Th1 and Th2 Cytokines and IgE Levels in Identical Twins with Varying Levels of Cigarette Consumption

Some have suggested that tobacco smoke may skew the immune system toward a Th2 pattern, however the effects of genetics or childhood exposures could explain these results. We compared PMBC supernatant or serum Th1 (INF-) and Th2 (IL-4, IL-5, and IL-13) cytokine and IgE levels in members of 45 pairs of nonasthmatic monozygotic twins with varying levels of current cigarette consumption to determine if smoking was associated with Th1/Th2 function after accounting for genetic factors. A statistically significant dose-response was observed between levels of smoking and IL-13 (p=0.05). Mean IL-13 level among heavy smokers (20+ cigarettes/day) was 146% higher than that among nonsmokers (+26.2 pg/mL; p=0.04). The mean IL-5 level among heavy smokers was 166% higher than that among light (<20 cigarettes/day) smokers (+3.4 pg/mL; p=0.03). No statistically significant differences in INF-, IL-4, or IgE levels were observed. Smoking appears to be associated with increased levels of IL-13.     

Expression of <Emphasis Type="Italic">MIF</Emphasis> and <Emphasis Type="Italic">TNFA</Emphasis> in psoriatic arthritis: relationship with Th1/Th2/Th17 cytokine profiles and clinical variables

Psoriatic arthritis (PsA) is an autoimmune inflammatory disease associated with psoriasis. The cause of this pathology is still unknown, but research suggests the diseases are caused by a deregulated cytokine production. MIF is a cytokine associated with immunomodulation of Th1, Th2, and Th17 cytokine profiles in inflammatory diseases. Based on this knowledge, the aim of this study was to determine the association of MIF and TNFA expression with Th1, Th2, and Th17 cytokine profiles in serum levels of PsA patients. A cross-sectional study was performed in 50 PsA patients and 30 control subjects (CS). The cytokine profiles were quantified by BioPlex MagPix system and the mRNA expression levels by real-time PCR. TNFA mRNA expression was 138.81-folds higher in PsA patients than CS (p < 0.001). Regarding MIF mRNA expression, no significant differences were observed; however, a positive correlation was identified between MIF mRNA expression and PsA time of evolution (r = ? 0.53, p = 0.009). An increase of Th1 (IFNγ: PsA = 37.1 pg/mL vs. CS = 17 pg/mL, p < 0.05; TNFα: PsA = 24.6 pg/mL vs. CS = 9.8 pg/mL, p < 0.0001) and Th17 cytokine profiles (IL-17: PsA = 6.4 pg/mL vs. CS = 2.7 pg/mL, p < 0.05; IL-22: PsA = 8.4 pg/mL vs. CS = 1.8 pg/mL, p < 0.001), were found in PsA patients. Th2 cytokines were not significantly different in both groups. In conclusion, a high expression of TNFA mRNA, as well as an increase of Th1 and Th17 cytokine profiles evaluated by IFNγ, TNFα, IL-17, and IL-22 cytokines, was observed in PsA patients.     

Correction of Th1-dominant Cytokine Profiles by High-dose Dexamethasone in Patients with Chronic Idiopathic Thrombocytopenic Purpura

To investigate the possible correcting of T helper (Th) cytokine profiles by high-dose dexamethasone (HD-DXM) therapy in chronic idiopathic thrombocytopenic purpura (ITP) with active disease, we determined the plasma levels of IFN-γ, IL-2, IL-4, IL-10, and TGF-β1 in 52 patients before and after oral administration of 40 mg/day DXM for four consecutive days. The cytokine levels were measured by enzyme-linked immunosorbent assay. The results showed that initial responses were reached in all patients and sustained response (SR) rate is 46.15%. The pretreatment plasma levels of both IFN-γ and IL-2 were significantly increased and those of IL-4, IL-10, and TGF-β1 significantly decreased, compared with those of the normal controls (P < 0.01), indicating a Th1-dominant cytokine profile typically found in ITP. After HD-DXM treatment, IFN-γ and IL-2 were decreased (P < 0.01), whereas IL-4 and IL-10 were increased (P < 0.05). There was no significant difference between the HD-DXM-treated patients and the normal controls (P > 0.05). TGF-β1 was also increased (P < 0.01) after HD-DXM treatment, but still lower than that of the normal controls (P < 0.05). During following-up, the cytokine profiles in the SRs remained stable compared to the posttreatment level (P > 0.05), but IFN-γ and IL-2 levels raised up, and IL-4, IL-10, and TGF-β1 levels reduced again in the relapsed patients (P < 0.01). Our data demonstrate that HD-DXM is an effective initial therapy for ITP, and the Th1 cytokine dominance could be corrected by HD-DXM.     

Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity

IL-23-dependent IL-17-producing T helper (Th) lymphocytes are associated with autoimmunity. We investigated the immunopathological mechanisms for activation of Th17 cells of patients with systemic lupus erythematosus (SLE). Concentration of cytokines/chemokine in plasma and culture supernatant from SLE patients and healthy controls were measured by ELISA or flow cytometry. Plasma IL-12, IL-17, IL-23 and CXCL10 concentrations and the number of Th17 cells were significantly elevated in SLE patients than control subjects (both p < 0.05). Elevated IL-12, IL-17 and CXCL10 concentrations correlated positively and significantly with SLEDAI (all p < 0.05). Plasma IL-12 and IL-17 showed significant and positive correlation with plasma Th1 chemokine CXCL10 concentration in SLE patients (all p < 0.05). Ex vivo inductions of IL-17 by IL-23 or IL-18 from co-stimulated lymphocytes were significantly higher in SLE patients than controls (all p < 0.05). The activated IL-23/IL-17 axis is important for the inflammatory immunity in SLE.     

In Vitro Effects of Sodium Benzoate on Th1/Th2 Deviation in Patients with Multiple Sclerosis

Interleukin 4 (IL-4) can improve the clinical manifestations in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Sodium benzoate (NaB) deviates the cytokine profile to Th2 (or IL-4 producing) cells in EAE and thus might be effective in the treatment of MS. Therefore, in this study the effect of different concentrations of NaB on the percentage and mRNA levels of IL-4 and interferon gamma (IFN-γ)-producing peripheral blood mononuclear cells (PBMCs) of 20 Relapsing-remitting multiple sclerosis (RR-MS) patients and eight healthy controls was evaluated in the presence of mitogen (phytohemagglutinin, PHA) or specific antigen (myelin basic protein, MBP). Our results showed that in the patient’s group the percentage of CD4⁺IL-4⁺ cells was significantly increased in the presence of all concentrations of NaB when PBMCs were stimulated by MBP (p = 0.001) or PHA (p < 0.03). The same results were obtained for normal donors in the highest concentration of NaB, 1000 µg/ml (p = 0.02). Moreover, in the patient’s group the percentage of CD4⁺IFN-γ⁺ cells was decreased significantly when the PBMCs were stimulated by PHA and NaB (p < 0.004) or by MBP and 1000 µg/ml of NaB (p < 0.03). The effect of NaB on IL-4 and IFN-γ production was also documented at the mRNA levels. In conclusion, our data suggest that NaB is able to induce IL-4 production by human PBMCs and therefore might be a useful candidate for conjunctive therapy in RR-MS.     

Selective Effect of Mercury on Th2-Type Cytokine Production in Humans

Mercury induces autoimmune disease and increases IL-4 production and IgE levels in certain rodent strains. The object of this study was to determine if mercury was capable of inducing Th2 cytokine production in human leucocytes. Human peripheral blood mononuclear cells (PBMC) were incubated with PMA/ionomycin or Con A in the presence or absence of methyl mercury (CH₃Hg) or mercuric chloride (HgCl₂). IL-4 and gamma-IFN were measured by ELISA. RESULTS: IL-4 production significantly increased at low concentrations of CH₃Hg (0.5 uM, p < 0.01), while gamma-IFN production was suppressed starting at CH₃Hg 2 uM (p = 0.004). Inorganic mercury (HgCl₂) increased IL-4 only at concentrations 10–20 times higher than CH₃Hg. These findings suggest a mechanism by which mercury could trigger or potentiate TH2 cytokine production in humans.     

