantial progress has been made in Ire
identification of cells and mediators involved in allergic
inflammation. As a result, an increased emphasis has been
placed on the role of inflammation in allergic disease. Extensive efforts have focused on the study of allergic .infJammalion,
ofleo employing experimental allergen challenge to elicit tare
phase responses. Despite years of inrensive investigation,
the exact mechanisms responsible for this inflammatory
response remain a puzzle. One of the fascinating characteristics of both lale phase reactions and chronic allergic
diseases, including rhinitis and asthma. is the preferential
accwnulation of eosinophils and the 'I1Iz subpopulation of Tlymphocytes at mucosal sites.
Many laboratories, including our own. have attempted to
understand the mechanisms of selective leucocyte recruiunent
in allergic disease, with the belief that this may lead to novel
treatments that prevent the accumulation of these cells within
the airways. Within the past 10 yrs, scientists have witnessed
an explosive growth in the knowledge of cell adhesion
molecules, an ever increasing class of molecules grouped
into several distinct families (e.g. integrins, selectins, and
members of the immunoglobulin supergene family) based
on functional and structural similarities. These molecules
are critical in mediating essentially every step in cell recruitment, including endothelial adhesion, diapedesis (transenclolb!lial migration) and cremotaxis. In a recent issue of Ire
Journal, MC>NJTroR'r et al. (1] provided an excellent review of
this rapidly advancing field and included a discussion of the
role of adhesion molecules in airway disease. These authors
are amongst the leaders in the study of the expression of
adhesion molecules in vivo at sites of human allergic inflammation. Th.e challenge for these and other investigators in
the field is to elucidate the pattern of regulated expression,
function, and co-<>rdinated interactions of these molecules.
It appears, based on the existence of numerous adhesion
molecules with varied specifi.cities and regulatory patterns,
that the answer will be quite complex. Nevertheless, numerous phannaceutical companies have alrea:fy begun to focus on
adhesion molecules as relevant targets in trying to design
novel anti-inflammatory agents that might be useful in the
treatment of a wide variety of diseases including asthma
Oearly, if and when such specific reagents becorre available,
they will be extremely important tools in dissecting. and
ultimately defining, the true importance of each adhesion
molecule during the inflammatory response. The purpose of
this brief review is to discuss the rationale for attempting to
block adhesion molecules as a possible therapeutic strategy,
Com:spoodence: B.S. Bochner, Johns Hopkins Asthma and Allergy Center.
5501 Hoplcins Bayview Boulevard, Baltimore, Maryland 21224-6801 USA.
and to summarize a number of approaches being taken to
achieve this.
.Fu:nctioos of adhesion molecules during various
inflammatory reactions
An important theme in the recruitment of circulating
leucocytes to inflammatory sites is the cascade of steps
orchestrated by a succession of adhesion molecules. The
initial step in inflammation is rolling of leucocytes along the
endothelial wall, as first clescribed in 1889 by Cof.INHElM [2]
with the use of intravital microscopy. This crucial first step
occurs despite the shear forces of blood flow, and has been
convincingly shown to be mediated by the selectin family of
adhesion molecules [3). Studies using artificial lipid bilayers
containing purified P-selectin, which will support leucocyte
rolling. confinn that non-selectins such as intercellular adhesion
molecule-I (ICAM-l) are neither necessary nor sufficient to
mediate initial rolling [4]. In addition, monoclonal antibodies
against P2-integrins do not inhibit rolling, whilst monoclonal
antibodies to L- and P-selectin do, further documenting the
importance of selectins in mediating the initial attachment
of leucocyteS under conditions of flow.
Many different kinds of adhesion molecules can participate
during cell adhesion. Known ligand binding pairs for
endothelial cell and leukocyte adl1esion molecules include
CDlla with ICAM-1 and ICAM-2, CDllb with ICAM-1,
very tare activation antigen4 (VLA4) (aAj}l) with vascular
cell adhesion molecule-1 (VCAM-1), and the caroohydrate
structure sialyi-Lewis X (sle") with E-selectin and P-selectin
[5, 6]. L-selectin binds to a sulphated 50 kD glycoprotein
termed GlyCAM-1 and to another 90 kD molecule [7]. The
ligand binding pairs for other P,-integrins include extracellular
matrix proteins, sucb as collagen, laminin and fibronectin
[8).
