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(Journal of Leukocyte Biology. 2001;70:749-755.)
© 2001 by Society for Leukocyte Biology

Increased CCR4 expression in active systemic lupus erythematosus

Kayoko Hase*, Kenji Tani*, Teruki Shimizu*, Yasukazu Ohmoto{dagger}, Kouji Matsushima{ddagger} and Saburo Sone*

* Third Department of Internal Medicine, School of Medicine, Tokushima University, Japan;
{dagger} Cell Technology Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan; and
{ddagger} Department of Molecular Preventive Medicine, School of Medicine, University of Tokyo, Japan

Correspondence: Kenji Tani, Third Department of Internal Medicine, School of Medicine, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima City 770-8503, Japan. E-mail: kenjikt{at}clin.med.tokushima-u.ac.jp


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ABSTRACT
 
CC chemokine receptor (CCR)4 is selectively expressed on Th2-type T cells and has been shown to be responsible for Th2-dominant immune responses. In this study, we analyzed the expression of CCR4 in active systemic lupus erythematosus (SLE) patients by FACS analysis using anti-human CCR4 monoclonal antibody and determined the clinical relevance in this disease. Higher expression of CCR4 was found on peripheral blood CD4+ T lymphocytes of active SLE patients than was found with healthy controls and inactive SLE patients. The CCR4 expression significantly correlated with the SLE disease activity index (SLEDAI) scores. The expression was dramatically decreased after the corticosteroid therapy in parallel with a serum level of double-stranded DNA antibody and SLEDAI scores. Moreover, we found that serum levels of IL-10 were increased in active SLE patients and significantly correlated with the CCR4 expression. This study suggests that Th2 immune response is predominant in the active state of SLE, and CCR4 may have relevance in regard to the disease course in SLE patients.

Key Words: CD4+ T lymphocyte • Th2 • disease activity index • IL-10 • IFN-{gamma}


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INTRODUCTION
 
CD4+ T lymphocytes can be subdivided into two distinct populations, T helper (Th)1 and Th2, defined by the spectrum of cytokines produced by these cells in mice and humans [1 ]. Th1 cells generate interleukin (IL)-2, interferon-{gamma} (IFN-{gamma}), and tumor necrosis factor-ß (TNF-ß) and promote cell-mediated immunity, whereas Th2 generate IL-4, IL-5, IL-6, and IL-10 and play a role in humoral immunity and allergic diseases [2 ]. There is evidence that a balance of Th1 and Th2 is crucial for an effective immune response and the outcome of infectious and autoimmune diseases [3 , 4 ]. Recently, great attention has been placed on the possibility of distinguishing Th1 versus Th2 cells on the basis of the differential expression of chemokine receptors [5 , 6 ]. Chemokines have been suggested to have a role in effector and amplification mechanisms of polarized Th1- and Th2-mediated immune responses, and their receptors might serve as targets for selective modulation of T-cell-dependent immunity. Of these chemokine receptors, CC chemokine receptor (CCR)4, a receptor for thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) [7 , 8 ], is selectively expressed on Th2-type T cells and has been shown to be responsible for Th2-dominant immune responses [9 ]. Although the factors that control the development and maintenance of polarized immune responses in autoimmune diseases such as systemic lupus erythematosus (SLE) are poorly understood, monitoring chemokine receptor expression on circulatory T lymphocytes may give some insight into these diseases.

SLE is known to be the prototype of human autoimmune disease characterized by polyclonal activation of B cells, resulting in the production of a wide range of autoantibodies. Because several cytokines produced by Th2 cells are known to promote antibody production by B cells [10 ], it has been speculated that Th2 cells may play an active role in the development of autoantibody-mediated autoimmune responses in SLE [11 ]. However, the data on the expression of Th1- and Th2-type cytokines in SLE patients and in murine lupus models have been controversial [12 13 14 15 ].

In this study, we have analyzed the expression of CCR4 on CD4+ T lymphocytes in the blood of SLE patients and controls by flow cytometry and observed an increased expression of CCR4 in active SLE patients, which correlated with the disease activity of SLE.


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MATERIALS AND METHODS
 
Patients and controls
The study involved 13 patients (1 male and 12 females) with SLE. Their mean age was 34.1 years (range: 17–54 years). The diagnosis of SLE was based on the American College of Rheumatism (ACR) criteria for SLE [16 ]. The disease activity of SLE was determined by the SLE disease activity index (SLEDAI) [17 ]. Active state was defined as points over or equal to six or an increase over or equal to three points. Seven patients (one male and six females) were classified in active SLE; six of them were indicated by having greater than or equal to six points (range: 6–17) on SLEDAI and one of them, by a four-point increase in SLEDAI. Two of the patients with active SLE were taking oral prednisolone (4 or 10 mg per day), but five of them received no corticosteroid therapy when they entered into this study. Six of 13 patients with SLE were classified in inactive SLE receiving 5–20 mg prednisolone per day. Healthy controls (five males and three females; mean age, 29.1 years; range, 24–43 years) were used. None of them showed any abnormalities on physical examination, chest radiography, or in lung function tests. No allergic disease was seen in SLE patients or healthy controls.

