Chemokine Receptors: Overview

10 Pages·0.106 MB·English

by  Murphy Ph.M.

Chemokine Receptors:
Overview
Philip M. Murphy*
Molecular Signaling Section, Laboratory of Host Defenses, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.02012.
INTRODUCTION introduction to the chapters devoted to individual
chemokine receptors.
Chemokine receptors are defined by their ability to
bind chemokines in a specific and saturable manner,
CHEMOKINE RECEPTOR
andtotransduceacellularresponse.Atthemolecular
STRUCTURE
level, this definition has been met by 16 human cell
surface proteins (named CXCR1 to CXCR5, CCR1
to CCR9, XCR1, and CX3CR1), which together The deduced amino acid sequences of chemokine
comprise the largest known structurally defined divi- receptorshave25–80%identity,indicatingacommon
sionoftherhodopsinsuperfamilyofseventransmem- ancestry. This has facilitated discovery of additional
brane domain, G protein-coupled receptors (GPCRs) familymembersbycrosshybridizationofcDNAsand
(Murphy, 1994; Premack and Schall, 1996; Yoshie genestoDNAprobesfromknownreceptors(Murphy,
et al., 1997; Locati and Murphy, 1999; Zlotnik et al., 1996). The structural boundary which separates che-
1999). In addition, four herpesvirus-encoded chemo- mokine receptors as a group from other types of G
kine receptors (ORFs US28 of human cytomegalo- protein-coupledreceptorsisnotsharp,andtheylacka
virus,ECRF3ofherpesvirussaimiri,UL12ofHHV-6 singlestructuralsignature.However,severalstructural
and no. 74 of HHV-8/Kaposi’s sarcoma herpesvirus fea-tures common to known chemokine receptors are
(KSHV;alsoknownasKSHVGPCR)(Isegawaetal., less common in other types of G protein-coupled
1998; Pease and Murphy, 1998), and two non- receptors,includingalengthof340–370aminoacids;a
signaling mammalian chemokine-binding proteins highly acidic N- terminal segment; the sequence
(D6 and the Duffy antigen receptor for chemokines, DRYLAIVHA, or a minor variation thereof, in the
DARC) (Horuk et al., 1994; Nibbs et al., 1997) have second intracellular loop; a short basic third intracel-
been described. Studied initially for their roles in lularloop,andacysteineineachofthefourextracellular
leukocyte trafficking, chemokine receptors are now domains (Murphy, 1994). A novel sequence which
known to have multiple additional functions, includ- contains all of these features is likely to represent a
ing regulation of development of the cardiovascular, chemokinereceptor.
gastrointestinal,immune,andcentralnervoussystems Thefoldedstructureofchemokinereceptorshasnot
(Tachibanaetal.,1998;Zouetal.,1998),andusageas beendetermined;howeveramodelcanbeconstructed
cell entry factors by HIV-1 (Cocchi et al., 1995; Feng for the transmembrane helices based on the known
etal.,1996;Bergeretal.,1999)andPlasmodiumvivax structureofrhodopsin(Ungeretal.,1997).Inaddition,
(Horuk et al., 1993), the causative agents of AIDS domain-specific antibodies have been used in some
and a form of malaria, respectively. The purpose of cases to establish the transmembrane topography of
this chapter is to provide an overview of the shared N-andC-terminiandtheloopregions,whicharecon-
and differential features of these molecules, as sistent with the rhodopsin model. Early biochemical
1972 Philip M. Murphy
crosslinking data were consistent with a monomer dirndl-like in the folded protein. The chemokine N-
structure for neutrophil IL-8 receptors (Moser et al., terminus is not usually important for docking but is
1991) and Duffy (Neote et al., 1993), whereas more typically critical for activation. Putative roles of the
recentdataconsistentwithadimerhavebeenreported transmembranedomainsincludedeterminationofthe
for CCR2 (Rodriguez-Frade et al., 1999), CCR5 conformation of the extracellular domains, contact
(Benkirane et al., 1997), and CXCR4 (Lapham et al., with the chemokine activation domain, and signal
1999).InthecaseofCCR2,adimerhasbeenimplicated transduction. Additional functional domains include
as the functional form of the receptor. This has fur- theC-terminus,whichtypicallycontainsmultipleserine
therstimulatedtheunsettleddebateastowhetherche- and threonine residues, some of which may be phos-
mokines bind to receptors as monomers or dimers. phorylateduponactivationandmayacttodesensitize
Although they exist as monomers at physiologic the receptor (Ali et al., 1999), domains in the second
concentrations,mostchemokinesformdimersathigh andthirdintracellularloopsimportantforGprotein-
concentrations. bindingandactivation(Damajetal.,1996),andacon-
A major unanswered question is how chemokines servedconsensussequencefortyrosinesulfationinthe
bind to receptors. Mutagenesis studies support a N-terminus(Farzan et al., 1999),which in the case of
Velcro-likeinteractionbetweenligandandreceptor,in CCR5mustbeutilizedforHIVcoreceptoractivity.
