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-Inducible 
-Chemokine CXCL10 Involvement in Graves’ Ophthalmopathy: Modulation by Peroxisome Proliferator-Activated Receptor- Agonists
Department of Medicine (A.A., S.M.F., P.F., E.F.) and Otorhinolaryngology Unit (S.S.F.), University of Pisa School of Medicine, I-56100 Pisa, Italy; Department of Clinical and Experimental Medicine and Surgery F. Magrassi–A. Lanzara, Second University of Naples (M.R.), 80100 Naples, Italy; and Department of Clinical Pathophysiology, Endocrinology Unit, University of Florence (P.R., M.S.), 50100 Florence, Italy
Address all correspondence and requests for reprints to: Dr. Alessandro Antonelli, Department of Internal Medicine, University of Pisa School of Medicine, Via Roma 67, I-56100 Pisa, Italy. E-mail: a.antonelli{at}med.unipi.it.
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Abstract |
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-chemokine CXCL10/inducing protein-10 play an important role in the initial phases of autoimmune thyroid disorders. Human thyrocytes in primary culture produce large amounts of CXCL10 when stimulated by interferon-
(IFN) and TNF.
Objective: Serum CXCL10 levels (sCXCL10) were measured in patients with active or inactive Graves’ ophthalmopathy (GO). The effects of IFN and TNF stimulation and peroxisome proliferator-activated receptor- (PPAR) activation on CXCL10 secretion in primary cultures of thyrocytes, orbital fibroblasts, and preadipocytes were tested.
Patients: Sixty consecutive patients with Graves’ disease, 60 age- and sex-matched patients with GO, and 60 controls were studied.
Results: sCXCL10 was higher (P < 0.0001) in Graves’ disease (120 ± 83 pg/ml; n = 60) and GO (122 ± 71; n = 60) patients than in age- and sex-matched euthyroid controls (72 ± 32; n = 60). Among GO patients, sCXCL10 levels were significantly higher in those (n = 14) with active disease (171 ± 197) than in those with inactive disease (114 ± 45 pg/ml; P < 0.003). In primary cultures of thyrocytes, retrobulbar fibroblasts and retrobulbar preadipocytes from GO patients, CXCL10 production was absent under basal conditions; dose-dependent secretion of CXCL10 was not induced by TNF alone, whereas stimulation with IFN or TNF plus IFN induced CXCL10 release. Treatment of all cell types with the PPAR agonist, rosiglitazone, dose-dependently (0.1–10 µM) suppressed IFN- plus TNF-induced CXCL10 release.
Conclusions: We conclude that in GO, thyrocytes and retrobulbar cell types participate in the self-perpetuation of inflammation by releasing chemokines under the influence of cytokines. PPAR activation plays an inhibitory role in this process.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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chemokines, especially CXCL10/inducing protein-10, play an important role in the initial phases of autoimmune thyroid disorders (7, 8, 9, 10, 11). In GD, CXCR3 is expressed in endothelial and inflammatory cells, such as thyrocytes (7, 10), and serum CXCL10 levels are significantly increased only in GD patients (GD-p) with recent onset of disease (7). Similarly, serum CXCL10 is increased in patients with newly diagnosed autoimmune thyroiditis, overall in association with hypothyroidism, suggesting that CXCL10 may be a marker of a more aggressive thyroiditis (8, 9). However, no study has examined CXCL10 involvement in patients with GO (GO-p).
These clinical observations together with the demonstration that human thyrocytes in primary culture produce large amounts of CXCL10 when stimulated by interferon- (IFN) and TNF (10) suggest that thyroid follicular cells can modulate the autoimmune response through the production of CXCL9/Mig and CXCL10 (7, 8, 9, 10). These chemokines can enhance the migration of Th1 lymphocytes into the gland, where they secrete IFN. In turn, IFN stimulates chemokine production by follicular cells, thus perpetuating the autoimmune process (8, 9, 10, 12). This pathogenetic hypothesis may apply to other autoimmune disorders: in particular, if orbital fibroblasts and orbital preadipocytes from GO-p secreted CXCL10 under IFN/TNF stimulation, a similar mechanism may be involved in the pathogenesis of GO.