Sampling of peripheral blood
Blood samples were collected in sterile tubes containing 100 U/ml heparin. Peripheral blood mononuclear cells (PBMC) were isolated from the peripheral blood on lymphocyte-separation medium (ICN Biomedicals, Aurora, OH) by the density gradient-separation method. The purity of PBMC, which was determined by cell differentiation after cytocentrifugation and staining with May-Giemsa stain, was 96%. More than 98% of the cells were viable, as judged by the Trypan blue dye exclusion test. PBMC were washed twice with phosphate-buffered saline (PBS) containing 1% bovine serum albumin, resuspended in PBS, and used in fluorescein-activated cell sorter (FACS) analysis as described below. Serum was separated from freshly drawn blood and stored at -20°C until cytokine analysis.

FACS analysis
The generation of a monoclonal antibody (mAb) against CCR4 [KM2160, mouse immunoglobulin G (IgG)1] was described previously [9 ]. PBMC were counted and adjusted to 1 x 106/ml. The cells were simultaneously stained directly with the optimal dilution of fluorescein isothiocyanate (FITC)-labeled anti-human CCR4 mouse mAb and phycoerythrin (PE)-labeled anti-human CD4 mouse mAb (PharMingen, San Diego, CA). All incubations were performed for 20 min followed by two washes. The stained cells were analyzed using a FACScan flow cytometer (Becton Dickinson, San Jose, CA). Appropriate FITC and PE control antibodies (PharMingen) were also included to monitor nonspecific antibody binding.

Assay for cytokines
Enzyme immunoassay for IL-10, IL-4, and IFN-{gamma} in serum was performed, essentially as described in detail previously [18 ]. The detection limit for cytokines was 20 pg/ml. MDC and TARC in serum were measured by performing sandwich enzyme-linked immunosorbent assay (ELISA) kits purchased from R&D Systems (Minneapolis, MN) according to the manufacturer’s instructions.

Statistical analysis
All results are expressed as mean ± SE. Statistical analysis was performed using the Student’s two-tailed unpaired t-test for comparisons between two groups. Correlations between two parameters were evaluated using Pearson’s test. Differences were considered significant if P values were 0.05 or less. Data were analyzed on a Macintosh computer using Statview software.


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RESULTS
 
Expression of CCR4 on CD4+ T lymphocytes of active SLE patients
CCR4 expression was analyzed by flow cytometry using anti-human CCR4 mAb (Fig. 1 ). Based on two-color flow cytometry, CCR4 was expressed only on 5.4 ± 0.4% of CD4+ T lymphocytes of healthy controls, which is consistent with previous studies [9 , 19 ]. The expression of CCR4 on CD4+ T lymphocytes of patients with inactive SLE was low (5.7±1.1%), similar to that of healthy controls. Conversely, significantly increased expression of CCR4 was found on CD4+ T lymphocytes from patients with active SLE (11.0±0.7%) when compared with that of healthy controls and inactive SLE patients. Recently, a chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) was shown to be selectively expressed in Th2 cells in health and disease [20 , 21 ], but unfortunately anti-CRTH2 mAb was not available in our laboratory.



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  		Figure 1. Levels of CCR4 expression on CD4+ T lymphocytes from patients with active SLE, inactive SLE, and healthy controls. PBMC were stained with FITC-conjugated anti-CCR4 antibody and PE-conjugated anti-CD4 antibody and then analyzed by flow cytometry. Results are expressed as mean ± SE.