which multiple low-affinity binding sites integrate to
produceanoverallhigh-affinitybindingenergy(Ahuja
CHEMOKINE RECEPTOR
et al., 1996; Berson and Doms, 1998; Paavola et al.,
SPECIFICITY
1998).Thereappeartobetwoclassesofbindingsites:
thefirstforchemokinedockingtoreceptor,thesecond
forreceptortriggering.Becauseoftheseventransmem- Chemokine receptors can bind multiple chemokines,
branedomains,thebindingsitesarenotcontiguousin and vice versa; however the specificities are generally
theprimarysequence,butinsteadaregatheredtogether restricted by chemokine class (Table 1 and Table 2).
Table 1 Chemokine receptor classification and specificity
Class Subtype Ligands
CC CCR1 MIP-1(cid:11), RANTES, MCP-3
CCR2a MCP-1, MCP-3, MCP-4
CCR3a Eotaxin, eotaxin 2, RANTES, MCP-2, MCP-3, MCP-4, MCP-5
CCR4 TARC, MDC
CCR5a MIP-1(cid:11), MIP-1(cid:12), RANTES, MCP-2
CCR6 LARC
CCR7 ELC, SLC
CCR8a I-309
CCR9 TECK
CMV US28a MIP-1(cid:11), MIP-1(cid:12), RANTES, MCP-1, fractalkine
HHV-6 UL12 MIP-1(cid:11), MIP-1(cid:12), RANTES, MCP-1
CXC CXCR1 IL-8, GCP-2
CXCR2 IL-8, GRO(cid:11), GRO(cid:12), GRO(cid:13), NAP-2, ENA-78, GCP-2
CXCR3 MIG, IP-10, I-TAC, eotaxin, SLC
CXCR4a SDF-1
ECRF3 IL-8, GRO(cid:11), NAP-2
CC/CXC KSHV GPCR IL-8, GRO(cid:11), RANTES, MCP-1, I-309
C XCR1 Lymphotactin
CX C CX3CR1a Fractalkine
3
Italicizedreceptorsareviralinorigin.Allothersarehuman.
aHIV-1coreceptors.
Chemokine Receptors: Overview 1973
Table2 Chemokine-bindingproteinswithseventransmembranedomainmotif,notyet
demonstrated to signal
Molecule Ligands
Duffy IL-8, NAP-2, GRO(cid:11), I-309, RANTES, MCP-1
D6 MIP-1(cid:11), RANTES, MCP-1
This provides for a simple nomenclature in which due to the inequality of chemokine and chemokine
each receptor is named by the chemokine class it receptor repertoires, tissue distribution, and biologi-
recognizes, followed by the letter R and an arabic cal usage among species. For example, IL-8 is found
numeralassignedbytheorderofdiscoveryrelativeto in human and rabbit, but not in mouse, and CXCR1
other receptors. Thus, CCR1 is the first receptor is expressed mainly in human neutrophils versus rat
specific for CC chemokines to be discovered. There macrophages(Dunstanetal.,1996).Fortunately,this
areseveralknownexceptionstothisrule:CXCR3also situation appears to affect only a minority of chemo-
binds two CC chemokines, eotaxin and SLC, but kine receptors.