Recently, the presence of peroxisome proliferator-activated receptor- (PPAR) has been demonstrated in thyroid tissue (13) and in orbital tissues from GO-p (14). Although originally implicated in adipocyte differentiation and glucose homeostasis (15), PPAR has recently been shown to be involved in the modulation of inflammatory responses. Treatment of endothelial cells with PPAR activators inhibits 1) IFN-induced mRNA and protein expression of CXCL10, CXCL9, and CXCL11/I-TAC (16); and 2) the release of chemotactic activity for CXCR3-transfected lymphocytes (16). Thus, PPAR activity may be involved in the regulation of IFN-induced chemokine expression in human autoimmunity, and PPAR activators might attenuate the recruitment of activated T cells at sites of Th1-mediated inflammation (16, 17, 18).
The aims of this study were, first, to measure serum CXCL10 levels in active or inactive GO-p; next, to test the effect of IFN stimulation on the secretion of the prototype CXC -chemokine, CXCL10, in primary cultures of cells obtained from the main tissues involved in the pathogenesis of GD and GO (thyrocytes, orbital fibroblasts, and preadipocytes); and, finally, to assess the effect of PPAR activation on IFN-inducible CXCL10 secretion in these cell types.
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Patients and Methods |
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Patients.
From our outpatient clinic, we selected 60 consecutive Caucasian GD-p and 60 age- and sex-matched GO-p (Table 1
). The diagnosis of GD was established from the clinical presentation (19). At the time of evaluation, all GD-p were clinically euthyroid, either by taking antithyroid drugs (32 patients) or levo-T4 (18 patients) or spontaneously (10 patients). In GO-p, eye disease activity was assessed by the clinical activity score (20). A score of 5 (maximal score, 10), including a worsening over the previous 2 months, indicated active GO. Inactive eye disease was defined as no changes in eye status over the previous 6 months. Of these 60 patients, 23 had not received immunosuppressive therapy at any time, 21 had been previously treated with corticosteroids, three had been treated with orbital irradiation, and 13 were treated with both. At the time of study, a median of 11 months (range, 6–42) had elapsed from the end of treatment. Total eye score was calculated as the sum of the products of each NOSPECS class by its grade (to this purpose, we substituted 1, 2 and 3, respectively, for grades a, b, and c) (21, 22). The durations of both eye and thyroid disease since their first signs and symptoms were recorded. At the time of evaluation, all GO-p were clinically euthyroid, either by taking antithyroid drugs (39 patients) or levo-T4 (12 patients) or spontaneously (9 patients).
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In both patients and controls, a blood sample was collected in the morning after an overnight fast, and serum was kept frozen until thyroid hormones, thyroid autoantibodies, CXCL10, IFN, and TNF measurements. All study subjects gave their informed consent to the study, which was approved by the local ethical committee.
Thyroid laboratory evaluation and ultrasonography. Neck ultrasonography was performed using a probe (AU5 with a sectorial 7.5-MHz transducer; Esaote S.p.A., Florence, Italy); thyroid volume was calculated using the ellipsoid formula, as previously described (8, 9). Thyroid function and thyroid autoantibodies were measured as previously described (8, 9).
In vitro studies
The effects of IFN, TNF, and PPAR agonists on the release of CXCL10 were investigated in primary cultures of human thyroid follicular cells, fibroblasts, and preadipocytes.
Thyroid follicular cells. Surgical thyroid tissue and peripheral blood were obtained from five GO-p, who were euthyroid at the time of surgery. Thyroidectomy was advised to GO-p mainly because of relapse of hyperthyroidism after a previous methimazole course in the presence of a large goiter and/or thyroid nodules. In addition, normal thyroid tissue was obtained from five patients (three undergoing parathyroidectomy and two with laryngeal intervention). Thyrocytes were prepared as reported previously (10, 24). The specimens were minced with scissors and digested with collagenase (1 mg/ml; Roche, Mannheim, Germany) in RPMI 1640 (Whittaker Bioproducts, Walkersville, MD) for 1 h at 37 C. Semidigested follicles were removed, sedimented for 2 min, washed, and cultured in RPMI 1640 supplemented with 10% fetal bovine serum (FBS; Seromed, Biochrom, Berlin, Germany), 2 mM glutamine, and 50 µg/ml penicillin/streptomycin at 37 C in 5% CO2 in plastic 75-cm2 flasks (Sarstedt, Verona, Italy).