Changes in CCR4 expression on CD4+ T lymphocytes of active SLE patients following therapy with high-dose prednisolone
Of seven active SLE patients, six began to receive therapy with high-dose corticosteroid (30–60 mg per day prednisolone). Of these six patients, five (cases 1, 3, 4, 5, and 6) had not been receiving corticosteroid therapy and began to receive oral prednisolone (30, 60, 50, 60, and 50 mg per day, respectively); one of these (case 5) received 1000 mg per day of methylprednisolone pulse therapy for three days followed by high-dose oral prednisolone. In the sixth patient (case 2), the dose of prednisolone was increased from 4 to 40 mg per day. To determine the effect of corticosteroid therapy on the CCR4 expression, the CCR4 expression was monitored after the therapy with high-dose corticosteroid. As shown in Figure 2A , at 2 weeks after the therapy with high-dose prednisolone, the CCR4 expression in cases 1, 2, and 3 was decreased to a level similar to that in healthy controls. This decrease was sustained for at least 4 weeks. In case 4, the CCR4 expression began to be decreased at 2 weeks and was to a level similar to that in healthy controls at 4 weeks. In cases 5 and 6, a significant decrease of the CCR4 expression was observed at 8 weeks. Figure 2B shows the average CCR4 expression on CD4+ T lymphocytes during the therapy with high-dose corticosteroid. The expression of CCR4 was 10.7 ± 0.8% before the therapy and was significantly decreased at 4 and 8 weeks after the therapy (6.1±0.7%, 4.4±0.8%, respectively).



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  		Figure 2. (A) Changes in CCR4 expression on CD4+ T lymphocytes of active SLE patients following therapy with high-dose prednisolone. PBMC obtained from active SLE patients before and after the therapy with high-dose prednisolone were analyzed by two-color immunofluorescence after staining with FITC-conjugated anti-CCR4 antibody and PE-conjugated anti-CD4 antibody. Lines indicate the controls. (B) Average of CCR4 expression on CD4+ T lymphocytes from six active SLE patients (0, 2, and 4 weeks) and five active SLE patients (8 weeks). Results are expressed as mean ± SE.

SLEDAI score and serum level of anti-double-stranded (ds)DNA antibody were monitered after the high-dose corticosteroid therapy (Table 1 ). Anti-dsDNA titer was determined by ELISA (SRL, Tokyo, Japan; normal range, <10 U/ml). Decreases in SLEDAI score were observed in four patients with active SLE (cases 1, 3, 4, and 5) at 2 weeks after the initiation of therapy and in one patient (case 6), at 4 weeks. The therapy did not change SLEDAI score in one patient (case 2). Serum level of anti-dsDNA antibody, which was more than the normal range in all six patients before the therapy, was decreased at 2 weeks after the therapy in five patients (cases 1, 2, 4, 5, and 6) and at 4 weeks in one patient (case 3). In five patients (cases 1, 2, 3, 5, and 6), it was decreased to normal range until 8 weeks. From these results, high-dose corticosteroid therapy was considered to decrease the disease activity of SLE.


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  		Table 1. Time Course of SLEDAI Score, Serum Anti-dsDNA Antibody, and Serum IL-10 in SLE Patients Undergoing Corticosteroid Therapy

Correlation of CCR4 expression with disease activity of SLE
As shown above, higher CCR4 expression was found in active SLE patients than was found in inactive SLE patients, and the level of CCR4 expression appeared to correspond to the disease activity of SLE in the course of corticosteroid therapy. Therefore, we examined the correlation between CCR4 expression and SLEDAI score in inactive SLE patients and active SLE patients before and after the therapy with high-dose corticosteroid. As shown in Figure 3 , the CCR4 expression significantly correlated with SLEDAI score, indicating that the CCR4 expression reflects the disease activity of SLE.



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  		Figure 3. Correlation between CCR4 expression on CD4+ T lymphocytes and SLEDAI score. PBMC obtained from inactive SLE patients and active SLE patients before and after the therapy with high-dose prednisolone were analyzed by two-color immunofluorescence after staining with FITC-conjugated anti-CCR4 antibody and PE-conjugated anti-CD4 antibody.

Serum cytokines
In inactive SLE patients, the serum level of IL-10 was similar to that in healthy controls. The serum level of IL-10 in active SLE patients was significantly higher than that in healthy controls and inactive SLE patients (Table 2 ). Next, we examined changes in the level of serum IL-10 of active SLE patients during the therapy with high-dose corticosteroid (Table 1) . In two patients (cases 3 and 4) and one patient (case 2), the serum level of IL-10 was decreased to the level similar to that of healthy controls at 2 and 8 weeks, respectively, after the therapy. In two patients (cases 1 and 5), slightly decreased serum IL-10 was observed at 4 and 2 weeks, respectively, after the therapy. Increased serum IL-10 was not detected in one patient (case 6). The level of serum IL-10 significantly correlated with SLEDAI scores. These results indicate that serum IL-10 closely corresponds to the disease activity of SLE consistent with previous studies [22 23 24 ]. The expression of CCR4 on CD4+ T lymphocytes significantly correlated with the level of serum IL-10 (Fig. 4 ), indicating that the expression of CCR4 may be related to Th2 immune response and disease activity of SLE. Serum IFN-{gamma} was detected in patients with active SLE (110±69 pg/ml) but not in patients with inactive SLE or healthy controls. No IL-4 was detected in serum from SLE patients or healthy controls.