apparently with lower affinity than its CXC ligands Chemokine receptors have been described on all
IP-10,MIG,andI-TAC(Sotoetal.,1998;Wengetal., leukocyte subsets studied (Luster, 1998; Mantovani
1998); KSHV GPCR binds multiple CC and CXC et al., 1998). Details of expression and regulation are
chemokines with comparable affinity (Arvanitakis complex, and in some cases controversial, and are
etal.,1997);US28bindsmultipleCCchemokinesand beyondthescopeofthisoverview;however,afewkey
theCX3Cchemokinefractalkine(Kledaletal.,1998); patterns can be summarized. Cells of the granulocyte
and Duffy binds multiple CC and CXC chemokines seriesappeartoexpressalimitedrepertoireofchemo-
with comparable high affinity (Chaudhuri et al., kine receptors. Neutrophils express predominantly
1994). CXCR1 and CXCR2, whereas human eosinophils
Each receptor has a distinct specificity for chemo- express mainly CCR3, the IL-8 receptors and, to a
kine ligands and leukocyte subsets; however, the more variable extent, CCR1. CCR3 has also been
specificities may overlap considerably. For example, reported on basophils and a small subset of TH2
CCR1 and CCR5 both bind MIP-1(cid:11) and RANTES T lymphocytes, consistent with a role in allergic
but can be distinguished by their specificities for inflammation.Monocytesandmacrophagesexpressa
MCP-3andMIP-1(cid:12) respectively.Thestructuralbasis broader repertoire, which includes CXCR1, CXCR2,
of specificity is counterintuitive. For example, CCR2 CXCR4,CCR1,CCR2,CCR5,CCR8,andCX3CR1.
is much more related structurally to CCR5 than is T lymphocytes express the complete chemokine
CCR1(82%versus56%aminoacididentity),buthas receptor repertoire, but in an incomplete and differ-
only one high-affinity ligand in common with CCR5, ential manner on specific subsets. TH1 and TH2 cells
whereas CCR1 has several. Instead, CCR2 shares have distinct receptor repertoires. Of note, CXCR3
several ligands with CCR1, yet the two receptors are and CCR4 have been reported to be markers of TH1
only 56% identical in amino acid sequence. and TH2 cells, respectively, although this has been
Promiscuous chemokine ligand–receptor relation- challenged. Little information has been reported for
ships are common. As a result, defining the che- mature B cells, although it is clear that CXCR5 is
mokine receptor responsible for stimulus–response expressedathighlevelsandisfunctionallyimportant.
coupling in primary cells is often not straightforward Additional information on this subject with extensive
due to overlapping specificities of receptors for lists of primary references can be found in the indi-
ligands and leukocytes, and a paucity of receptor vidual receptor chapters.
subtype-selective blocking agents. Not only can
distinct receptor subtypes specific for the same
chemokine and the same function be coexpressed on
CHEMOKINE RECEPTOR
the same cell, but also distinct chemokines acting at
SIGNALING
separate receptors coexpressed on the same cell can
induce the same cellular response. Although anti-
receptor monoclonal antibodies and mice with tar- Aspects of signaling common to all known mamma-
geted gene disruptions are now being used to resolve lianchemokinereceptorsincludeinductionofcalcium
specificities in vivo, problems of interpretation persist flux and chemotaxis, and marked inhibition of both
1974 Philip M. Murphy
by Bordetella pertussis toxin (Bokoch, 1995; Ward coreceptor activity by CCR5 or CXCR4 (Alkhatib
et al., 1998). The latter reflects coupling of receptors et al., 1997; Amara et al., 1997; Farzan et al., 1997),
in primary cells to G-type heterotrimeric G proteins, or its inhibition by cognate chemokines, or, as
i
whose (cid:11) subunits are covalently ADP-ribosylated by mentioned previously, for proadhesive activity by
pertussis toxin, which inactivates the protein. There CX3CR1 (Imai et al., 1997).