A salient point is the specificity of the selectins for
caroohydrate moieties. Although leucocyte adhesion to all
three selectins is dependent on sJ..eX [6], important differences
in binding characteristics have been noted. FIJ'Stly, HL60
cells trealed with various proteases retain the ability to bind Eseledin but not P-selectin (9]. SecoOO!y, growth of HI.f{) cells
in tunicamycin~ which blocks synthesis of oligosaccharide
precursors, inhibits E-selectin binding to a greater extent than
P-seledin [9]. Thirdly, cells which oo not bind to tre selectins
can be transfected with the enzyme a.l-3 fucosyltrnnsfemse,
and will then bind to E-selectin but not P-selectin [9]. Finally,
soluble E-selectin completely inhibits P-selectin binding, but
soluble P-selectin only partially inhibits E-selectin binding
(9]. It therefore appears that clifferences in the sLel' supporting
1240
M. WEIN, B.S. BOCHNER
structures (e.g. glycoprotein vs glycolipid) and subtleties in the
carbohydrate configuration may be important in determining
selectin ligand specificities.
The importance of distinct adhesion molecuJes and
cytokines in mediating eosinophil recruitment during
allergic inOammatory reactions
In asthma, there is now strong evidence that selective
recruitment of eosinophils is a critical event The nwnber of
eosinophils is strikingly increased in sputum, blood, and
bronchoalveolar lavage fluid from asthmatic individuals [10].
The importance of these cells is also supported by the finding
that inhalation of eosinophil major basic protein causes
increased airway reactivity in animals, and by the correlation
between eosinophil number and clinical severity, as measured
by lung function. airway responsiveness, and symptom scores.
The fact that oosinophils accumulate in large number.>, despite
being present in peripheral blood at much lower levels,
suggests that pathways must exist that selectively pennit their
local influx and sUIVival.
One level of specificity may occur via the interaction
between the eosinophil and the vascular endothelium. It has
recently been demonstrated that both eosinophils and
neutrophils bind to cytokine-activated endothelium under
conditions of srear stress (11]. These adre:sive internctions are
due in part to L-selectin on the surface of the leucocyte,
since monoclonal antibodies recognizing L-selectin inhibit
adhesion. However, one unique anti-L-selectin antibody only
inhibited eosinophil adhesion, suggesting that eosinopbils but
not neutrophils may use a distinct epitope on the L-selectin
molecule during adhesion under flow conditions. Thus,
eosinophils, like neutrophils, use L-selectin to bind to activated
endothelium under nonstatic conditions, but potential differences in the epitopes used by eosinophils and neutrophils, as
well as differences in chemoattractants and other stimuli that
induce shedding of L-selectin, may play a role in situations
where preferential eosinophil recruitment is observed
Binding of eosinophils to activated endothelium under
static conditions might also differ among grnnulocyte subtypes.
For example, the sle''{-containing carbohydrate ligands for
E-selectin on eosinophil and neutrophils appear to be different
[12], and eosinophil adhesion to endothelial cells can involve
VCAM-1, a ligand for the integrin molecule VLA-4 (CD49d
ICD29 or <XNI31) expressed on eosinophils but not neutrophils
[13]. llA increases VCAM-1 expression on cultured human
wnbilical vein endothelial cells, without altering expression of
E-selectin or ICAM-1, resulting in conditions that support
adhesion of eosinophils but not neutrophils [14]. Other
reports confirm the importance of interleukin-4 (ll.A) driven
eosinophil recruitment llA transgenic mice have allergic-like
eosinophilic inflammation [15], and innoculation with a
tumour cell line transfected with the IL-4 gene induces
marked eosinophil accumulation at the tumour site [16].
The role of chemotactic factors in cell adhesion has attrocted
more attention since the discovery of the platelet factor
4fmtercrine/chemokine superfamily of 8-10 leD cytokines,
which appear to have restricted target cell specificity [17].
While members of the C-X-C class of chemokioes (C-X-C
referring to the position of the first two cysteines in the
conserved motif) are relatively specific for neutrophils, several
members of the C.C brnrx:h of chermkines, such as RANIES
(and to a less extent macrophage inflammatory protein-a
(MIPla)) are chemotactic for eosinophils but not neutrophils
[18, 19].