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  		Table 2. Serum IL-10 in Healthy Controls and SLE Patients



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  		Figure 4. Correlation between CCR4 expression on CD4+ T lymphocytes and serum IL-10 levels in SLE patients. PBMC obtained from inactive and active SLE patients before and after therapy with high-dose prednisolone were analyzed by two-color immunofluorescence after staining with FITC-conjugated anti-CCR4 antibody and PE-conjugated anti-CD4 antibody.

MDC and TARC in serum
We next analyzed the level of serum MDC and TARC, which were known to be CCR4 ligands, by ELISA. As shown in Figure 5A , the serum level of MDC in active SLE patients (1203±207 pg/ml) was slightly higher than that in healthy controls (985±48 pg/ml), but the difference was not significant. Conversely, the serum level of MDC in inactive SLE patients was significantly lower than that in healthy controls and active SLE patients. Figure 5B shows changes in the level of serum MDC of active SLE patients during the therapy with high-dose corticosteroid. The serum level of MDC was significantly decreased at 2 weeks after the therapy. The significantly decreased level of MDC continued at least until 8 weeks after the therapy. There was no significant difference in the serum level of TARC among normal controls, inactive SLE patients, and active SLE patients (428±24, 454±70, 587±109 pg/ml, respectively), and the serum level of TARC in active SLE patients was not decreased by high-dose corticosteroid therapy (unpublished results).



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  		Figure 5. (A) Serum MDC of healthy controls, inactive SLE patients, and active SLE patients. Results are expressed as mean ± SE. (B) Changes in serum MDC of active SLE patients following therapy with high-dose prednisolone. Number of patients is as follows: 0 w (n=6), 2 w (n=3), 4 w (n=5), and 8 w (n=5). Results are expressed as mean ± SE.


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DISCUSSION
 
In this study, to assess Th2 predominance in SLE, we analyzed the expression of CCR4 on CD4+ T lymphocytes of SLE patients using anti-CCR4 mAb. This paper demonstrates for the first time that increased expression of CCR4 is found on peripheral blood CD4+ T lymphocytes of active SLE patients relative to that found in healthy controls and patients with inactive SLE. The expression was rapidly decreased after the therapy using high-dose corticosteroid. These results suggest that the expression of CCR4 serves as a useful marker of Th2 predominance and the disease activity of SLE and may have relevance in regard to the disease course in SLE.

The predominance of Th1 or Th2 immune response may be of great importance for various autoimmune diseases including SLE. Although SLE might be considered to be a disease characterized by Th2 because it is characterized by B-cell hyperactivity and autoantibody production, the data on Th2 predominance in murine models and in SLE patients have been controversial. Increases in number of IL-4-producing cells have been found in the murine lupus model [25 ], and neutralization of IL-4 [26 ] or IL-10 [27 ] was shown to prevent the disease. Conversely, some studies have suggested that the Th2-type response may be less important than the Th1 response in the lupus model. Santiago et al. [28 ] showed that expression of an IL-4 transgene by B cells in lupus mice protected rather than enhanced the development of lupus nephritis. Gene knockout of IFN-{gamma} or the IFN-{gamma} receptor eliminates disease in the murine lupus model [29 , 30 ]. Although these results suggest that Th1- and Th2-type responses are involved in the immune response of SLE, it is possible that differences in experimental approaches could be responsible for conflicting results concerning Th1 or Th2 predominance. Similarly, in SLE patients, increased production of Th1-type cytokines (IL-2 and IFN-{gamma}) [31 ] and Th2-type cytokines (IL-4, IL-6, and IL-10) [32 ] has been shown to be responsible for the pathogenesis of SLE. In this study, we also found increased amounts of IL-10 and IFN-{gamma} in serum from patients with active SLE. However, the results of this study, examining the expression of CCR4, a new Th2 marker, show that the expression of CCR4 was increased on CD4+ T lymphocytes from active SLE patients, indicating that the Th2 response may have a critical role in the pathogenesis of SLE. Recently, Campbell et al. [33 ] showed that CCR4 is selectively expressed on skin-homing peripheral blood lymphocytes, and Yamamoto et al. [19 ] demonstrated that CCR4-expressing CD4+ T cells in the blood are increased in patients with atopic dermatitis as compared with normal subjects. Further study is necessary to elucidate the critical role of CCR4 in the pathogenesis of SLE.

