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General Mechanisms of Leukocyte Circulation with an Emphasis on the Pulmonary Vasculature
Introduction
The Multistep Model of Leukocyte Extravasation
The Special Case of Leukocyte Recruitment into the Lung
Initiation of Airway Responses: From Antigen Capture to Presentation to T Cells
T Cells on the Road: From Lymphoid Tissue to the Inflamed Lung
Molecular Mechanisms for T Helper Cell Recruitment in Lung Inflammation
Chemokines: Chemotactic Cytokines and More
Chemokine Receptor Expression on T Cells
Chemokines and Chemokine Receptors in Lung Diseases
Asthma
Chemokines in Animal Models of Airway Hypersensitivity
Chemokine Receptors in Allergic Airway Disease Models: The Lesson from Gene Knockout Animals
Studies of Chemokines and Chemokine Receptor Expression in Asthmatic Patients
Chemokines and Chemokine Receptors in COPD
Chemokines and Chemokine Receptors in Sarcoidosis
Therapeutic Perspectives
Concluding Remarks
Keywords: lymphocyte homing; T cell; chemokines; asthma; COPD
T-cell trafficking into pulmonary tissue is a critical component of the host defense response. Migration of T cells into the lung also appears to orchestrate inflammation, tissue injury, and remodeling of tissue architecture. Chemotactic cytokines, called chemokines, play a major role in regulating T-cell localization into areas of inflammation. Various functions have been ascribed to chemokines, including many proinflammatory activities mediated by chemotaxis, integrin activation, and degranulation of distinct leukocyte subsets expressing different chemokine receptors. This review focuses on recent data either from clinical observations or animal models that have highlighted the importance of chemokine biology in several lung diseases. These include asthma, chronic obstructive pulmonary disease (COPD), and sarcoidosis. This knowledge opens new opportunity for the development of novel anti-inflammatory therapies into which the rapidly evolving chemokine field appears to be heading.
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GENERAL MECHANISMS OF LEUKOCYTE CIRCULATION WITH AN EMPHASIS ON THE PULMONARY VASCULATURE |
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Introduction
Leukocytes circulating within the vascular system constitute a combat-ready army, which patrols the endothelial walls of the blood vessels in search of specific signals that dictate extravasation and mobilization within tissues (1, 2). These extravasation signals are made up of a variety of molecules displayed by endothelial cells, which are most often induced or upregulated in response to inflammatory signals (3). Inflammation induces dramatic modifications in leukocyte trafficking. However, the molecular mechanisms that control homeostatic and inflammation-dependent trafficking are very similar and often share the same molecular components. T lymphocytes constitute an amazing paradigm for understanding how the complexity of trafficking behavior has a sound teleological basis on leukocytes' functional heterogeneity (4). In contrast to neutrophils or eosinophils that represent relatively simple cells with nonspecific inflammatory effector functions, T cells are extraordinarily endowed with the capacity to initiate, amplify, and terminate antigen-specific immune responses. Their trafficking patterns are a reflection of these abilities and the need of T cells to interact with populations of antigen-presenting cells and effector cells in anatomically distinct and specific microenvironments (4). Such complex patterns of lymphocyte recirculation rely on an integrated guidance system based on the combinatorial involvement of a large number of receptor-ligand interactions (3).
The Multistep Model of Leukocyte Extravasation
Leukocyte extravasation is thought to involve a series of sequential steps by which the leukocyte initially makes transient contacts with the vessel wall (tethering and rolling), it stops (activation and firm adhesion), and finally migrates through
endothelial cells (diapedesis) and within tissues (5). This multistep process is mediated by the interaction of different adhesion molecules and chemoattractants exposed on the luminal
side of the endothelium and receptors expressed on circulating leukocytes. However, it should be pointed out that such a
model has been determined from studies on the systemic circulation and may not fully apply to the unique features of the
pulmonary circulation. Leukocyte tethering and rolling is predominantly mediated by selectins, which bind at fast on-and-off rates to the carbohydrate moieties of selectin ligands (6, 7).