are several noteworthy exceptions to this. First, con-
stitutive signalingby the viralreceptor KSHVGPCR
is completely insensitive to pertussis toxin; the pre- CHEMOKINE RECEPTOR
sumptive G protein involved has not yet been iden-
FUNCTION IN HEALTH AND
tified (Arvanitakis et al., 1997). Second, although
DISEASE
CX3CR1cansignalinaconventionalpertussistoxin-
sensitive chemotactic pathway in response to its
soluble chemokine ligand fractalkine, it can also Themainfunctionsharedbychemokinesandchemo-
function as a powerful cell–cell adhesion molecule by kinereceptorsisleukocytechemotaxis,which,together
bindingtomembrane-boundfractalkineinapertussis with differential expression, allows for orchestration
toxin-insensitive manner (Imai et al., 1997). Third, of specific leukocyte trafficking in vivo. Despite the
inhibition of chemokine action in primary cells by redundancy in organization, there is increasing evi-
pertussis toxin is often incomplete, perhaps reflecting dence from gene knockout and immunologic neu-
coupling to other classes of G proteins. Consistent tralization experiments for substantial specificity in
with this, several chemokine receptors, including chemokine and chemokine receptor function in vivo,
CCR1, CXCR1, CXCR2, and CCR2, signal in affecting three main areas: organ development, sus-
a pertussis toxin-insensitive manner in cell lines ceptibility to infection, and inflammation (Table 3)
cotransfected to express receptor and proteins from (Gerard, 1999). This implies that chemokines which
the G class, including G which is preferentially shareleukocytespecificitiesandreceptorswhichshare
q 16
expressed in hematopoietic cells (Kuang et al., 1996; chemokine specificities may not always be expressed
Xie et al., 1997). at equivalent levels and in the same temporal and
Signaling by the IL-8 receptors, CXCR1 and spatial context in vivo, and there is increasing experi-
CXCR2, has been studied most extensively, and mental evidence for this (Amichay et al., 1996).
includes additional common elements such as stim- Differential expression of combinations of chemo-
ulation of phospholipase C(cid:12)2 and inhibition of kines or receptors could allow sequential action,
adenylyl cyclase (Hall et al., 1999), and at least two directing leukocytes with high specificity to their
differences: selective activation of phospholipase D in vivo targets (Foxman et al., 1997). In this scenario,
and the NADPH oxidase by CXCR1 (Jones et al., agents that neutralize single chemokines or block
1996). Activation of CCR1 and CCR2 has also been single chemokine receptor subtypes could be very
showntoinhibitadenylylcyclase(Myersetal.,1995), effective at terminating the entire signaling relay,
consistent with coupling to G. Activation of several and may be useful therapeutically in diseases where
i
chemokinereceptorshasbeenassociatedwithprotein chemokine-dependent inflammation contributes to
tyrosine phosphorylation, including pyk-2 in the case pathology.
of CCR5 (Davis et al., 1997). IL-8 signaling to the Chemokines and chemokine receptors can be
Ras/Raf/MAP kinase/PI-3 kinase pathway has also looselydividedintothreefunctionalgroups:immune,
been reported (Knall et al., 1996). Unusual dual inflammatory, and an overlap group. Immune
signaling pathways have been reported for RANTES chemokine receptors, such as CXCR5 and CCR7,
in T cells. At low concentrations pertussis toxin- bind ligands that are constitutively expressed in a
sensitivecalciumfluxoccurs,whereasathighconcen- restricted manner and regulate basal leukocyte traf-
trations, threshold (cid:24)1mM, activation of ZAP70 in a ficking (Forster et al., 1996; Gunn et al., 1998a,b,
pertussis toxin-insensitive manner is observed. The 1999; Tangand Cyster, 1999; Saeki et al., 1999). This
receptor mechanism for this latter phenomenon has group of receptors regulates organization of the
not yet been defined (Bacon et al., 1995). lymphoid system and determines the migration and
Activation of chemokine receptors ultimately position of T cells, B cells, and dendritic cells within
results in desensitization, which has been associated specific areas of organized lymphoid tissue. In con-
withphosphorylationofserines andthreonines inthe trast, inflammatory receptors, such as CXCR1,
C tail, and clathrin-mediated endocytosis (Ali et al., CXCR2, CCR2, and CCR3, regulate emergency
