| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Departments of
*
Dermatology and
Radiation Oncology, Heinrich-Heine-University, Düsseldorf, Germany;
Institut National de la Santé et de la Recherche Médicale, Laboratoire d’Immunologie Cellulaire et Clinique, Centre de Recherches Biomedicales des Cordeliers, Paris, France;
Finnish Institute of Occupational Health, Section of Dermatology, and Skin and Allergy Hospital, Helsinki University Central Hospital, and
¶
Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland;
||
Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary; and
#
Neurocrine Biosciences, San Diego, CA 92130
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Accumulating clinical and experimental evidence suggests that allergens such as birch or grass pollen (2), as well as house dust mite Ags Dermatophagoides pteronyssinus ((Der p) 1 and 2), 4 play a role in the initiation and amplification of atopic skin inflammation (3). Furthermore, 90% of atopic dermatitis patients show lesions colonized with Staphylococcus aureus (4) and exhibit a significant reduction of colonization in nonlesional skin (5). Various products of S. aureus, such as peptidoglycan (PGN) and superantigens, are known to induce the expression of proinflammatory cytokines in monocytes and dendritic cell (DC) subsets (6). Clinical observations showing an improvement of patients following antistaphylococcal therapy support a role for S. aureus in the pathogenesis of atopic dermatitis (7).
Histopathologically, atopic dermatitis skin lesions show an inflammatory infiltrate composed of predominantly CD4+ and cutaneous lymphocyte-associated Ag plus memory T cells (8). Skin-selective homing of memory and effector T cells represents an important immunological event in the initiation and amplification of atopic dermatitis lesions. In early phases of the disease, memory T cells with a Th2 phenotype infiltrate the skin at sites of atopic skin inflammation; however, chronic lichenified atopic dermatitis lesions are characterized by the dominance of skin-infiltrating Th1 cells (9).
Chemokines are small, secreted proteins that mediate directional migration and critically regulate organ-specific homing of distinct leukocyte subsets in vivo (10, 11). This superfamily of chemotactic proteins (45 in the human) is thought to be among the first functional protein families completely characterized at the molecular level (10). This offers, for the first time, the opportunity to identify all relevant members associated with physiological or pathological processes.
Although insights into the pathogenesis of atopic dermatitis have evolved over the past several years, the etiology of this disorder remains elusive. In the present study, we systematically analyzed the expression of all known chemokines in chronic inflammatory skin diseases and identified CCL18/DC-CK1/PARC to be specifically associated with atopic dermatitis. Allergen exposure, as well as staphylococcal products, markedly induced this chemokine in vitro and in vivo, suggesting important chemokine-driven processes during the initiation and amplification of atopic skin inflammation.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Six-millimeter punch biopsies were taken, after obtaining informed consent, from either healthy individuals (n = 14) or patients with atopic dermatitis (n = 15), psoriasis (n = 48), or lupus erythematosus (n = 9). The clinical diagnosis of cutaneous lupus erythematosus was confirmed by histological evaluation, serological examinations, and UV-provocation testing. Atopic dermatitis patients were identified according to the criteria defined by Hanifin and Rajka (12). Furthermore, patients suffering from chronic plaque psoriasis in typical locations were enrolled into the study. Normal skin samples were obtained from patients undergoing plastic surgery and reporting no history of atopic disorders or inflammatory skin diseases.
Moreover, atopic dermatitis patients with a history of house dust mite allergy underwent atopic dermatitis patch testing as described previously (13). Briefly, atopy patch tests were performed with house dust mite Ags containing a mix of Dermatophagoides farinae and D. pteronyssinus species (Chemotechnique Diagnostics, Malmö, Sweden). For staphylococcal enterotoxin B (SEB) patch tests, SEB (Sigma-Aldrich, St. Louis, MO) at 0.226 µg/µl in 0.9% NaCl solution was applied in Finn chambers (Epitest, Hyrylä, Finland) on healthy-appearing dorsal skin of atopic dermatitis patients. For the induction of chemical-induced allergic skin inflammation, NiSO4 at 5% in petrolatum (Epikon, Espoo, Finland) was applied in small Finn Chambers (Epitest) on nonlesional back skin of nickel-sensitized patients (n = 7) with no history of atopic dermatitis.