E- and P-selectins are upregulated on endothelial cells by cytokines such as tumor necrosis factor-alpha (TNF-
), while their
ligands are expressed on different leukocyte subsets. The expression of selectin/selectin ligands is confined to the microvilli
present on the leukocyte's surface allowing efficient interactions with the microvascular endothelium (8). Rolling leukocytes dramatically slow their transit time in microvessels but
the transient nature of selectin-mediated interactions makes it
impossible to stop leukocyte motion.
A different type of adhesion molecules, namely integrins, can
support firm adhesion of leukocytes. Integrins are a large family of heterodimeric cell surface receptors composed of noncovalently linked and 
transmembrane proteins, which can
bind to cell-surface-associated and extracellular matrix proteins (11, 12). Some of these receptors such as 41 and 47,
which recognize vascular cell adhesion molecule-1 (VCAM-1)
and mucosal addressin cell adhesion molecule-1 (MadCAM-1),
can also support rolling, albeit less efficiently than selectins
(13). On circulating leukocytes these receptors are generally
in a low affinity/avidity state and do not bind efficiently to
their ligands expressed on endothelial cells. Rolling allows the
leukocyte to sample the endothelial surface for the presence
of a third class of molecules, the chemoattractants, which bind
to specific seven transmembrane receptors that are coupled to
intracellular heterotrimeric Gi proteins (14). Signals transmitted by this class of receptors rapidly upregulate integrin's avidity
or affinity, resulting in stable adhesion to the endothelial cells
(15). The subsequent steps of transendothelial migration and
extravascular locomotion are still ill-defined but certainly involve the concerted action of chemoattractants, integrins, and other adhesion molecules. For this multistep key-lock mechanism to operate effectively, a number of factors are necessary.
The interaction of intravascular leukocytes with endothelial
cells occurs under extreme physical conditions, with flowing
blood pushing forward cells that touch the vessel wall. Because of their relatively low shear stress and small caliber,
postcapillary venules are generally the specialized microvessels where the multistep cascade of leukocyte extravasation
operates. However, important exceptions are the spleen, liver,
and the lung, where leukocyte extravasation may follow more
complex paradigms (2, 16).
The Special Case of Leukocyte Recruitment into the Lung
The pulmonary vasculature presents some unique features, which make leukocyte recruitment into the lung a special case. The human lung is supplied by two arterial systems, the pulmonary and bronchial circulation, which deliver blood to the parenchyma and the airways, respectively. As pointed out by others (17), the mechanisms of leukocyte recruitment may differ in these two different anatomic locations, and for this reason it is important to point out that a bronchial circulation does not exist in mice, which represents a commonly used animal model to study airway inflammation. Because of the enormous extension of capillaries, it is estimated that the great majority of leukocyte-endothelial interactions in the lung occur within the capillary network, where the small size of the microvessels (5 to 6 µm average diameter) does not allow rolling but actually requires leukocytes to squeeze between endothelial cells (18). In these conditions, leukocyte recruitment into the lung may not always obey classic models of sequential rolling, adhesion, and transmigration. The short distance between leukocytes in transit in the capillary network and alveolar epithelial cells may facilitate responses to inflammatory signals elicited within the airways. It is well documented that alveolar capillaries are the primary sites of neutrophil extravasation into the lung (19). Classic multistep leukocyte extravasation may still occur in pulmonary postcapillary venules (20), but its contribution to the overall leukocyte recruitment is difficult to evaluate and most likely subject to change depending on the inflammatory conditions (16, 21, 22).