In this study, we found that CCR4 expression significantly correlated with serum levels of IL-10. We showed that the level of serum IL-10 corresponded to the disease activity of SLE, consistent with previous studies. For example, an increased level of serum IL-10 was observed in patients with active SLE [34 ]. PBMC from SLE patients were shown to produce higher IL-10 and to express higher levels of IL-10 mRNA than normal controls [22 , 23 ]. In an animal model, Llorente et al. [27 ] showed that in B/W F1 lupus mice, neutralization of IL-10 ameliorated the disease. Moreover, a recent study [24 ] indicated that anti-double-stranded DNA enhanced IL-10 release from resting PBMC, demonstrating that the autoantibodies deviated the immune response toward the Th2 pathway and subsequently enhanced the autoantibody production. These results showed that IL-10 plays a pivotal role in the pathogenesis of SLE. Although increased IL-10 may not simply reflect the Th2 predominance, because IL-10 can be produced by not only Th2 cells but also Th1 cells [35 ], the expression of CCR4, which correlated with serum IL-10 level shown in this study, may correspond to the disease activity of SLE.

Recently, Sozzani et al. [36 ] showed that IL-10 up-regulates CCR5 expression in human monocytes. Therefore, in this study, we examined whether IL-10 can up-regulate the CCR4 expression in vitro, but IL-10 (10 ng/ml) did not affect the expression of CCR4 on CD4+ T lymphocytes [IL-10 (+): 0 h, 3.7%; 24 h, 2.5%; 48 h, 2.5%; IL-10 (-): 0 h, 3.7%; 24 h, 4.4%; 48 h, 2.5%].

We showed that the CCR4 expression in patients with active SLE was higher than that in healthy controls and patients with inactive SLE and was decreased by the treatment with high-dose corticosteroid. The CCR4 expression significantly correlated with SLEDAI scores. These results indicate that CCR4 may have a role in the pathogenesis of SLE. CCR4 is a receptor for TARC and MDC, which are produced mainly by antigen-presenting cells (APC) such as mature dendritic cells [7 , 8 , 37 ]. In the disease sites, TARC and MDC produced by APC in Th2-dominant conditions induce chemotactic migration of circulating CCR4-expressing Th2 cells [9 , 38 ]. Recruited Th2 cells, upon activation by APC, may produce cytokines such as IL-3, IL-4, and granulocyte-macrophage colony-stimulating factor (GM-CSF), which further promote the production of TARC from APC [9 ]. Activated T cells can also produce TARC and MDC. TARC is selectively produced by Th2 cells, whereas Th1 and Th2 cells can produce MDC [7 , 8 , 38 , 39 ]. Thus, production of TARC and MDC and selective expression of CCR4 on Th2 cells may represent an important biological amplification mechanism to promote local Th2-type responses. Although TARC [40 ] and MDC expression [39 ] in dendritic cells and T cells in skin biopsy specimens of subjects with atopic dermatitis was shown, the role of TARC and MDC in SLE has not been demonstrated. In this study, we measured the serum level of MDC and TARC, but there was no significant difference in MDC and TARC between healthy controls and active SLE patients. However, it is interesting that the serum level of MDC was significantly lower in inactive SLE patients, who all received corticosteroid therapy, than in healthy controls, and high-dose corticosteroid therapy decreased the serum level of MDC but not TARC in active SLE patients. However, the mechanism of the suppressive effect of corticosteroid in production of MDC is unclear. To determine the significance of MDC and TARC in pathogenesis of SLE, it is necessary to examine their production and expression in the disease site such as skin lesions.

The mechanism by which CCR4 expression is up-regulated in active SLE remains to be elucidated. Recent studies showed that the expression of CCR4 is up-regulated upon T-cell receptor (TCR)-mediated activation of Th2 cells [41 ] and that repeated antigen challenge results in an increased frequency of CCR4-expressing Th2 cells [42 ]. These results suggest that CCR4 expression may be up-regulated by the interaction with antigen, although the etiologic antigen of autoimmunity in SLE has not been clearly understood.

In conclusion, we have shown that CCR4-expressing Th2 cells are increased in active SLE patients and might play an active role in the development of autoantibody-mediated autoimmune disorder in SLE. Although neutralization of CCR4 may have any therapeutic effect in vivo, further study is necessary to elucidate the critical role of CCR4 in the pathogenesis of SLE.


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ACKNOWLEDGEMENTS
 
This work was supported in part by a Grant-in-Aid for General Scientific Research (C) from the Ministry of Education, Science and Culture and the Ministry of Health and Welfare of Japan. We are grateful for the critical reading of the paper by Dr. Jim Turner.

Received February 27, 2001; revised June 28, 2001; accepted June 29, 2001.