Another important step in the recruitment of leucocytes
involves the process of lmnsendothelial migration. Treatment
of endothelial monolayezs with ll.rl or tumour necrosis factor
(TNF), which induces the expression of E-selectin, ICAM-1,
and VCAM-1, was shown to in~ eosinophil transendolhclial migration f20]. Transendothelial migration through
ll.r !-treated endothelium was almost completely inhibited by
antibodies to CD 18 (P2 integrin) on the leucocyte, whilst
anti-P,-integrin antibody had little or no effect L20]. However,
when eosinophil transendothelial migration across ll...-1
activated endothelium was examined in the presence of
various leucocyte chemotactic factors, both P.- and P,-intcgrins
were found to mediate eosinophil transendothelial migration
[21). These data suggest that chemoattractants can promote
VLA-4NCAM- I interactions in vitro, and may, thereby,
activate eosinophil but not neutrophil transendotbelial migration
responses.
Recent work examining the interaction between extracellar
matrix proteins and eosinophils suggests another avenue for the
selective accumulation of eosinophils, again with special
attention to the p, family of integrins. The adhesion molecule
beterodimer a.6J31 (CD49f/CD29) has been shown to mediate
eosinophil adhesion to laminin [22]. Binding of eosinophils
via these receptors may help to immobilize them within
tissues. Binding of leucocytes to fibronectin is mediated by
a4Pl. and for eosinophils, adhesion to ftbronectin has been
shown to increase their survival, an effect blocked by anti-o:4
antil:xx:ti.es or by antilxx:lies to n..,..3, suggesting that a4{31 3:tS as
a receptor to stimulate autocrine generation of cytokines [23].
VLA-4 is expressed on other cell types, suggesting additional mechanisms for selective eosinophils recruitment An
alternative hypothesis for the selective accumulation of
eosinophils is that they may experience enhanced survival
under some cin:umstances, such as in the presence of certain
cytokines (e.g. ll.r3, ll.r5 or granulocyte macrophage colony
stimulating factor (GM-CSF)). ll.r5 selectively enhances
adhesion of eosinophil~. but not neutrophils, in a f3z-integrindependent fashion [24], and neutralizing antibody to ll.r5
prevents lung eosinophilia in vivo [25). Therefore, selective
eosinophil-activating cytokines may play an important role in
eosinophil recruitment responses by prolonging the survival of
recruited eosinopbils once they have entered a tissue site.
One final piece of evidence for the existence of indqx!ndent
mechanisms of leucocyte recruitirent is the observation that in
patients with leucocyte adhesion deficiency type I (a disease
where leucocytes are congenitally deficient in the expression
of P,-integrins) neutrophils cannot be recruited into inflamed
or infected skin sites, whilst eosinophils and mononuclear
cells do accumulate [26]. The existence of a P,-independent
pathway is also supported by the finding thai anti-~-integrin
antibodies are ineffective at preventing neutrophil inftltration
into the lung during experimental pneumonias caused by
Streptococcus pnewtumiae [27]. Interestingly, patients with
leucocyte adhesion deficiency type 1 do not suffer from frequent pneumonias and are able to mobilize neutrophils into the
lungs. These data illustrate important differences between the
function of adhesioo molecules on various leucocyte sublypes,
ADHESION MOLECULE ANTAGONISTS IN ALLERGIC DISEASE
and suggest that differences may also exist in the types of
adhesion molecules responsible for cell recruitment into
different tissues.
Pos9ble pbannacological approaches to interrupt cell
adhesion events
Based on the potential importance of cell adhesion
molecules in allergic and other inflammatory rea:tions, various
approaches are being developed to generate specific antagonists. One such approach is to intemlpt airways inflammation aJ tre early Sleps involving ~lial internctions.
In theory, leucocyte-endothelial interactions might be blocked
with soluble, recombinant forms of llte adhesion molecules, or
oligopeptides derived from U1ese molecules. However.
the biological half-life and affinity for their respective ligands
may Limit the usefulness of this approach. Therefore,
most initial studies have used blocking rnonoclonal antil:xx:lies
developed in mice. In monkeys, infusion of monoclonal
antibodies against &selectin inhibited the influx of oeutrophils
associated with the pulmonary late phase response [28), whilst
the eosinophil influx that occurs foUowing repeated antigen
challenge was attenuated by infusion of anti-ICAM-1 antibody
[29]. In a ra1 model of pulmonary inflamm.ation mediated by
neutrophils. another aoti-E-selectin antibody was found to
attenuate lung injwy [30]. Early studies using an anti-<X4
antibody revealed inhibition of chemotactic factor-induced
accumulation of eosinopbils in guinea-pig skin [31 J. Since
these antibodies are produced in a different species, their
half-life is relatively short, and antibodies against these
immunoglobulins may be produced by the host In an
attempt to avoid these problems, many companies are
"hwnanizing" antibodies. Tn this approach molecular biological
ntetbods are employed to replace the mouse Fe por1ion of the
immunoglobulin G (lgG) antibody with a human Fe jX>rtiOn,
which presel'Ves the structure and function of the mouse antihuman antigen binding (Fnb) domains. Such reagents have
already been produced. and clinical trials are wulerway to
detennine their safety and efficacy in a number of inflammatory diseases.