1999;Oppermannetal.,1999;Yangetal.,1999).This leukocyte trafficking to tissue sites of inflammation
process may beimportant forreceptor resensitization by binding ligands whose expression is less spatially
and chemotaxis. Signaling is not required for HIV restricted than immune chemokines, and instead is
Chemokine Receptors: Overview 1975
Table 3 Function of chemokine receptors in vivo: phenotypes associated with targeted gene disruptions in mice and
naturally occurring inactivating mutations in humans
Receptor Viable? Development Major phenotypes
Mouse CXCR2 Yes Abnormal Neutrophil and B cell expansion in blood, lymph nodes,
spleen, and bone marrow
Impaired neutrophil recruitment to i.p. thioglycollate
Mouse CXCR4 No Abnormal Ventricular septal defect
Impaired B cell lymphopoiesis
Impaired bone marrow myelopoiesis
Defective cerebellar and gastric vascular development
Mouse CXCR5 Yes Abnormal Absent inguinal lymph nodes
Absent or abnormal Peyer’s patches
Defective B cell trafficking and localization
Mouse CCR1 Yes Normal Impaired lung granuloma formation to
Schistosoma mansoni eggs
Reduced pancreatitis-induced pulmonary inflammation
Increased susceptibility to Aspergillus fumigatus
Abnormal TH1/TH2 cytokine balance in
S. mansoni egg challenge
Abnormal steady-state and induced trafficking and
proliferation of myeloid progenitor cells
Mouse CCR2 Yes Normal Reduced monocyte recruitment after i.p. thioglycollate
Reduced lung granuloma size to PPD challenge
Abnormal TH1/TH2 cytokine balance in PPD challenge
Increased susceptibility to Listeria
Reduced atherogenesis
Mouse CCR5 Yes Normal Increased susceptibility to Listeria
Increased susceptibility to LPS-induced endotoxemia
Enhanced DTH reaction
Increased humoral responses to T cell-dependent
antigenic challenge
Human CCR5 Yes NAD Resistance to HIV-1 and AIDS
Human Duffy Yes NAD Resistance to Plasmodium vivax form of malaria
highly temporally restricted by primary proinflam- Chemokines and chemokine receptors may also play
matory cytokines (e.g. IL-1 and TNF). a role in T lymphocyte differentiation into TH1 and
Chemokinesandchemokinereceptorsalsoregulate TH2 phenotypes, as suggested by studies of CCR1
hematopoiesis. Analysis of knockout mice has shown and CCR2 knockout mice in schistosome egg
that CXCR4 is required for B cell lymphopoiesis and challenge of the lung; however the mechanism under-
bonemarrowmyelopoiesis,andthatCXCR2,CCR1, lying this is not yet clear (Boring et al., 1997; Gao
and CCR2 regulate hematopoietic progenitor cell et al., 1997).
growthanddistribution(Broxmeyeretal.,1996,1999; In addition to leukocytes, some chemokine recep-
Reid et al., 1999).In particular, CXCR2 is a negative tors are also expressed on various other cell types,
regulator of myeloid progenitors, which may explain includingerythrocytes,endothelialcells,neurons,and
in part the massive expansion of neutrophils in microglial cells of the brain (Hadley et al., 1994;
mice lacking this receptor (Cacalano et al., 1994). Horuketal.,1997;Guptaetal.,1998).Thebiological
1976 Philip M. Murphy
significance of this is still undefined for most MCV(Kledaletal.,1997;Damonetal.,1998),which
receptors, with the exception of CXCR4 (Tachibana suggests a mechanism for immune evasion by these
et al., 1998; Zou et al., 1998). Consistent with viruses, and, reciprocally, argues for the importance
expression in endothelial cells and neurons, genetic ofchemokinesinantiviralhostdefense.Furthermore,
elimination of CXCR4 in mice causes defective various orthopoxviruses encode two structurally
neuronal cell migration in the cerebellum during uniqueclassesofsecreted,broad-spectrumchemokine
development, a ventricular septal defect, and defec- scavengers, one of which also binds IFN(cid:13) (reviewed
tive gastric vascular development. Another bio- in McFadden et al., 1998). Neither has structural
logic process regulated by chemokines outside the homology to other proteins currently recorded in the
hematopoietic system is angiogenesis. ELR-positive public databases. To date, no naturally occurring
and -negative chemokines have been shown to have mammalian chemokines have been identified that
angiogenicandangiostaticactivity,respectively,when have chemokine receptor antagonist activity.
injected in the rat cornea or overexpressed in animal
models of cancer (Koch et al., 1992; Strieter et al.,
1995). Whether this activity occurs physiologically is
DEVELOPMENT OF CHEMOKINE
not yet known.