For the induction of chemical-induced irritant skin inflammation, the chemical irritant sodium lauryl sulfate (Merck, Darmstadt, Germany) at 1% in water was applied in large Finn Chambers (Epitest) on nonlesional back skin of Ni-sensitized patients (n = 7). The clinical score of patch test lesions was evaluated according to the recommendations of International Contact Dermatitis Research Group (14). Furthermore, the degree of inflammation was histopathologically analyzed and scored by two independent investigators (Table I).
|
Cell isolation and cell culture
Human primary epidermal keratinocytes, dermal fibroblasts, and dermal microvascular endothelial cells were purchased from Cambrex (San Diego, CA) and cultured as described (15). Cells were treated with TNF-
(10 ng/ml), IL-1
(5 ng/ml), IFN-
(20 ng/ml), and IL-4 (50 ng/ml; R&D Systems, Minneapolis, MN) for 18 h or left untreated. Skin single-cell suspensions were prepared from 6-mm biopsies after mechanical disintegration and enzymatic digestion as described previously (16). Single-cell suspensions of atopic dermatitis skin were stimulated with the house dust mite Ag Der p 2 (0.3 µM; Allergopharma, Reinbeck, Germany) for 24 h. Furthermore, PBMCs were treated with SEB (1 µg/ml; Sigma-Aldrich).
DC generation and stimulation
Interstitial DCs and Langerhans cells were generated from peripheral blood monocytes as described previously (17, 18). Briefly, mononuclear cells were isolated from peripheral blood and cultured for 6 days in the presence of GM-CSF and IL-4 for the generation of interstitial DC-type cells (17) or in the presence of GM-CSF, IL-4, and TGF- plus TNF- during the last 2 days of the culture for the generation of LC-type cells (18). For stimulation experiments, cells were cultivated for 2 days in the presence of either LPS (25 ng/ml), lipoteichoic acid (LTA; 10 µg/ml), PGN (10 µg/ml), SEB (10 ng/ml), or mannan from Saccharomyces cerevisiae (10 µg/ml). All reagents were purchased from Sigma-Aldrich. The murine CD40L-transfected fibroblast cell line (CD40L L cells) was kindly provided by Schering-Plough (Dardilly, France), and also used as a stimulator of DC maturation at the ratio of one CD40L L cell per five DCs (19). After 6 and 24 h, cells and supernatants were harvested for further analyses.
Quantitative real-time PCR (TaqMan) analysis
Quantitative real-time PCR analyses were performed as previously described (11, 15). Skin biopsies were homogenized in liquid nitrogen using a Mikro-Dismembrator U (Braun Biotech, San Diego, CA), and RNA was extracted with a TRIzol reagent according to the manufacturer’s instructions (Invitrogen Life Technologies, Karlsruhe, Germany). Four micrograms of RNA were treated with DNase I (Boehringer Mannheim, Mannheim, Germany) and reverse transcribed with oligo dT14–18 (Invitrogen Life Technologies) and random hexamer primers (Promega, Madison, WI) using standard protocols. A total of 25 ng of cDNA were amplified in the presence of 12.5 µl of TaqMan Universal Mastermix (Applied Biosystems, Foster City, CA), 0.625 µl of gene-specific TaqMan probe, 0.5 µl of gene-specific forward and reverse primers, and 0.5 µl of water. As an internal positive control, 0.125 µl of 18S RNA-specific TaqMan probe and 0.125 µl of 18S RNA-specific forward and reverse primers were added to each reaction. Gene-specific probes used FAM as a reporter, whereas probes for the internal positive control (18S rRNA) were associated with the VIC reporter. Alternatively, 25 ng of cDNA were amplified in the presence of target-specific primer combinations and SYBR Green Mastermix (Applied Biosystems, Foster City, CA). Chemokine ligand- and receptor-specific primers and target-specific probes were obtained from Applied Biosystems. Samples underwent the following stages: stage 1, 50°C for 2 min; stage 2, 95°C for 10 min; and stage 3, 95°C for 15 s followed by 60°C for 1 min. Stage 3 was repeated 40 times. Gene-specific PCR products were measured by means of an ABI PRISM 7700 or 5700 Sequence Detection Systems (Applied Biosystems) continuously during 40 cycles. Target gene expression was normalized between different samples based on the values of the expression of the internal positive control (18S rRNA) or ubiquitin.