Initiation of Airway Responses: From Antigen Capture to Presentation to T Cells
The lung parenchyma is continuously exposed to a variety of inhaled particles and antigens, among which are a variety of potentially pathogenic agents. Most antigens are ingested by alveolar macrophages and cleared by the mucociliary system, whereas some of them are recognized and captured by immature dendritic cells (23). Antigens associated with an inflammatory stimulus trigger maturation and migration of dendritic cells to tissue-draining lymph nodes (Figure 1), where these cells produce interleukin-12 (IL-12) and induce development of T helper type 1 (Th1) cells (24). Recent studies have shown that the encounter of T cells with dendritic cells within lymphoid tissues is guided by two T-cell zone-expressed chemokines, secondary lymphoid tissue chemokine (SLC) and EBI1 ligand chemokine (ELC), which bind the chemokine receptor CCR7 (27, 28). This receptor is expressed on naïve T cells and a subset of memory T cells and is strongly upregulated during maturation of dendritic cells, allowing their colocalization (29). In contrast, the dynamics of dendritic cell migration and priming of T helper cell, type 2 (Th2) cell differentiation, which occurs upon repeated exposure to inhaled allergens leading to allergic respiratory diseases such as asthma, are not clearly understood. A possible scenario envisions that certain inhaled antigens that are not associated with inflammatory stimuli are carried to draining lymph nodes by immature dendritic cells, which have been shown to favor Th2 cell differentiation in vitro and in vivo (30, 31). However, because immature dendritic cells do not express CCR7, it is difficult to envisage how these cells could migrate to regional lymph nodes to activate T cells.
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T Cells on the Road: From Lymphoid Tissue to the Inflamed Lung
Once effector T cells have been generated, their recruitment into the lungs is a critical event for the pathogenesis of airway inflammatory diseases. However, T cells are generally not the first inflammatory cells recruited into the lung. In animal models of allergic airway responses and in human asthma, T cells are always preceded by neutrophils, monocytes, and eosinophils and accumulate slowly over a few days (32). T-cell recruitment following bacterial or viral infections of the lung is also preceded by neutrophil infiltration (19, 23). Unlike cells of the innate immunity, such as neutrophils and eosinophils, T lymphocytes need to encounter the antigen in the secondary lymphoid organs (Figure 1). The antigen-activated T cells acquire effector functions and then home to sites of inflammation, thus providing an explanation for the different homing kinetics of T lymphocytes as compared with other inflammatory cells. The timing and location of adhesion and chemotactic molecules' expression within the airways are likely to be important determinants of how T helper cell recruitment is controlled; these phenomena will be discussed in the following sections within the framework of distinct lung pathologies. A large body of literature indicates a role for several adhesion molecules and chemotactic agents in the recruitment of inflammatory cells into the lung. In the next sections, we will discuss in detail the involvement of chemokines and their receptors in the recruitment of lymphocytes in airway inflammation.
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Chemokines: Chemotactic Cytokines and More
Recent studies have pointed out that among trafficking signals, chemokines and their receptors provide a central paradigm to understand the mechanisms regulating the tissue-specific recruitment of inflammatory cells. More than 40 chemokines and 20 chemokine receptors have been identified (35, 36). These small chemotactic cytokines have been divided into four subfamilies on the basis of the position of one or two conserved cysteine residues located near the N-terminus of the protein defining four structural motifs: CXC, CC, C, and CX3C (37). These molecules exert most of their biologic effects by binding to a large family of Gi-protein-coupled seven-transmembrane receptors leading to activation of multiple intracellular signaling pathways (38). A major function of chemokines is to dictate the extravasation and migration of leukocytes that express a large repertoire of chemokine receptors. In addition to promoting leukocyte migration, chemokines are potent cellular activators (39, 40). After binding to their receptors on neutrophils, basophils, and other cells, chemokines elicit granule exocytosis, oxidative burst with the release of superoxide and can affect gene expression, proliferation, and apoptosis (41). Many types of tissue resident cells, including smooth muscle, neurons, stromal cells, endothelial and epithelial cells have been found to express chemokine receptors (Table 1).