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REFERENCES
 
    1
  1. Mosmann, T. R., Coffman, R. L. (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties Annu. Rev. Immunol. 7,145-173[Medline]
    2. 2
  2. Romagnani, S. (1994) Lymphokine production by human T cells in disease states Annu. Rev. Immunol. 12,227-257[Medline]
    3. 3
  3. Surcel, H. M., Troye-Blomberg, M., Paulie, S., Andersson, G., Moreno, C., Pasvol, G., Ivanyi, J. (1994) Th1/Th2 profiles in tuberculosis, based on the proliferation and cytokine response of blood lymphocytes to mycobacterial antigens Immunology 81,171-176[Medline]
    4. 4
  4. Tani, K., Murphy, W. J., Chertov, O., Salcedo, R., Koh, C. Y., Utsunomiya, I., Funakoshi, S., Asai, O., Herrmann, S. H., Wang, J. M., Kwak, L. M., Oppenheim, J. J. (2000) Defensins act as potent adjuvants that promote cellular and humoral immune responses in mice to a lymphoma idiotype and carrier antigens Int. Immunol. 12,691-700[Abstract/Free Full Text]
    5. 5
  5. Bonecchi, R., Bianchi, G., Bordignon, P. P., D’Ambrosio, D., Lang, R., Borsatti, A., Sozzani, S., Allavena, P., Gray, P. A., Mantovani, A., Sinigaglia, F. (1998) Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s J. Exp. Med. 187,129-134[Abstract/Free Full Text]
    6. 6
  6. Sallusto, F., Lenig, D., Mackay, C. R., Lanzavecchia, A. (1998) Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes J. Exp. Med. 187,875-883[Abstract/Free Full Text]
    7. 7
  7. Imai, T., Baba, M., Nishimura, M., Kakizaki, M., Takagi, S., Yoshie, O. (1997) The T cell-directed CC chemokine TARC is a highly specific biological ligand for a CC chemokine receptor 4 J. Biol. Chem. 272,15036-15042[Abstract/Free Full Text]
    8. 8
  8. Imai, T., Chantry, D., Raport, C. J., Wood, C. L., Nishimura, M., Godiska, R., Yoshie, O. (1998) Macrophage-derived chemokine is a functional ligand for the CC chemokine receptor 4 J. Biol. Chem. 273,1764-1768[Abstract/Free Full Text]
    9. 9
  9. Imai, T., Nagira, M., Takagi, S., Kakizaki, M., Nishimura, M., Wang, J., Gray, P. W., Matsushima, K., Yoshie, O. (1999) Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine Int. Immunol. 11,81-88[Abstract/Free Full Text]
    10. 10
  10. Snapper, C. M., Mond, J. J. (1993) Towards a comprehensive view of immunoglobulin class switching Immunol. Today 14,15-17[Medline]
    11. 11
  11. Goldman, M., Druet, P., Gleichmann, E. (1991) Th2 cells in systemic autoimmunity: insights from allogeneic diseases and chemically-induced autoimmunity Immunol. Today 12,223-227[Medline]
    12. 12
  12. Akahoshi, M., Nakashima, H., Tanaka, Y., Kohsaka, T., Nagano, S., Ohgami, E., Arinobu, Y., Yamaoka, K., Niiro, H., Shinozaki, M., Hirakata, H., Hariuchi, T., Otsuka, T., Niho, Y. (1999) Th1/Th2 balance of peripheral T helper cells in systemic lupus erythematosus Arthritis Rheum 42,1644-1648[Medline]
    13. 13
  13. Horwitz, D. A., Gray, J. D., Behrendsen, S. C., Kubin, M., Rengaraju, M., Ohtsuka, K., Trinchieri, G. (1998) Decreased production of interleukin-12 and other Th1-type cytokines in patients with recent-onset systemic lupus erythematosus Arthritis Rheum 41,838-844[Medline]
    14. 14
  14. Takahashi, S., Fossati, L., Iwamoto, M., Merino, R., Motta, R., Kobayakawa, T., Izui, S. (1996) Imbalance towards Th1 predominance is associated with acceleration of lupus-like autoimmune syndrome in MRL mice J. Clin. Investig. 97,1597-1604[Medline]
    15. 15
  15. Segal, R., Bermas, B. L., Dayan, M., Kalush, F., Shearer, G. M., Mozes, E. (1997) Kinetics of cytokine production in experimental systemic lupus erythematosus: involvement of T helper cell 1/T helper cell 2-type cytokines in disease J. Immunol. 158,3009-3016[Abstract]