Fibroblast and preadipocyte cell cultures. Orbital adipose/connective tissue explants were obtained from five patients undergoing orbital decompression for severe GO during the inactive phase of the disease [all previously treated with antithyroid medication and systemic corticosteroids (21, 22), euthyroid at the time of surgery (three taking levo-thyroxine after thyroidectomy); none treated with orbital radiotherapy]. GO tissue samples were minced and placed directly in plastic culture dishes, allowing preadipocyte fibroblasts to proliferate as described previously (25, 26). Cells were propagated in medium 199 containing 20% FBS (Invitrogen Life Technologies, Inc., Paisley, UK), penicillin (100 U/ml), and gentamicin (20 µg/ml) in a humidified 5% CO2 incubator at 37 C and maintained in 75-cm2 flasks with medium 199 containing 10% FBS and antibiotics.
To initiate adipocyte differentiation, orbital cells were grown to confluence in six-well plates in medium 199 with 10% FBS. Differentiation was carried out as reported previously (25); cultures were changed to serum-free DMEM/Ham’s F-12 (1:1; Sigma-Aldrich Corp., St. Louis, MO) supplemented with biotin (33 µM), pantothenic acid (17 µM), transferrin (10 µg/ml), T3 (0.2 nM), insulin (1 µM), carbaprostacyclin (0.2 µM; Calbiochem, La Jolla CA), and, for the first 4 d only, dexamethasone (1 µM) and isobutylmethylxanthine (0.1 mM). The differentiation protocol was continued for 10 d, during which time the medium was replaced every 3–4 d. In separate experiments, fibroblasts derived from the same patients’ orbital tissues were maintained for the same period of time in medium lacking several of the components necessary for complete adipocyte differentiation (i.e. carbaprostacyclin, dexamethasone, and isobutylmethylxanthine).
Control fibroblasts and preadipocytes were obtained from unaffected dermal tissues of the same patients.
Orbital preadipocyte fibroblast cultures (25, 26) were plated in one-well culture chamber slides (Nalge Nunc International, Rochester, NY) in medium 199 containing 10% FBS, grown to confluence, and subjected to either the differentiation protocol or nondifferentiation conditions. Cells were washed twice with 1x PBS, fixed in 10% formalin overnight at room temperature, and rinsed in 60% isopropanol before staining with filtered 0.21% Oil Red O in isopropanol/water for 1 h. Washed cells were stained with Mayer’s hematoxylin solution (MHS-32, Sigma-Aldrich Corp.) for 5 min and rinsed with tap water before being visualized using an Olympus IX50 light microscope (New Hyde Park, NY) and photographed at x20.
CXCL10 secretion assay.
For CXCL10 secretion assays, 3000 cells were seeded onto 96-well plates in growth medium. After 24 h, the growth medium was removed, and cells were washed in PBS and incubated in phenol red- and serum-free medium. Cells were incubated (24 h) with IFN (R&D Systems, Minneapolis, MN; 500, 1,000, 5,000, and 10,000 U/ml) and 10 ng/ml TNF (R&D Systems), alone or in combination (16). The concentration of TNF was selected in preliminary experiments to yield the highest responses. After 24 h, the supernatant was removed and kept frozen at –20 C until CXCL10 assay.
To investigate the effect of PPAR activators on IFN-induced chemokine secretion, cells were stimulated (24 h) with IFN (1000 U/ml) and TNF (10 ng/ml) in the absence or presence of increasing concentrations (0, 0.1, 1, 5, and 10 µM) of the pure PPAR agonist, rosiglitazone (RGZ; Glaxo, Welwyn, UK), and conditioned medium was assayed by ELISA for CXCL10 concentrations. All experiments were repeated three times with the three different cell preparations.
Cell cultures and RGZ treatment. Cultures of thyrocytes were treated (24 h) with 0.1, 1.0, 5, 10, or 20 µM RGZ. Control cultures were grown (24 h) in the same medium containing vehicle (absolute ethanol, 0.47%, vol/vol) without RGZ. Some cultures were examined by phase contrast microscopy using an Olympus IX50.