Activation of Peripheral Th17 Lymphocytes in Patients with Asthma

A recently identified interleukin (IL)-17-producing T-helper (Th) lymphocyte subset, which comprises Th17 cells producing hallmark cytokines IL-17A, IL-17F and IL-22, is involved in chronic inflammatory diseases. Elevated gene and protein expressions of IL-17 are manifested in allergic asthma. We further characterized the activation of Th17 cells in asthmatic patients. Peripheral blood mononuclear cells (PBMC) were purified from 31 asthmatic patients and 20 sex- and age-matched control subjects. The number of IL-17A secreting cells in peripheral blood was enumerated by enzyme-linked immunosorbent spot assay. Cell surface expression of Th17-related chemokine receptor CCR6, and plasma level of IL-17A, IL-17F and IL-22, and ex vivo production of IL-17A and IL-22 were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. The number of peripheral Th17 lymphocytes, expression of CCR6 on Th cells, and ex vivo IL-23, anti-CD3 and anti-CD28 induced production of IL-22 by PBMC were significantly elevated in asthmatic patients compared with control subjects (all p < 0.01). This clinical study further confirmed increased number of peripheral Th17 lymphocytes and cell surface expression of CCR6 receptors on Th cells in asthmatic patients. Pro-inflammatory cytokine IL-23 can exacerbate disease severity by activating pathogenic Th17 lymphocytes to release downstream inflammatory cytokine IL-22 in asthma.     

Susceptibility to pulmonary disease due to Mycobacterium avium–intracellulare complex may reflect low IL-17 and high IL-10 responses rather than Th1 deficiency

It remains unclear why some individuals and not others are susceptible to non-tuberculous mycobacterial lung disease (NTMLD). To determine whether NTMLD is associated with defects or biases in Th1/Th2/Th17 immunity, blood leukocytes from NTM patients with nodular bronchiectasis, their adult offspring, and healthy population controls were stimulated with staphylococcal enterotoxin B (SEB), tuberculin and sensitin to measure cytokine production. In response to SEB, NTM patients exhibited higher frequencies of IFNγ-producing CD4⁺ T cells than population controls (P < 0.001). In supernatant, levels of IL-17 were lower in patients than adult offspring. Sensitin elicited higher IFNγ responses from patients than controls (P < 0.05). Patients also produced more IL-10 in supernatant than controls after culture with tuberculin (P < 0.01) or sensitin (P < 0.05), but IL-10-producing CD4⁺ T cells were undetectable. NTMLD is not associated with deficient IFNγ production, but may be associated with reduced Th17 immunity and/or a predisposition towards IL-10 production from non-CD4⁺ T cells.     

Immunotherapy of Patients with Recurrent Spontaneous Miscarriage and Idiopathic Infertility: Does the Immunization-Dependent Th2 Cytokine Overbalance Really Matter?

Recurrent spontaneous miscarriage (RSM) and idiopathic infertility (IIF) are partially caused by immunologic disturbances. Paternal lymphocyte immunization (PLI) is proposed for restoration of the proper Th1/Th2 balance in these patients, but still there are controversies on PLI mechanism, its efficacy and identification of patients who may benefit from this therapy. The study group consisted of n = 34 RSM and n = 42 IIF women with unexplained miscarriage or IIF. PLI was offered as a treatment in both groups. Peripheral blood lymphocyte (PBL) populations (CD3⁺, CD3⁻/CD19⁺, CD3⁺/CD4⁺, CD3⁺/CD8⁺, CD3⁻/CD16⁺CD56⁺) were studied before immunization, while PBL cytokine secretion (IFN-γ, TNF-α, IL-10, IL-5, IL-4, IL-2), before and after immunization, pre-conceptionally in both groups. The reference PBL ratio and cytokine levels were adopted from previously studied normal fertile women. PBL populations, concentration and ratio of Th1/Th2 cytokines did not differ between RSM and IIF patients. Compared to the results observed in normal fertile women the levels of IFN-γ, TNF-α and IL-2 were higher, while IL-10 lower in both RSM and IIF patients (p < 0.01). After immunization a decrease of IFN-γ (RSM and IIF groups) and IL-4 and IL-10 (RSM group) were observed, as well as an increase in TNF-α/IL-4 ratio (RSM group) (p < 0.05). No differences in Th1/Th2 concentration and ratio between patients with successful and unsuccessful pregnancy were observed. No significant correlations between success and particular cytokine concentration were observed. Concentrations of Th1/Th2 cytokines and PBL populations did not differ between RSM and IIF women. Th1 shift in both RSM and IIF patients was observed in comparison to fertile women. Treatment with PLI-induced pre-conceptionally cytokine changes which neither indicated Th2 shift nor correlated with subsequent pregnancy success.     