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Chemokine Receptor Expression on T Cells
Different leukocyte subsets possess a unique combination of chemokine receptors or "chemokine receptor profile," which identifies the homing potential of each type of cell (42). Chemokine receptor expression is exquisitely regulated depending on the stage of activation and differentiation of T cells and coordinates tissue localization and encounters with antigen presenting cells (43). Functional subsets of naïve, central memory, effector memory, follicular helper, skin-homing, and gut-homing T cells have been identified on the basis of selective expression of certain chemokine receptors. For instance, skin-homing and intestinal homing T cells respectively express the chemokine receptors CCR4 and CCR9 in a mutually exclusive manner (44, 45). Recent studies have attempted to address the chemokine receptor profile of T cells trafficking to the human lung and have reported that these cells are distinct from either gut-homing or skin-homing T cells, raising the possibility of the existence of distinctive lung-homing chemokine receptors (46). In the aforementioned study, T cells isolated from human bronchoalveolar lavage fluid (BALF) were found to predominantly express chemokine receptors CXCR3, CCR5, and CCR4. However, surprisingly, no differences were reported between T cells isolated from asthmatic and nonasthmatic subjects.
Given the functional diversity and distinct trafficking properties of Th1 and Th2 cells (47), it is perhaps not surprising that numerous chemokine receptors were found to be differentially expressed among these cells (29, 48). Th1 cells have been shown to preferentially express CCR5 and CXCR3, whereas
Th2 cells were reported to preferentially express CCR3, CCR4,
CCR8, and the chemoattractant receptor CRTh2 (49).
Macrophage inflammatory protein (MIP)-1 is a ligand of
CCR5, whereas interferon (IFN)-inducible protein-10 (IP-10),
monokine induced by IFN-
(Mig), and IFN-inducible T-cell
-chemoattractant (I-TAC) are ligands of CXCR3, all of which have been shown to attract preferentially Th1 cells. By contrast, eotaxin, a CCR3 ligand; I-309, a CCR8 ligand; thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), both CCR4 ligands, have
been shown to attract Th2 cells.
A fundamental feature of Th1 and Th2 type inflammatory responses is the coordinated involvement of multiple leukocyte subsets. In pulmonary bacterial infections, chronic obstructive pulmonary disease (COPD), and sarcoidosis, Th1/Tc1 cells are found to colocalize with monocyte/macrophages and neutrophils. By contrast, in allergic inflammation eosinophils, basophils, and mast cells accompany Th2 cells. Expression of CCR1 and CCR5 by monocytes/macrophages, neutrophils, and Th1 cells has been suggested to mediate recruitment of these cells by the same set of chemokines (39). Similarly, expression of CCR3 and CRTh2 by eosinophils and Th2 cells and expression of CCR4 by Th2 cells and basophils has been suggested to coordinate their colocalization during allergic airway inflammatory responses (53).
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Asthma
Asthma is a chronic inflammatory disease of the small airways that is characterized by mononuclear, eosinophil, and mast cell infiltration of the submucosa along with mucous gland hyperplasia and subepithelial fibrosis. The inflammatory response in asthma is tightly associated with airway hyperresponsiveness to antigen-specific and nonspecific stimuli. CD4+ Th2 cells are believed to play a crucial role in orchestrating airway inflammation in asthma by regulating the production of IgE and the growth and differentiation of mast cells, basophils, and eosinophils. In asthmatics, CD4+ T cells producing IL-4, IL-5, and IL-13 have been identified in bronchoalveolar lavage (BAL) and airway biopsies (56, 57). After allergen challenge Th2 lymphocytes are increased in the airways of allergic asthmatics. Recent studies have shown that messenger RNA (mRNA) for IL-13 is expressed in CD3+ cells in airway biopsies of both allergic and nonallergic asthmatics (58, 59), suggesting that the Th2 phenotype characterizes asthma, independent of the cause. Because chemokines influence inflammatory-cell trafficking and contribute to shaping the immune response, much effort has been devoted toward documenting a role of chemokines in asthma.