The effect of RGZ was examined both in cells grown in differentiation medium (differentiated cultures; after 10 d) and in cells grown for the same period in medium lacking several of the components necessary for complete adipocyte differentiation (nondifferentiated cultures) (25). Cultures of fibroblasts and preadipocytes were treated (24 h) with 0.1, 1.0, 5, 10, or 20 µM RGZ after the initial 10-d period. Control cultures were grown (24 h) in the same medium containing vehicle (absolute ethanol, 0.47%, vol/vol) without RGZ. Some cultures were examined by phase contrast microscopy using an Olympus IX50. Parallel cultures were stained with Oil Red O and examined under light microscopy.
For quantitation of total protein in cell preparations, lysis and homogenization were performed, and the sample was immediately assayed for its protein concentration by conventional methods (15).
ELISA for CXL10, IFN, and TNF
CXCL10 levels were measured in serum and culture supernatants, and IFN and TNF concentrations were measured in serum using commercially available kits (R&D Systems). The mean minimum detectable dose was 1.67 pg/ml for CXCL10, 8 pg/ml for IFN, and 0.12 pg/ml for TNF; the intra- and interassay coefficients of variation were, respectively, 3.0% and 6.9% for CXCL10, 2.8% and 6.4% for IFN, and 5.9% and 10.4% for TNF. Samples were assayed in duplicate. Quality control pools of low, normal, or high concentrations for all parameters were included in each assay.
Data analysis
Values are given as the mean ± SD for normally distributed variables or as the median and interquartile range. Mean group values were compared using one-way ANOVA for normally distributed variables or by the Mann-Whitney U or Kruskal-Wallis test. Proportions were compared by the 
2 test. Post hoc comparisons of normally distributed variables were carried out using the Bonferroni-Dunn test.
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Results |
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Serum CXCL10 levels were higher than control values in both GD-p and GO-p (Table 1 and Fig. 1). Among the latter, those with active disease (i.e. higher clinical activity score) had more severe eye disease, a shorter duration of the disease, and about 50% higher serum CXCL10 levels than patients with inactive ophthalmopathy (Table 2). IFN was detectable in the serum of 7% of the controls, 36% of the GD-p, and 57% of the GO-p (2 = 34.2; P < 0.0001). IFN levels were higher in GO-p than in GD-p [median, 24 (interquartile range, 13–55) vs. 13 (interquartile range, 10–35) pg/ml; P = 0.021], but were not different between inactive and active GO-p [22 (interquartile range, 13–52) vs. 31 (interquartile range, 14–63) pg/ml; not significant]. Serum TNF was detectable in 95% of controls and in all GD-p and GO-p; mean levels were slightly higher in inactive and active GO-p than in GD-p and controls, but the difference was not statistically significant [4.5 (interquartile range, 3.0–5.8), 4.5 (interquartile range, 3.1–6.0), 3.9 (interquartile range, 2.6–5.2), and 3.6 (interquartile range, 2.1–5.0), pg/ml, respectively; not significant].
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In primary thyrocyte cultures, CXCL10 was undetectable in the supernatant. IFN dose-dependently induced CXCL10 release (Fig. 2A), whereas TNF alone had no effect. However, the combination of TNF and IFN had a significant synergistic effect on CXCL10 secretion (1601 ± 225 vs. 224 ± 51 pg/ml with IFN alone; P < 0.0001; Fig. 2B). Treatment of thyrocytes with RGZ, added at the time of IFN and TNF stimulation, dose-dependently inhibited CXCL10 release (Fig. 2C). RGZ alone had no effect and did not affect cell viability or total protein content (data not shown). The data obtained with thyrocytes from normal thyroid tissue were not statistically different from those obtained from GO-p (data not shown).
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) and preadipocytes (Fig. 4A) IFN dose-dependently induced CXCL10 release. The combination of TNF and IFN had a significant synergistic effect on CXCL10 secretion [in fibroblasts, 1466 ± 218 vs. 259 ± 119 pg/ml with IFN alone (P < 0.0001; Fig. 3B); in preadipocytes, 2633 ± 438 vs. 196 ± 96 pg/ml (P < 0.0001; Fig. 4B)]. Treatment of retrobulbar fibroblasts and preadipocytes with RGZ, added at the time of IFN and TNF stimulation, dose-dependently inhibited CXCL10 release (Figs. 3C and 4C). The data obtained with fibroblasts or preadipocytes from unaffected dermal tissues of the same patients were not statistically different from those obtained with their retrobulbar fibroblasts and preadipocytes (data not shown). RGZ alone had no effect and did not affect cell viability or total protein content in retrobulbar fibroblasts and preadipocytes (data not shown). RGZ did not cause significant adipogenic changes (as judged by Oil Red O staining) in either cell type after a 24-h period of incubation (data not shown).