Serine Protease Activity of Cur l 1 from <Emphasis Type="Italic">Curvularia lunata</Emphasis> Augments Th2 Response in Mice

Rationale  Studies with mite allergens demonstrated that proteolytic activity augments allergic airway inflammation. This knowledge is limited to few enzyme allergens. Objective  The objective of this study is to investigate the effect of serine protease Cur l 1 from Curvularia lunata in airway inflammation/hyper-responsiveness. Methods  Cur l 1 was purified and inactivated using a serine protease inhibitor. Balb/c mice were sensitized with enzymatically active Cur l 1 or C. lunata extract. Sensitized mice were given booster dose on day 14 with active or inactivated Cur l 1. Intranasal challenge was given on day 28, 29, and 30. Airway hyper-responsiveness was measured by plethysmography. Blood, bronchoalveolar lavage fluid (BALF), spleen, and lungs from mice were analyzed for cellular infiltration, immunoglobulins, and cytokine levels. Results  Mice challenged with enzymatically active Cur l 1 demonstrated significantly higher airway inflammation than inactive Cur l 1 group mice (p < 0.01). There was a significant difference in serum IgE and IgG1 levels among mice immunized with active Cur l 1 and inactive Cur l 1 (p < 0.01). IL-4 and IL-5 were higher in BALF and splenocyte culture supernatant of active Cur l 1 than inactive Cur l 1 mice. Lung histology revealed increased eosinophil infiltration, goblet cell hyperplasia and mucus secretion in active group. Conclusion  Proteolytic activity of Cur l 1 plays an important role in airway inflammation and the inactivated Cur l 1 has potential to be explored for immunotherapy.     

Decreased Secretion of Th2 Cytokines Precedes Up-regulated and Delayed Secretion of Th1 Cytokines in Activated Peripheral Blood Mononuclear Cells from Patients with Insulin-Dependent Diabetes Mellitus

Recent evidence suggests that autoimmune animal diabetes is associated with an imbalance between the Th1 and Th2 arms of the cellular immune system. However, limited data is available regarding the Th1/Th2 imbalance in human Insulin dependent diabetes mellitus (IDDM) patients. Therefore, we examined the peak levels, secretory pattern and total cytokine production (calculated as the area under the curve, AUC) of the Th1 cytokines, IL-2 and IFN-γ, and Th2 cytokines, IL-4 and IL-10, from stimulated peripheral blood mononuclear cells, from 17 IDDM patients and 24 normal controls. In contrast to controls, diabetic patients were characterized by an early, uniformly low secretion of Th2 cytokines, followed by a late increased secretion of Th1 cytokines. This resulted in significant differences in secretory patterns of IFN-γIL-2, IL-4 and IL-10 between the two groups;P<0.001,P<0.005,P<0.005 andP<0.001, respectively. No correlation was found in the diabetic patients between any profiles of the cytokines and their various clinical parameters, including age, gender, disease duration, insulin requirements or glycated hemoglobin levels. In conclusion, our data provides the first comprehensive evidence for an independent and persistent impairment of both Th1 and Th2 cytokine secretory patterns in IDDM patients.     