Immunohistochemistry
For immunohistochemical analyses, skin sections were fixed in acetone and preprocessed with H2O2, followed by an avidin- and biotin-blocking step (Avidin/Biotin Blocking kit; Vector Laboratories, Burlingame, CA). Sections were stained with mAbs against human CCL18 (polyclonal goat IgG; R&D Systems, Minneapolis, MN), or isotype control Ab (Jackson ImmunoResearch Laboratories, West Grove, PA). Development of the staining was performed with a Vectastain ABC kit and an AEC kit (Vector Laboratories). Sections were counterstained with hematoxylin.
ELISA
For the detection of the CCL18 protein, a CCL18-specific ELISA system (Human CCL18 DuoSet; R&D Systems) was used according to the manufacturer’s instructions. Dilution series of recombinant human CCL18 protein were used for standard curves (R&D Systems).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The chemokine superfamily represents one of the first protein families completely characterized at the molecular level (10). To identify family members involved in the pathogenesis of chronic inflammatory skin diseases, we performed comprehensivequantitative real-time PCR analyses of skin specimens of healthy individuals (n = 14), cutaneous lupus erythematosus patients (n = 9), and nonlesional or lesional skin of psoriasis (n = 48) and atopic dermatitis (n = 15) patients using primer sets for all known human chemokines. Our results indicated that chronic inflammatory skin diseases could be distinguished at the molecular level by their chemokine expression profiles (Fig. 1). In particular, CCL18 was specifically and significantly up-regulated in lesional atopic skin when compared with normal skin or lesional skin of other inflammatory skin diseases (p < 0.01; Fig. 1a). Among all known chemokines, CCL18 represented the most highly expressed ligand in atopic dermatitis and the absolute amount of CCL18 mRNA in lesional atopic skin was >100-fold higher than that of CCL17/TARC, a chemokine previously reported to be associated with an atopic skin phenotype (Fig. 1, a and b; Ref. 20). Quantitative real-time PCR analyses demonstrated a significant induction of CXCL8/IL-8 transcripts in lupus erythematosus patients (p < 0.05; Fig. 1d); however, no significant association of CXCL8 was shown with a psoriatic phenotype. In contrast to CXCL8, the CC chemokine CCL20/MIP-3 was significantly and specifically up-regulated in lesional psoriatic skin (p < 0.05; Fig. 1c) as it was shown recently (21).
|
To identify the anatomical location and define the cellular origin of CCL18, we performed immunohistochemical analyses of skin sections from healthy individuals as well as nonlesional and lesional skin from atopic dermatitis patients using CCL18-specific Abs (Fig. 2). CCL18 was absent in the normal skin of healthy or nonlesional skin of atopic individuals, but abundant expression was observed in lesional atopic dermatitis (Fig. 2, a–e). CCL18-positive cells within the dermis exhibited a dendritic morphology (Fig. 2d, inset) and demonstrated two patterns of distribution. First, CCL18-producing cells were evenly dispersed within the dermal compartment suggesting a network of immunological sentinels (Fig. 2d). Second, CCL18-positive cells clustered in perivascular pockets showing a close anatomical association with skin-infiltrating lymphocytes (Fig. 2e). Within the epidermis, cells with a dendritic morphology, as well as keratinocytes of the uppermost layers, showed immunoreactivity for CCL18 (Fig. 2, f–h).
|
Because primary proinflammatory cytokines (i.e., TNF- and IL-1), Th cell-derived effector cytokines (i.e., IL-4 and IFN-), and microbial products are known to play a crucial role in the initiation and amplification of atopic skin inflammation (1, 22, 23), we investigated their role in the regulation of CCL18. In vitro, stimulation of cultured human primary keratinocytes and dermal fibroblasts with IFN- induced CCL18 expression (Fig. 3a). Next to IFN-, the type 2 cytokine IL-4 up-regulated the expression of CCL18 transcripts in cultured dermal fibroblasts (Fig. 3a). In contrast to structural cells, resting Langerhans-type cells, and especially interstitial-type DCs, expressed CCL18-specific transcripts at significantly higher levels (>100-fold; Fig. 3, b and c).