    16. 16
  16. Tan, E. M., Cohen, A. S., Fries, J. F., Masai, A. T., McShane, D. J., Rothfield, N. F., Schaller, J. G., Talal, N., Winchester, R. J. (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus Arthritis Rheum 25,1271-1277[Medline]
    17. 17
  17. Bombardier, C., Gladman, D. D., Urowitz, M. B., Caron, D., Chang, C. H. (1992) Committee on prognosis studies in SLE. Derivation of the SLEDAI Arthritis Rheum 35,630-640[Medline]
    18. 18
  18. Sone, S., Yanagawa, H., Nishioka, Y., Orino, E., Bhaskaran, G., Ogura, T., Nii, A., Mizuno, K., Heike, Y., Ogushi, F. (1992) Interleukin-4 as a potent down-regulator for human alveolar macrophages capable of production tumor necrosis factor-alpha and interleukin-1 Eur. Respir. J. 5,174-181[Abstract]
    19. 19
  19. Yamamoto, J., Adachi, Y., Onoue, Y., Adachi, Y. S., Okabe, Y., Itazawa, T., Toyoda, M., Seki, T., Morohashi, M., Matsushima, K., Miyawaki, T. (2000) Differential expression of the chemokine receptors by the Th1- and Th2-type effector populations within circulating CD4+ T cells J. Leukoc. Biol. 68,568-574[Abstract/Free Full Text]
    20. 20
  20. Nagata, K., Tanaka, K., Ogawa, K., Kemmotsu, K., Imai, T., Yoshie, O., Abe, H., Tada, K., Nakamura, M., Sugamura, K., Takano, S. (1999) Selective expression of a novel surface molecule by human Th2 cells in vivo J. Immunol. 162,1278-1286[Abstract/Free Full Text]
    21. 21
  21. Cosmi, L., Annunziato, F., Iwasaki, M., Galli, G., Manetti, R., Maggi, E., Ngata, K., Romagnani, S. (2000) CRTH2 is the most reliable marker for the detection of circulating human type 2 Th and type 2 T cytotoxic cells in health and disease Eur. J. Immunol. 30,2972-2979[Medline]
    22. 22
  22. Llorente, L., Richaud-Patinm, Y., Wijdenes, J., Alcocer-Varela, J., Maillot, M. C., Durand-Gasselin, I., Fourrier, B. M., Galanaud, D., Emilie, D. (1993) Spontaneous production of interleukin-10 by B lymphocytes and monocytes in systemic lupus erythematosus Eur. Cytokine Netw. 4,421-427[Medline]
    23. 23
  23. Viallard, J. F., Pellegrin, J. L., Ranchin, V., Schaeverbeke, T., Dehais, J., Longy-Boursier, M., Ragnaud, J. M., Leng, B., Moreau, J. F. (1999) Th1 (IL-2, IFN-{gamma}) and Th2 (IL-10, IL-4) cytokine production by peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus (SLE) Clin. Exp. Immunol. 115,189-195[Medline]
    24. 24
  24. Sun, K. H., Yu, C. L., Tang, S. J., Sun, G. H. (2000) Monoclonal anti-double-stranded DNA autoantibody stimulates the expression and release of IL-1ß, IL-6, IL-8, IL-10 and TNF-{alpha} from normal human mononuclear cells involving in the lupus pathogenesis Immunology 99,352-360[Medline]
    25. 25
  25. Luzina, I. G., Knitzer, R. H., Atamas, S. P., Gausse, W. C., Papadimitriou, J. C., Sztein, M. B., Storrer, C. E., Handwerger, B. S. (1999) Vasculitis in the Palmerston North mouse model of lupus: phenotype and cytokine production profile of infiltrating cells Arthritis Rheum 42,561-568[Medline]
    26. 26
  26. Nakajima, A., Hirose, S., Yagita, H., Okumura, K. (1997) Roles of IL-4 and IL-12 in the development of lupus in NZB/WF1 mice J. Immunol. 158,1466-1472[Abstract]
    27. 27
  27. Llorente, L., Zou, W., Levy, Y., Richaud-Patin, Y., Wijdenes, J., Alcocer-Varela, J., Morel-Fourrier, B., Brouet, J. C., Alarcon-Segovia, D., Galanaud, P., et al (1995) Role of interleukin-10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erytematosus J. Exp. Med. 181,839-844[Abstract/Free Full Text]
    28. 28
  28. Santiago, M. L., Fossati, L., Jacquet, C., Muller, W., Izui, S., Reininger, L. (1997) Interleukin-4 protects against a genetically linked lupus-like autoimmune syndrome J. Exp. Med. 185,65-70[Abstract/Free Full Text]