Chemokines in Animal Models of Airway Hypersensitivity
Mouse models of allergic airway disease have been extensively used to dissect the role of cytokines and chemokines during an inflammatory response in vivo. Although not entirely faithful to human asthma, these models have proved to be useful to study the role of specific chemokines in inflammation and airway hyperreactivity.
Data from several laboratories have indicated both a temporal as well as a spatial distribution of chemokines in the
lung. Chemokines such as RANTES (regulated upon activation,
normal T-cell expressed and secreted), MIP-1, and monocyte
chemoattractant (MCP)-5 are upregulated early on after allergen challenge but cannot easily be correlated with the recruitment of defined leukocyte subsets (60). In contrast, the kinetics
of production of eotaxin, MCP-1, MDC, and TARC correlate
with the recruitment of specific leukocyte subsets expressing
the receptors for these chemokines (61). Eotaxin and its
recently discovered relatives eotaxin-2 and eotaxin-3 have
been clearly implicated in airway recruitment of eosinophils
expressing CCR3 (36, 61, 64). These molecules could also
attract basophils and some Th2 cells expressing CCR3 (49,
69), and it will be interesting to see whether different eotaxins
have distinct roles in pathogenesis. A critical role has also
been suggested for MDC, which can recruit Th2 cells and basophils expressing CCR4 (63, 70).
As discussed, chemokines generate chemotactic gradients in vivo. The arrival and accumulation of different inflammatory cells at different stages of the inflammatory reaction has a direct influence on the chemotactic gradients. Various inflammatory cells can in fact produce large amounts of chemokines themselves and produce cytokines such as IL-4, IL-13, and TNF, which can enhance/change the production of chemokines from certain lung parenchymal cells (Figure 2). Studies reporting neutralization of eotaxin, RANTES, MCP-1, MDC, TARC, and MCP-5 support a contribution of each of these molecules in allergic airway responsiveness and inflammatory cell migration (62, 63, 70). It thus appears that the induction and evolution of allergic airway inflammation is the result of a coordinated effort that is dependent upon multiple chemokines for the recruitment and activation of different populations at specific stages of the inflammatory reaction.
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Chemokine Receptors in Allergic Airway Disease Models: The Lesson from Gene Knockout Animals
Ten different receptors for the CC chemokine family have so
far been identified. In general, multiple CC chemokines have
promiscuous bindings to multiple receptors (Table 1). Initial
studies on antigen-induced airway hyperreactivity models have
concentrated on CCR2, which binds members of the MCP-1
family. CCR2 appears to be expressed on monocytes, lymphocytes, mast cells, and basophils. Although one study has suggested that the neutralization of MCP-1 inhibits airway hyperreactivity in mice (62), CCR2-deficient mice show augmented
production of Th2 cytokines IL-4 and IL-13 and enhanced airway hyperreactivity when challenged by inhalation with ovalbumin (OVA) (73) (Table 2). These apparently contradictory findings could be explained if one considers that CCR2 binds
to additional chemokines (Table 1). Consistent with a role for
MCP-1 in promoting Th2 cell development, MCP-1
/ mice
exhibited a reduction in Th2 cytokine production as compared with MCP-1+/+ (74, 75).
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CCR3, which specifically binds eotaxin, is expressed on
eosinophils and basophils. Because recent data have reported
a low expression of this receptor also on Th2 cells, it has been
suggested that the sharing of CCR3 may allow these different
inflammatory cell types to colocalize at sites of eotaxin production (49), thus suggesting that this receptor may be involved
in the recruitment of inflammatory cells, leading to airway
damage and airway hyperreactivity. Surprisingly however,
CCR3/- and eotaxin-deficient mice are not protected in an
allergen-induced hyperreactivity mouse model (54, 76). Even
though disruption of CCR3 reduces airway eosinophil accumulation by 50%, CCR3/ mice show enhanced bronchial
constriction in response to methacholine (Table 2).