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Discussion |
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are elevated in patients with GD, particularly in those with active ophthalmopathy; 2) both IFN and TNF (synergistically with IFN) dose-dependently induce the release of CXCL10, not only by primary thyrocytes, but also from retrobulbar fibroblasts and preadipocytes obtained from GO-p; and 3) the PPAR agonist, RGZ, exerts a dose-dependent inhibition of IFN- and TNF-induced CXCL10 secretion in thyrocytes, orbital fibroblasts, and preadipocytes.
The finding of increased levels of CXCL10 in active GO is in agreement with previous studies showing an involvement mainly of Th1 cytokines in GD and GO (1, 2, 3, 27, 28). In particular, it has been shown that in GO, the active phase is characterized by the presence of proinflammatory and Th1-derived cytokines, whereas other cytokines, among them Th2-derived cytokines, do not seem to be associated with a specific stage of GO (4). In our series, serum IFN was detectable only in 36% of GD-p and 57% of GO-p, in agreement with the results of another study (29), in which 28% of patients with Hashimoto’s thyroiditis and 58% of GD-p had detectable serum IFN levels. Likewise, serum TNF levels were slightly, although not significantly, higher in inactive and active GO-p than in GD-p. These results are in agreement with those observed in another study (30).
The increase in CXCL10 concentrations was unrelated to hyperthyroidism per se, because all of our patients were clinically euthyroid at the time of study. Inactive GO was associated with CXCL10 levels that, although higher than those in normal controls, were similar to those in GD-p and lower than those in active GO-p. These data clearly suggest that CXCL10 is transiently involved in the active phase of GO, when the inflammatory process is sustained by Th1-mediated immune responses, whereas CXCL10 levels decline in long-standing GO. This finding may be regarded as a result of the negative feedback of Th2 cytokines on IFN production. Thus, a switch from a Th1 to a Th2 phenotype appears to occur in GO, in line with a previous report showing that lymphocytes obtained from the orbital tissue of GO-p had a prevalent Th1 profile, whereas patients with remote-onset hyperthyroidism had a large majority of Th2 lymphocytes (3). This phenomenon has been reported in other long-standing autoimmune diseases. For example, in multiple sclerosis, simultaneous measurements of CXCL10 in serum and cerebrospinal fluid have shown higher CXCL10 levels in phase with acute, recent-onset disease or during exacerbations, suggesting a pathogenetic role for the chemokine in mediating relapse (31, 32, 33). The prognostic value of increased or rising CXCL10 levels in patients with GO remains to be established.
Cytokine production in autoimmune thyroid disorder (34) has been variably interpreted as being sustained by thyrocytes (35), intrathyroidal lymphocytes (27), or the activation of humoral reactions at sites other than the thyroid (30). The question thus arises of whether increased CXCL10 levels in GO-p with active disease reflect the immune response in orbital GD. All of our patients had a clinical history of Graves’ hyperthyroidism. However, it is unlikely that the thyroid disease alone caused the observed elevation in cytokine levels. Firstly, all patients were euthyroid before enrolment in our study. Secondly, no correlations were found between cytokine and thyroid hormone levels. Thirdly, we did not find any correlation between cytokine levels and the presence or titer of circulating thyrotropin receptor, thyroid peroxidase, or thyroglobulin antibodies, as reported for different cytokines (30, 34). Finally, the increase in CXCL10 was more pronounced in GO-p with active inflammatory disease in the orbit than in those with inactive GO. Thus, the CXCL10 increase is likely to reflect, at least in part, the presence of orbital inflammation.
The difference between active and inactive GO is the presence of a lymphocytic infiltrate (34, 36); therefore, the increased production of CXCL10 might be sustained by orbital lymphocytes. However, our in vitro studies demonstrate that CXCL10 can be produced by nonlymphoid cells in the orbit. In fact, both fibroblasts and preadipocytes from GO-p were induced to secrete CXCL10 by stimulation with increasing doses of IFN. Stimulation of fibroblasts or preadipocytes with TNF alone was not able to induce chemokine secretion, but combinations of IFN and TNF synergistically increased CXCL10 secretion, similar to what was observed in human thyrocytes (10) and endothelial cells (16). Interestingly, orbital fibroblasts and preadipocytes responded in a similar fashion to fibroblasts and preadipocytes of dermal origin, suggesting that this kind of activation is a general physiological phenomenon.