|
Allergen and superantigen exposure induces CCL18 expression in vivo
Topical exposure of nonlesional skin of atopic dermatitis patients to relevant allergens induces skin lesions mimicking atopic dermatitis, supporting a crucial role for allergens in triggering atopic skin inflammation (12). To obtain further insights into the pathogenesis of atopic skin inflammation, atopic dermatitis patients (n = 8) with a history of house dust mite allergy were subjected to atopy patch testing. Before as well as 2, 6, and 48 h after allergen exposure, skin specimens were obtained and analyzed by quantitative real-time RT-PCR or immunohistochemistry (Fig. 4, a–c). CCL18 transcripts were significantly induced 48 h after topical exposure to D. pteronyssinus and D. farinae Ags (p < 0.05; Fig. 4a). Looking at the individual kinetics of chemokine expression, CCL18 mRNA was induced as early as 2–6 h after house dust mite major allergen exposure in the majority of atopic dermatitis patients (Fig. 4a). Confirming the results of quantitative real-time PCR analyses, immunohistochemical evaluation of atopy patch test lesions showed markedly increased numbers of CCL18-positive cells 48 h after house dust mite allergen exposure (Fig. 4, b and c). To further analyze the capacity of specific allergens to regulate CCL18 expression in atopic skin, single cell suspensions of lesional atopic dermatitis skin were treated with recombinant Der p 2, in vitro. CCL18 mRNA was markedly induced (25-fold) 24 h after Der p 2 stimulation, indicating a role for this chemokine in allergen-specific immune responses (Fig. 4d).
|
To further investigate the role of CCL18 in nonatopic eczematous skin inflammation, we induced allergic or irritant contact dermatitis using NiSO4 or SLS epicutaneous patch tests, respectively. For this purpose, Ni-sensitized patients were exposed to the relevant hapten NiSO4 or to the chemical irritant SLS, skin biopsies were obtained before as well as 2, 6, and 48 h after chemical exposure and subsequently CCL18 expression was determined using real-time PCR and immunohistochemistry (Fig. 5). Although no significant differences in clinical and histological scores between NiSO4- and SLS patch-tested patients were observed (Table I), a significant induction of CCL18 mRNA and protein was exclusively observed during the induction of allergic skin inflammation (p < 0.05; Fig. 5). All Ni-sensitized patients showed a marked induction of CCL18 after exposure with the relevant hapten NiSO4; however, treatment with the chemical irritant SLS did not regulate the expression of this chemokine (Fig. 5).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In the present study, we demonstrate that chronic inflammatory skin diseases display distinct chemokine profiles, which help to distinguish atopic dermatitis, psoriasis, cutaneous lupus erythematosus, and normal skin at the molecular level. One member of the chemokine superfamily, CCL18, was specifically and significantly up-regulated in lesional atopic skin when compared with normal skin or lesional skin of other inflammatory skin diseases. Among all known chemokines, CCL18 represents the most highly expressed ligand in atopic dermatitis and the absolute amount of CCL18 mRNA in lesional atopic skin was >100-fold higher than those seen for CCL17, a chemokine previously reported to be associated with an atopic skin phenotype indicating a crucial role for this chemokine in atopic inflammation (20). Expression profiling of chronic inflammatory skin diseases also resulted in an unexpected and surprising observation. Although CXCL8/IL-8 was originally extracted from psoriatic scales (20), and thought to play an important role in the pathogenesis of psoriasis, its expression was not significantly up-regulated in psoriatic skin. In this context, it may be important to note that CXCL8 was recently abandoned as a therapeutic target in psoriasis supporting comprehensive profiling approaches to obtain insights into the etiology of diseases (27). In contrast to CXCL8, the CC chemokine CCL20 was significantly and specifically up-regulated in lesional psoriatic skin as it was shown recently (21). Furthermore, lesional skin of lupus erythematosus patients showed a significant induction of CXCL8 transcripts.