CCR4 is the high-affinity receptor for the CC chemokines TARC and MDC. CCR4 is very highly expressed by Th2 cells. It is also found on dendritic cells, monocytes, basophils, and platelets. The effect of the CCR4 deletion in vivo was studied using an OVA-induced murine model of Th2-mediated airway inflammation (77). Notably, the CCR4 deletion had no effect either in the OVA-induced eosinophilia, or in the OVA-induced bronchial hyperreactivity (Table 2).
Another chemokine receptor expressed by in vitro polarized Th2 cells is CCR8. Indeed the ligands for this receptor,
I-309 in humans and T-cell activation-specific gene 3 (TCA3)
in mice, are chemotactic for Th2 cells in vitro. CCR8-deficient
mice were generated and tested in two different models of allergic airway inflammation. Interestingly, CCR8/ mice had a
similar phenotype to IL-4/ mice under comparable experimental conditions, as both knockouts display reduced blood
eosinophilia and impaired peribronchial eosinophil recruitment that is associated with attenuation of Th2 cytokines (78).
Importantly, airway hyperresponsiveness was markedly reduced in a cockroach allergen mouse model of asthma (Table
2). In general, results with gene ablated mice should be interpreted with caution, as either compensatory mechanisms from
gene knockout mice or strain differences could mask the importance of each of these receptors. However, CCR8 seems to
be unique among other chemokine receptors in that it appears
to have an important and nonredundant function both in the
recruitment of inflammatory cells and in the regulation of the
allergic airway hyperreactivity response.
Studies of Chemokines and Chemokine Receptor Expression in Asthmatic Patients
In allergic airway responses, mast cells, basophils, eosinophils, T cells, dendritic cells, alveolar macrophages, and airway epithelial cells can all produce a plethora of chemoattractants and chemokines that promote accumulation of inflammatory cells in the lung. Numerous studies on asthmatic patients have documented that members of both the CC and the CXC family chemokines are upregulated after allergen challenge. Although it is likely that these molecules play a role in disease development, it has been difficult to identify their specific contribution to the overall inflammatory phenomenon. Initial investigations in human populations have focused on eotaxin. Besides being an eosinophil chemoattractant, eotaxin induces degranulation of eosinophils and causes IgE-independent degranulation of basophils (40). In asthmatic patients there is evidence of an increased number of cells expressing eotaxin mRNA in the bronchial mucosa and a correlation between the bronchial mucosal expression of eotaxin and airway hyper- responsiveness (68).
As discussed, eotaxin and its homologues, eotaxin 2 and 3, bind to a sole chemokine receptor, CCR3, which, in addition to eosinophils and basophils, has been reported to be expressed on a subpopulation of human, in vitro polarized Th2 cells. We have recently analyzed expression of several chemokine receptors, including CCR3, in the cells that infiltrate the airways of allergen-challenged asthmatics (79). Although the large majority of T cells infiltrating the bronchi after allergen challenge produced IL-4, none expressed CCR3. This therefore casts doubt on the role of this receptor in guiding Th2 cell trafficking during the asthmatic inflammatory response. Interestingly, expression of functional CCR3, as well as other chemokine receptors, has been reported on airway epithelial cells (79, 80), thus suggesting that certain chemokines in the airways could also influence airway epithelial cell function.
In contrast to CCR3, CCR4 was found to be expressed by
most IL-4-producing cells recruited into the lungs (79). The expression of CCR4 was paralleled by strong expression of its
ligands MDC and TARC in the airway epithelial cells after allergen challenge (Figure 3), suggesting that unlike eotaxin/CCR3,
the CCR4/ligands axis may be involved in Th2 recruitment in
the lung after allergen challenge. IL-4, in combination with
TNF-, has been shown to upregulate TARC production by airway epithelial cells (81). Therefore, it is possible that the CCR4
ligands induced by IL-4 in Th2 diseases such as asthma chemoattract CCR4+ T cells, which in turn are induced to produce more
IL-4, establishing a mechanism for amplifying Th2 responses.