Together, these results are compatible with the view that the production of IFN and TNF by Th1-activated lymphocytes at the orbital level induces CXCL10 secretion by orbital fibroblasts and preadipocytes; in turn, the chemokine induces the migration of Th1 lymphocytes into the orbit, thereby perpetuating the autoimmune cascade. Recently, it has been shown that mice overexpressing CCL21 have significant lymphocytic infiltration of the thyroid without clinical disease. Therefore, although it is clear that chemokines are critical for lymphocyte trafficking to the thyroid in thyroid autoimmunity, other factors may be necessary for the development of disease (37).
PPAR has recently been shown to modulate inflammatory responses in endothelial cells (16, 17, 18). Furthermore, 1) in two murine models of colitis, PPAR ligands decrease inflammation in part by reducing CXCL10 levels (18, 38); and 2) in dendritic cells, PPAR agonists down-regulate the synthesis of CXCL10 and RANTES (CCL5) (17), both chemokines involved in the recruitment of Th1 lymphocytes. With regard to the mechanism of these actions, PPAR activators may act in two different ways: 1) decreasing CXCL10 promoter activity and inhibiting protein binding to the two nuclear factor-
B sites (16); or 2) thiazolidinediones reducing CXCL10 protein levels in a dose-dependent manner at concentrations (nanomolar) that did not affect mRNA levels or nuclear factor-B activation (18).
Together, this evidence indicates that PPAR activators might attenuate the recruitment of activated T cells at sites of Th1-mediated inflammation. Our data fully support this hypothesis. Treatment of thyroid follicular cells, orbital fibroblasts, or preadipocytes with a pure PPAR activator, RGZ, at near-therapeutic doses, significantly inhibited IFN-stimulated CXCL10 secretion, strongly suggesting that PPAR might be involved in the regulation of IFN-induced chemokine expression in human thyroid autoimmunity and GO. In support of this pathogenic sequence is the finding that the expression of the PPAR gene is higher in orbital adipose/connective tissue from patients in the active stage of GO than in tissues from controls or inactive GO-p (14). Thus, the increased orbital fat tissue observed in GO may be a consequence of the overexpression of PPAR caused by the inflammatory process. With regard to this, a recent case report described a type 2 diabetic patient who experienced exacerbation of GO with expansion of the orbital fat during treatment with the PPAR agonist, pioglitazone (39). In cultured retrobulbar preadipocytes, PPAR agonists caused a 2- to 13-fold increase, and a PPAR antagonist caused a 2- to 7-fold reduction, in adipogenesis (39). Other studies (25, 40) have confirmed the adipogenetic potential of PPAR agonists on orbital preadipocytes, suggesting that PPAR antagonists could provide a novel therapy for GO-p in the active stage of the disease. In the current studies, we did not find any significant adipogenetic effect of RGZ in fibroblasts or preadipocytes, mainly because of the short incubation period (24 h; thiazolidinediones need 10 d or more to exert their adipogenic effects) (25). The present data, however, do not provide sufficient evidence that PPAR agonists may be useful in treatment of GO. Additional studies are needed to establish whether in active GO the antiinflammatory effects of PPAR activation, by RGZ or other thiazolidinediones, can be exploited without the risk of expanding retrobulbar fat mass, and whether PPAR agonists and nonsteroidal antiinflammatory drugs or glucocorticoids may interact to exert their antiinflammatory action.
In conclusion, in GO, thyrocytes and retrobulbar cell types participate in the self-perpetuation of inflammation by releasing chemokines under the influence of cytokines. PPAR activation plays an inhibitory role in this process.
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Footnotes |
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Abbreviations: FBS, Fetal bovine serum; GD, Graves’ disease; GD-p, GD patient; GO, Graves’ ophthalmopathy; GO-p, GO patient; IFN, interferon-; PPAR, peroxisome proliferator-activated receptor-; RGZ, rosiglitazone; s, serum; Th1, helper T cell type 1; Th2, helper T cell type 2.
Received July 28, 2005.
Accepted November 16, 2005.
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, not significantly different from the preceding dose (by Bonferroni-Dunn test).