The highly abundant and specific expression of CCL18 in atopic dermatitis suggests an as yet unknown function in this disease. The gene-encoding human CCL18 is located in chromosome 17q11.2. To date, no receptor and no rodent homologue has been identified for this chemokine. However, whole genome scale DNA microarray analyses in a cynomolgus monkey (Macaca fascicularis) demonstrated that CCL18 was one of the most strongly up-regulated genes in a monkey asthma model, linking this chemokine with the pathogenesis of atopic diseases (28).
CCL18 was detected in the germinal centers and T cell areas of lymph nodes both representing sites where primary B and T cell responses are initiated (29). Furthermore, CCL18 is chemotactic for T cells (30) suggesting that this chemokine plays a role in the organization of T cell responses. This idea is supported by a recent study demonstrating that human CCL18 enhanced Ag-specific primary CD8+ T cell responses when coadministered with malaria vaccines in mice (31). In this study, we report that CCL18 was absent in the normal skin of healthy individuals and in the nonlesional skin of atopic individuals but showed abundant expression in lesional atopic dermatitis. The CCL18-positive cells within the dermis exhibited a dendritic morphology and they were either evenly dispersed within the dermal compartment suggesting a network of immunological sentinels, or clustered in perivascular pockets showing a close anatomical association with skin-infiltrating lymphocytes. Within the epidermis, Langerhans cells and keratinocytes in the uppermost layers showed immunoreactivity for CCL18. Hence, CCL18 is expressed at the interface between the environment and the host and is produced by cells constantly screening foreign Ags.
Clinically, atopic dermatitis patients show an increased frequency of microbial infections and current concepts suggest that staphylococcal products play an important role in the initiation and amplification of atopic skin inflammation (22, 23, 24, 32). Indeed, CCL18 was significantly induced in the skin of atopic dermatitis patients after topical exposure to SEB in vivo. Moreover, superantigen (SEB) stimulation of PBMCs markedly increased CCL18 expression in vitro confirming recent observations by Schutyzer et al. (33).
Although CCL18-producing cells were absent in normal and nonlesional atopic dermatitis skin, monocyte-derived resting interstitial-type and Langerhans-type DCs showed constitutive and abundant expression of CCL18 suggesting that regulation of this chemokine may depend on cell culture conditions. In monocytes, LPS, PGN, mannan and CD40L markedly induced the expression of CCL18. Furthermore, Th-derived effector cytokines and proinflammatory cytokines could induce CCL18 in structural cells of the skin such as keratinocytes and dermal fibroblasts. Although the absolute amount of CCL18 transcripts produced by structural cells of the skin in vitro was low in comparison to Langerhans-type and especially interstitial-type DCs, cytokines released from skin-infiltrating effector T cells may contribute to the abundant expression of CCL18 in atopic skin during acute and chronic phases of the disease (9). Our findings support previous observations that have described abundant expression of CCL18 by immature DCs in vitro (24, 34) and CCL18 production by lung macrophages as well as alveolar epithelial cells in vivo (22) but they substantially extend our understanding about its regulation and pathophysiological role (35).
Topical exposure of nonlesional skin of atopic dermatitis patients to relevant allergens induces skin lesions mimicking atopic dermatitis, supporting a crucial role for allergens in triggering atopic skin inflammation (12). Indeed, CCL18 was significantly induced in skin specimens of atopic dermatitis patients with a history of house dust mite allergy after topical exposure to D. pteronyssinus and D. farinae Ags, in vivo. Furthermore, treatment of single cell suspensions of lesional atopic dermatitis skin with the recombinant house dust mite allergen Der p 2 markedly induced CCL18, indicating a role for this CC chemokine in allergen-specific immune responses.
This notion is supported by our findings showing the induction of CCL18 during hapten-induced allergic, but not in chemical-induced irritant skin inflammation.
Taken together, findings of the present study suggest a model in which exposure to allergens and microbial products induces CCL18 production in atopic individuals and CCL18 consequently mediates the recruitment of T cells and ensures their encounter with allergen- or superantigen-loaded DCs. Subsequently, effector mediators such as IL-4, IFN-, or CD40L derived from activated skin-infiltrating T cells may amplify CCL18 production and atopic skin inflammation.