    29. 29
  29. Peng, S. L., Moslehi, J., Craft, J. (1997) Roles of interferon-{gamma} and interleukin-4 in murine lupus J. Clin. Investig 99,1936-1946[Medline]
    30. 30
  30. Haas, C., Ryffel, B., Le, H. M. (1998) IFN-{gamma} receptor deletion prevents autoantibody production and glomerulonephritis in lupus-prone (NZBxNZW) F1 mice J. Immunol. 160,3713-3718[Abstract/Free Full Text]
    31. 31
  31. Al-Jandai, M., Al-Balla, S., Al-Dallan, A. (1993) Cytokine profile in systemic lupus erythematosus, rheumatoid arthritis, and other rheumatic diseases J. Clin. Immunol. 13,58-67[Medline]
    32. 32
  32. Richaud-Patin, Y., Alcocer-Varela, J., Llorente, L. (1995) High levels of TH2 cytokine gene expression in systemic lupus erythematosus Rev. Invest. Clin. 47,267-272[Medline]
    33. 33
  33. Campbell, J. J., Haraldsen, G., Pan, J., Rottman, J., Qin, S., Ponath, P., Andrew, D. P., Warnke, R., Ruffing, N., Kassman, N., Wu, L., Butcher, E. (1999) The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells Nature 400,776-780[Medline]
    34. 34
  34. Lacki, J. K., Leszczynski, P., Kelemen, J., Muller, W., Mackiewiez, S. H. (1997) Cytokine concentration in serum of lupus erythematosus patients: the effect on acute phase response J. Med. 28,99-107[Medline]
    35. 35
  35. Gerosa, F., Pganin, C., Peritt, D., Paiola, F., Scupoli, M. T., Aste-Amezaga, M., Frank, I., Trinchieri, G. (1996) Interleukin-12 primes human CD4 and CD8 T cell clones for high production of both interferon-{gamma} and interleukin-10 J. Exp. Med. 183,2559-2569[Abstract/Free Full Text]
    36. 36
  36. Sozzani, S., Ghezzi, S., Iannolo, G., Luini, W., Borsatti, A., Polentarutti, N., Sica, A., Locati, M., Mackay, C., Wells, T. N. C., Biswas, P., Vicenzi, E., Poli, G., Mantovani, A. (1998) Interleukin 10 increases CCR5 expression and HIV infection in human monocyte J. Exp. Med. 187,439-444[Abstract/Free Full Text]
    37. 37
  37. Vulcano, M., Albanesi, C., Stoppacciaro, A., Bagnati, R., D’Amico, G., Struyf, S., Transidico, P., Bonecchi, R., Prete, A. D., Allavena, P., Ruco, L. P., Chiabrando, C., Girolomoni, G., Mantovani, A., Sozani, S. (2001) Dendritic cells as a major source of macrophage-derived chemokine/CCL22 in vitro and in vivo Eur. J. Immunol. 31,812-822[Medline]
    38. 38
  38. Iellem, A., Colantonio, L., Bhakta, S., Sozzani, S., Mantovani, A., Sinigaglia, F., D’Ambrosio, D. (2000) Inhibition by IL-12 and IFN-{alpha} of I-309 and macrophage-derived chemokine production upon TCR triggering of human Th1 cells Eur. J. Immunol. 30,1030-1039[Medline]
    39. 39
  39. Galli, G., Chantry, D., Annunziato, F., Romagnani, P., Cosmi, L., Lazzeri, E., Manetti, R., Maggi, E., Gray, P. W., Romagnani, S. (2000) Macrophage-derived chemokine production by activated human T cells in vitro and in vivo: preferential association with the production of type 2 cytokines Eur. J. Immunol. 30,204-210[Medline]
    40. 40
  40. Vestergaard, C., Bang, K., Gesser, B., Yoneyama, H., Matsushima, K., Larsen, C. G. (2000) A Th2 chemokine, TARC, produced by keratinocytes may recruit CLA+CCR4+ lymphocytes into lesional atopic dermatitis skin J. Investig. Dermatol. 115,640-646[Medline]
    41. 41
  41. D’Ambrosio, D., Iellem, A., Bonecchi, R., Mazzeo, D., Sozzani, S., Mantovani, A., Sinigaglia, F. (1998) Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells J. Immunol. 161,5111-5115[Abstract/Free Full Text]
    42. 42
  42. Lloyd, C. M., Delaney, T., Nguyen, T., Tian, J., Martinez-A, C., Coyle, A. J., Gutierrez-Ramos, J. C. (2000) CC chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo J. Exp. Med. 191,265-273[Abstract/Free Full Text]



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