Since the primary amino acid structures for most adhesion
molecules are known, scientists at some companies are using
a different strategy. Several investigations have produced
chimeric molecules containing a human Fe fragment linked in
the Fab jX>Sition to two molecules of the functional lectin
domains of eitrer P-, E- or L-selectin [6, 32}. These selecti.nimmWloglobulin fusion proteins can bind to the carbohydrate
ligands preventing cells from recognizing the selectins expressed on cells in various tissue sites [33]. Both humanized
antibodies and engineered chimeric molecules should be
metabolized slowly, like human IgG, with a half-life of
severnl weeks. This may translate into significantly prolonged
ther.q>eutic usefulness.
Analogues of the selectins may be used, not only to block
cell adhesion but also to alter the functional status of
leucocytes. For example, P-selectin binding has been shown
to diminish superoxide production [34], and pretreatment
with a soluble form of P-selectin can actually redoc.e neutrophil
binding to endothelium [35]. These studies indicate that
therapy with soluble fonns of the adhesion molecules
themselves has the potential to modify the immune response
1241
and suppress inflammation in a multifaceted fashion. Another
approach is to develop soluble carbohydrate-based counterIigands which bind to the selectins, preventing them from
attaching to carbohydrate structures in vivo. Several 00111panies
are developing glycosylared structures, which act as com~ve
inhibitors by binding selectins and blocking selectin-mcdiated
adhesion.
A recent trend in asthma therapy has been to focus on the
inflammatory aspect of the disease, resulting in increased use
of anti-inflammatory agents, such as cromolyn, nedocromil and
glucocorticosteroids. One of the major phannaoological effects
of corticosteroid~. which has been recognized for years, is the
inhibition of cell recruitment in vivo [36]. Although the
mechanisms by which this occurs is not entirely clear, it
appean; to be the result of the ability of corti~ids to inhibit the production ancVor release of many cytokines, some of
which (e.g. TI.rl, ll.A, 1NF. TI.r5) are probably responsible for
cell recruitment in allergic inflammation [37]. Therefore,
strategies that are being employed to modulate cytok:ine
activity have the potential to prevent allergic ceU recruitment,
by reducing the nUOlber of circulating eosinophils or by
preventing cytoJcine..indoced expression of adhesion molecules.
especially on d1e surface of l11e endothelium. Many such
reagents are already in various stages of development or in
clinical trials. For example, antibodies against 'INF blocked
mast cell-mediated neutrophil infiltration in a mouse model
[38), whilst a combination of anti-ll.r1 and anti-TNF antibodies
blocked allergen-induced &selectin expression in human skin
explants [39]. Antibodies to cytolcine receptors. soluble forms
of the receptors themselves, have been used to block various
proinflammatory effects of cytokines. For example, preliminary results from a phase I hwnan trial with a soluble fonn of
tre TI.r J receptor showed remarkable efficacy in preventing llte
cutaneous late phase response [40]. Therefore, soluble hwnan
cytokine receptors. receptor antagonists, or cytokine-ncutralizing reagents may prove useful in preventing many adhesion
molecule-dependent leucocyte recruitment responses.
Conclusions
The recent explosion of information in ceU adhesion has
dmrnatically improved our understanding of the mechanisms
involved in leucocyte accUOlulation. Only when specific
cytokine and adhesion molecule antBgonists are developed and
used in weU-designed human trials will we truly understand
their individual roles and myriad interactions in allergic
inflammation. Whilst the potential for such agents is enormous, there are many obstacles. We still do not fully
understand how various tissues differ with respect to adhesion
molecules, whether the functional participation of an adhesion
molecule can be altered, based on the inciting cause of
inflammation, and whether tissue-specific homing mechanisms
exist in humans. In addition, for the successful treatment of
chronic diseases, such as asthma, effective antagonists must
exist in a form that pennits chronic administrnlion (perhaps in
a topically active fonn) and yet does not cause excessive
immunosuppression. The road ahead is a long one, but
through the development of adhesion molecule antagonists,
.investigators will finally have the necessary tools to study the
role of these molecules in inflammatory diseases including
asthma and allergic .lhinitis.
1242
M. WEIN, B.S. BOCHNER
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