Partial Reversal of Obesity-Induced Insulin Resistance Owing to Anti-Inflammatory Immunomodulatory Potential of Flaxseed Oil

The present study was designed to assess the potential of supplementation of diet with Flaxseed (Linum usitatissimum, L.) oil (FXO), on obesity-related inflammation and reversal of obesity-induced insulin resistance. Swiss Albino mice, C57bl/6 mice and co-culture of 3T3-L1 adipocytes – RAW 264.7 macrophages to mimick obese adipose tissue environment were used for the study. Oral gavage of FXO at concentrations of 4, 8 or 16?mg/kg body weight (bwt) for 4 weeks or high-fat diet (HFD, 60% energy as fat) supplemented with dietary FXO (4, 8 or 16?mg/kg?bwt) was given to the mice. FXO was characterised using gas chromatography – mass spectrometry. FXO supplemented HFD-fed mice (4?mg/kg?bwt exhibited reduced adiposity index, serum glucose levels and triglycerides (8 and 16?mg/kg?bwt) and improvement in insulin sensitisation (4, 8 and 16?mg/kg?bwt) when compared with HFD mice. The co-culture showed a dose-dependent shift in cytokines towards anti-inflammatory (IL-4) state, with a decrease in pro-inflammatory TNF-α (p?<?0.05). For immunomodulatory studies a dose-dependent increase (p?<?0.05) was observed in antigen-specific levels of Th2 (IL-4) cytokine, serum anti-ova IgG1 and IgE levels. Suppression in anti-ova IgG2a_, IgG2b, and IgG3 and antigen-specific Th1 cytokines like TNF-α and IFN-γ significantly (p?<?0.05) was observed at 16?mg/kg?bwt dosage. The results indicate that FXO exhibits an anti-inflammatory immunomodulatory potential and may partially relieve symptoms of obesity-associated insulin resistance.     

Th17 and Th1 Lymphocytes Are Correlated with Chronic Periodontitis

T cells are involved in the homeostasis of periodontal tissues and mediate bone loss in periodontitis, but the involvement of T-helper cells in chronic periodontitis (CP) in a Chinese population is still unclear. This study aimed to assess the distribution of peripheral and local T helper (Th17) and Th1 in CP. Sixty-eight patients with CP and 43 healthy controls were recruited from April 2012 to July 2014 at the Department of Stomatology, People’s Hospital of Xinjiang Uygur Autonomous Region (China). The proportions of Th17 (CD3⁺CD4⁺IL-17⁺) and Th1 (CD3⁺CD4⁺IFN-γ⁺) T-cells in peripheral blood samples were assessed by flow cytometry. Immunohistochemistry was used to quantify interleukin-17 (IL-17) and interferon-gamma (IFN-γ) protein levels in gingival biopsy samples. mRNA levels of IL-17, IFN-γ RORγt, and T-bet in gingival biopsy samples were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The proportions of circulating Th17 cells and Th1 cells were both more abundant in CP patients than in controls (Th17: 1.05% ± 0.87% vs. 0.62% ± 0.49%, P < 0.01; Th1: 13.93% ± 7.94% vs. 8.22% ± 4.50%, P < 0.001). Positive correlations were obtained between the proportion of circulating Th17 cells and probing depth (PD) (r = 0.320, P = 0.001) and between the proportion of circulating Th1 cells and PD (r = 0.372, P < 0.001). IL-17 and IFN-γ protein levels in gingival biopsy samples were markedly increased in CP compared to controls (both P < 0.05). Relative IFN-γ, IL-17A, and T-bet mRNA levels in CP biopsies were higher compared to controls (all P < 0.05). These results suggest that elevated peripheral and local Th17 and Th1 cells might be involved in the pathogenesis of CP.     

Th17 responses to pneumococcus in blood and adenoidal cells in children

Pneumococcal infections cause a large global health burden, and the search for serotype-independent vaccines continues. Existing conjugate vaccines reduce nasopharyngeal colonization by target serotypes. Such mucosal effects of novel antigens may similarly be important. CD4⁺ Th17 cell-dependent, antibody-independent reductions in colonization and enhanced clearance have been described in mice. Here we describe the evaluation of T helper type 17 (Th17) cytokine responses to candidate pneumococcal protein vaccine antigens in human cell culture, using adenoidal and peripheral blood mononuclear cells. Optimal detection of interleukin (IL)-17A was at day 7, and of IL-22 at day 11, in these primary cell cultures. Removal of CD45RO⁺ memory T cells abolished these responses. Age-associated increases in magnitude of responses were evident for IL-17A, but not IL-22, in adenoidal cells. There was a strong correlation between individual IL-17A and IL-22 responses after pneumococcal antigen stimulation (P < 0·015). Intracellular cytokine staining following phorbol myristate acetate (PMA)/ionomycin stimulation demonstrated that  > 30% CD4⁺ T cells positive for IL-22 express the innate markers γδT cell receptor and/or CD56, with much lower proportions for IL-17A⁺ cells (P < 0·001). Responses to several vaccine candidate antigens were observed but were consistently absent, particularly in blood, to PhtD (P < 0·0001), an antigen recently shown not to impact colonization in a clinical trial of a PhtD-containing conjugate vaccine in infants. The data presented and approach discussed have the potential to assist in the identification of novel vaccine antigens aimed at reducing pneumococcal carriage and transmission, thus improving the design of empirical clinical trials.     