In conclusion, CCL18 represents a chemokine, which is associated with an atopy/allergy skin phenotype, expressed at the interface between the environment and the host, secreted by cells constantly screening for foreign Ags and regulated by microbial products and allergen exposure. Hence, CCL18 may play an important role in the initiation and amplification of atopic skin inflammation.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
1 This study was supported by the European Union (QLK4-CT-2001-00366), the German Research Foundation (SFB503), and the Finnish Medical Foundation. 
2 A.P., M.G., M.-C.D.-N., and A.L. contributed equally.
3 Address correspondence and reprint requests to Dr. Bernhard Homey, Department of Dermatology, Heinrich-Heine-University, Moorenstrasse 5, D-40225 Düsseldorf, Germany. E-mail address: Bernhard.Homey{at}uni-duesseldorf.de
4 Abbreviations used in this paper: Der p, house dust mite Ag Dermatophagoides pteronyssinus; PGN, peptidoglycan; DC, dendritic cell; SEB, staphylococcal enterotoxin B; LTA, lipoteichoic acid.
Received for publication May 28, 2004. Accepted for publication August 13, 2004.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
. J. Exp. Med. 179:1109./CCL20 and CC chemokine receptor 6 in psoriasis. J. Immunol. 164:6621.Related articles in The JI:
This article has been cited by other articles:
|
|
 |
|
  A. Kato, R. T. Chustz, T. Ogasawara, M. Kulka, H. Saito, R. P. Schleimer, and K. Matsumoto Dexamethasone and FK506 Inhibit Expression of Distinct Subsets of Chemokines in Human Mast Cells J. Immunol., June 1, 2009; 182(11): 7233 - 7243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-B. Kim, C.-K. Kim, K. Iijima, T. Kobayashi, and H. Kita Protein Microarray Analysis in Patients With Asthma: Elevation of the Chemokine PARC/CCL18 in Sputum Chest, February 1, 2009; 135(2): 295 - 302. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Li, T. Syrovets, S. Paskas, Y. Laumonnier, and T. Simmet Mature Dendritic Cells Express Functional Thrombin Receptors Triggering Chemotaxis and CCL18/Pulmonary and Activation-Regulated Chemokine Induction J. Immunol., July 15, 2008; 181(2): 1215 - 1223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. W T van Lieshout, J. Fransen, M. Flendrie, A. M M Eijsbouts, F. H J van den Hoogen, P. L C M van Riel, and T. R D J Radstake Circulating levels of the chemokine CCL18 but not CXCL16 are elevated and correlate with disease activity in rheumatoid arthritis Ann Rheum Dis, October 1, 2007; 66(10): 1334 - 1338. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Wimmer, S. K. Khaldoyanidi, M. Judex, N. Serobyan, R. G. DiScipio, and I. U. Schraufstatter CCL18/PARC stimulates hematopoiesis in long-term bone marrow cultures indirectly through its effect on monocytes Blood, December 1, 2006; 108(12): 3722 - 3729. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. d. Nadai, A.-S. Charbonnier, C. Chenivesse, S. Senechal, C. Fournier, J. Gilet, H. Vorng, Y. Chang, P. Gosset, B. Wallaert, et al. Involvement of CCL18 in Allergic Asthma J. Immunol., May 15, 2006; 176(10): 6286 - 6293. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Schutyser, A. Richmond, and J. Van Damme Involvement of CC chemokine ligand 18 (CCL18) in normal and pathological processes J. Leukoc. Biol., July 1, 2005; 78(1): 14 - 26. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. van der Voort, M. Kramer, E. Lindhout, R. Torensma, D. Eleveld, A. W. T. van Lieshout, M. Looman, T. Ruers, T. R. D. J. Radstake, C. G. Figdor, et al. Novel monoclonal antibodies detect elevated levels of the chemokine CCL18/DC-CK1 in serum and body fluids in pathological conditions J. Leukoc. Biol., May 1, 2005; 77(5): 739 - 747. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