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T cells expressing CCR8 were also increased in bronchial biopsies from challenged asthmatics in comparison to sham-challenged asthmatics (79). Confocal analysis of the CCR4 and CCR8 expression has revealed that the CCR8+ Th2 cells represented a subset of the CCR4+ Th2 population. Interestingly, we found a highly significant inverse correlation between the number of CCR8+, but not CCR4+ cells, infiltrating the airway mucosa and the maximal decrease in FEV1 during the late-phase reaction that follows allergen challenge (79). These results, together with the finding that the disruption of the CCR8 gene results in a marked reduction of the allergen-induced airway hyperresponsiveness, suggest that CCR8 is involved in the recruitment of lymphocytes that could lead to airway obstruction and increased airway damage.
Chemokines and Chemokine Receptors in COPD
COPD is a disease characterized by progressive development
of airflow limitation associated with a chronic inflammatory
process that differs from that seen in asthma, with different
mediators, inflammatory effects, and response to treatment.
Compared with asthma, information on chemokines/chemokine receptors in COPD is scanty. Reliable animal models are
lacking and the disease has been relatively neglected until recent years. A consistent finding in COPD is the increased frequency of neutrophils in the sputum that correlates negatively
with pulmonary function (82). For this reason investigators
have initially focused on IL-8. In patients with COPD, IL-8
was increased and correlated with the neutrophil numbers
(82). More recent observations have shown that CD8+ T cells
are overrepresented in the lungs of patients with COPD and
that they are inversely related to the lung function (83, 84). T
cells in the bronchial mucosa of COPD patients have a predominant Th1/Tc1 phenotype in that they express IFN- but
do not express IL-4 (79).
A recent analysis of chemokine receptor expression in COPD clearly indicated that the infiltrating T cells have a different chemokine receptor expression pattern when compared with asthma in that they express high levels of CXCR3 but do not express CCR4 nor CCR8 (79, 85). These findings are in agreement with a number of published studies in vitro and in vivo where CXCR3 was consistently found associated with Th1/ Tc1 responses (50, 86). Interestingly, neutrophils, which are an invariable cell component in COPD, have been shown to produce, among other chemokines, all the three ligands for CXCR3: IP-10, MIG, and I-TAC (87, 88). These observations suggest that neutrophils might contribute selective chemotactic signals that participate in the tissue-specific homing of Th1/ Tc1 lymphocytes, in keeping with the frequent association of neutrophils with type 1 responses. A number of experimental in vivo studies support such a scenario. For instance, depletion of neutrophils in a mouse model of Chlamydia infection results in a severe reduction in the number of Type 1 CD8+ T cells and a delay in the resolution of the infection (89). Furthermore, in a murine model of contact hypersensitivity, the neutrophil infiltration at the site of hapten challenge was shown to be essential for the subsequent recruitment of CD8+ T cells and the elicitation of contact hypersensitivity (90). This sequence of events may help explain why recruitment of T cells in the lung is delayed relative to that of neutrophils.
Chemokines and Chemokine Receptors in Sarcoidosis
Pulmonary sarcoidosis is characterized by the infiltration of T
lymphocytes and macrophages, and the formation of noncaseating granulomas in the lung. BALF from patients typically show a lymphocytosis predominantly with activated CD4+
T cells. The majority of these cells produce IFN- (91), consistent with the findings of elevated levels of the Th1 differentiation factor IL-12 in the BALF (92, 93). These BAL T cells
highly express CXCR3 (94). The coexpression of CXCR3 and
IFN- on lung T cells has recently been confirmed by immunohistochemical analysis of lung biopsies of sarcoid patients
(79). In parallel to CXCR3 expression, the CXCR3 ligand IP-10 has been found to be elevated both in the BALF and in the
lung of patients (94). IP-10 expression in granulomas localizes
to macrophages and epithelioid cells. Furthermore, alveolar
macrophages from patients with active pulmonary sarcoidosis
spontaneously secrete more IP-10 than patients with inactive
disease or healthy control subjects. In addition to IP-10, RANTES is also highly expressed in sarcoid tissue (95, 96). Among other receptors RANTES binds CCR5 that has also
been found to be preferentially expressed by Th1 cells (50,
97). Thus, it is possible that IP-10 and RANTES act together
in regulating the inflammatory infiltrate of sarcoid lesions.