RECEPTOR ANTAGONISTS
Apartfromrolesindevelopment,hostdefense,and
inflammation, certain chemokine receptors may also
function paradoxically and pathologically as promi- Because of their specificity for leukocyte subsets,
crobial factors, the result of exploitation or subver- chemokine receptors are logical targets for drug
sion by specific microorganisms (McFadden et al., development in human diseases characterized by
1998; Pease and Murphy, 1998). The herpesvirus inflammation. Over the past decade, substantial
chemokine receptors mentioned earlier represent one progress has been made in identifying targets and
mode of exploitation. The functions of these mole- disease associations, and more recently in developing
cules are not yet understood, but possibilities include blocking strategies (Baggiolini and Moser, 1997).
immuneevasionthroughchemokinescavenginginthe Animal models in which IL-8 has been neutralized
caseofCMVUS28(Bodaghietal.,1998;Vieiraetal., immunologicallyhavepointedtoCXCR1andCXCR2
1998), and Kaposi’s sarcoma tumorigenesis in the as targets for diseases characterized by acute
case of KSHV GPCR (Arvanitakis et al., 1997). neutrophil-mediated inflammation, such as pustular
Betterunderstoodarethesubsetofhumanchemokine psoriasis, glomerulonephritis, and ischemia–reper-
receptors which are exploited by HIV as coreceptors, fusion injury, as may occur during angioplasty. Still,
andfunctionwithCD4astargetcellentryfactors.Of the available data do not discriminate specific roles
these, CCR5 and CXCR4 appear to be the most of CXCR1 and CXCR2 in clinical disease. A small
important in pathogenesis, and have distinct specifi- molecule antagonist specific for CXCR2 has been
city for two major classes of HIV viruses, defined by reported by White et al. (1998) from SmithKlein-
leukocyte cytotropism. CCR5 is essential for efficient Beecham, but not yet evaluated preclinically.
person-to-person HIV transmission and may also CCR3 is an attractive target in allergic inflam-
regulatetherateofdiseaseprogression,asrevealedby mation and asthma because it appears to be the
analysis of the naturally occurring inactive allele dominant chemokine receptor in human eosinophils,
CCR5(cid:1)32 (reviewed in Moore et al., 1997; Doms and is also expressed on basophils and a subset of
and Peiper, 1997; Berger et al., 1999). Similarly, TH2 lymphocytes. Consistent with this, genetic
study of a defective Duffy allele affecting the pro- elimination of eotaxin, a major CCR3 ligand, in the
moterhasrevealedtheobligateusageofnormalDuffy mouse results in (cid:24)50% reduction in airway inflam-
by the protozoan Plasmodium vivax as a receptor for mation after ovalbumin sensitization and challenge
erythrocyte entry in the pathogenesis of malaria (Rothenberget al., 1997). Extrapolationof thisresult
(Horuk et al., 1993; Horuk, 1994; Tournamille et al., to humans is restricted by the relative overexpression
1995). of CCR1 in mouse versus human eosinophils, the
Virally encoded chemokines have also been existence of other CCR3 ligands, and the potential
discovered, in several herpesviruses (e.g. HHV-8, for compensatory mechanisms in a nonconditional
mouse cytomegalovirus) and in molluscum conta- knockout. Direct CCR3 knockout will solve the
giosumvirus(MCV),ahumanpoxviruswhichcauses second of these problems, but other strategies to
the skin disease molluscum contagiosum. Interest- determine the significance of CCR3 in disease are
ingly,broad-spectrumchemokinereceptorantagonist clearly needed.
activity has been reported for several of these mole- Using specific neutralizing antibodies, Kennedy
cules, including vMIP-II of HHV-8 and MC148R of etal.havefoundthatacuteandrelapsingcomponents
Chemokine Receptors: Overview 1977
ofexperimental allergicencephalomyelitis in mice are remains relatively poorly developed and in which
regulated by MIP-1(cid:11) and MCP-1, respectively, sug- advances may have the greatest impact on further
gesting potential roles of CCR1 and/or CCR5 and knowledge of the biology of the system is in chemo-
CCR2 in the corresponding phases of multiple kine receptor pharmacology. At present the system
sclerosis in humans (Kennedy et al., 1998). Selective can be viewed as extremely rich in endogenous
small-molecule antagonists have been reported forall agonists, but equally poor in selective antagonists.
three of these receptors (Hesselgesser et al., 1998; Filling this void may facilitate biological experiments
Baba et al., 1999), but their effects in this and other thatcannotbedoneeasily,oratall,usinggeneticand
disease models have not yet been published. Genetic immunologicapproachescurrentlyinuse,andleadto
knockouts in the mouse have revealed that CCR2 new treatments of human disease.
and its ligand MCP-1 contribute to the severity of
atherosclerosis in dietary challenges (Boring et al.,
1998), providing justification for investigation of spe- References
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