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The idea of interfering with the ability of inflammatory cells to adhere to and migrate through endothelium during certain disease states is probably as old as the concept of leukocyte circulation itself (98). Indeed many long known anti-inflammatory drugs, such as glucocorticoid or nonsteroidal anti-inflammatory drug (NSAID) treatments, seem to exert their beneficial effects, at least in part, by modulating the expression and function of adhesion molecules, thereby limiting the activation and recruitment of leukocytes (19).
Expansion in our understanding of the processes involved in inflammatory cell recruitment has revealed new molecular targets for pharmacologic intervention. As previously discussed, Th1 and Th2 cells, which play a pivotal role in inflammation and host response to pathogens, have been recognized to possess distinct homing patterns, and rapid progress has been made in the identification of adhesion and chemokine receptors implicated in the differential trafficking of these cells. This knowledge promises to translate into innovative therapeutics for a variety of inflammatory disorders. Chemokine receptors hold the greatest promise for a number of reasons. First, the large number of receptors with highly specialized functions and their exquisite flexibility of expression suggest that these molecules encode for most of the specificity of the leukocyte recruitment process. Second, seven transmembrane receptors have an exceptionally good track record for being susceptible to low-molecular-weight therapeutic drugs that can be taken orally. Finally, targeting specific chemokine-receptor pairs should allow for the development of anti-inflammatory drugs specific for subsets of leukocytes, which avoid the broad immunosuppressive actions of current drugs such as steroids (99).
Numerous antibodies, receptor-blocking mutant chemokines,
and small molecules are being evaluated for the treatment of
asthma and other inflammatory lung diseases (Table 3). Orally
active small molecules represent the best approach for generating chemokine receptor antagonists with the greatest therapeutic value. Small-molecule antagonists of chemokine receptors are emerging from mass screening of chemical libraries,
and several potent small molecule antagonists of chemokine
receptors are beginning to enter clinical trials (100). The
benefits of controlling inflammation by limiting mobilization of inflammatory cells must, however, be carefully weighed
against the costs of interrupting specific lymphocyte/leukocyte
functions. A note of caution comes from data obtained in
CCR1/ (104). Compared with CCR1+/+, CCR1-deficient mice
exhibited a higher rate of mortality when infected with Aspergillus fumigatus and a defect in parasite clearance, associated with a reduced granuloma formation when infected with Schistosoma mansoni. These results are consistent with an important role of CCR1 in neutrophil function.
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Because of the clinical importance of chemokines and the potential benefit of pharmaceutical intervention in the chemokine pathway, there have been many recent advances in the chemokine field. A number of recent studies have shown that distinct sets of chemokines and their receptors are responsible for directing and positioning various population of leukocytes within sites of inflammation in different lung diseases. In addition to cell migration, chemokines can also influence the outcome of the immune response by altering the cytokine profile and by mediating the activation and degranulation of distinct leukocyte populations. The coordinated production of specific chemokines and the expression of distinct receptors on different leukocyte subsets are thus likely to dictate the type, intensity, and severity of inflammatory responses, making chemokine receptors ideal targets for therapeutic interventions. Given the strong impetus of both academic and pharmaceutical research in the chemokine field, validations of these targets, through systematic clinical trials of the novel agents currently in development, may not be too far away.
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Correspondence and requests for reprints should be addressed to Francesco Sinigaglia, M.D., Roche Milano Ricerche, via Olgettina 58, I 20132, Milan, Italy. E-mail: francesco.sinigaglia{at}roche.com
(Received in original form March 5, 2001 and accepted in revised form July 11, 2001).
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