Effects of atorvastatin on the Th1/Th2 polarization of ongoing experimental autoimmune myocarditis in Lewis rats

ObjectiveExperimental autoimmune myocarditis (EAM) in rats is a T cell-mediated disorder and the involvement of Th1/Th2 unbalance has been demonstrated. This study was designed to test the hypothesis that 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, atorvastatin, affects T cell-mediated autoimmunity through modulating the balance of Th1/Th2 and reduces the severity of EAM.MethodsMyocarditis was induced in 23 Lewis rats by injection of porcine cardiac myosin. High-dose (10 mg/kg/day) or low-dose (1 mg/kg/day) atorvastatin or vehicle was administered orally for 3 weeks to rats with EAM at the same time of immunization. Seven Lewis rats received neither immunization nor statins therapy were used as normal controls. On day 21 after immunization (the climax of inflammation), echocardiography was examined and the severity of myocarditis was evaluated by histopathological evaluation. The area ratio (affected/entire area percentage) of myocardial lesions was determined in histological sections. Heart weight/body weight ratio was determined and the serum lipid levels were measured. Levels of serum IFN-γ, IL-2, IL-4 and IL-10 were measured by ELISA.ResultsCardiac function was improved in the two atorvastatin-treated groups compared to the untreated group. Heart weight/body weight ratio and the degree of inflammation were significantly lower in the two dosage statin-treated groups than that in the untreated one. Furthermore, treatment with atorvastatin decreased the expression levels of Th1 cytokine (IFN-γ and IL-2), and increased the expression levels of Th2 cytokine (IL-4 and IL-10). Atorvastatin attenuated the histopathological severity of myocarditis. Plasma lipid levels did not differ between the groups.ConclusionsAtorvastatin ameliorates EAM by inhibiting T cell responses and suppressing Th1-type and inflammatory cytokines production and this activity is independent of cholesterol reduction, whereas Th2-type cytokines production was promoted. Atorvastatin may have beneficial effects on myocarditis by modulating the Th1/Th2 balance. These results demonstrate an important role of Th1/Th2 polarization in the pathogenesis of EAM and suggest that HMG-CoA reductase blockade may be a promising new strategy for the treatment of organ specific autoimmune diseases.     

Role of Th1 and Th2 Cytokines in Immune Response to Uncomplicated Plasmodium falciparum Malaria

The relative balance between Th1 and Th2 cytokines appears crucial, since the role of cytokines has been evaluated in several studies by comparison of clinically heterogeneous groups of patients. The aim of this study is to determine the role of proinflammatory Th1 cytokines, interleukin-12 (IL-12) and gamma interferon (IFN-γ), and anti-inflammatory Th2 cytokines, IL-4 and IL-10, in a homogeneous group of patients with uncomplicated Plasmodium falciparum malaria. Levels of IL-12, IFN-γ, Il-4, and IL-10 in serum for 20 adult patients and 15 healthy control subjects were determined by an immunoenzymatic assay. Serum levels of Th1 cytokines, IL-12 (8.6 ± 2.8 pg/ml; controls, 3.2 ± 0.7 pg/ml) and IFN-γ (39.2 ± 67.6 pg/ml; controls, 8.4 ± 6.3 pg/ml), were significantly increased at admission; 3 days later, levels of IL-12 in serum remained significantly high (8.8 ± 2.6 pg/ml), whereas IFN-γ levels returned to control values. The anti-inflammatory response of Th2 cytokines (IL-10 and IL-4) was distinct. Levels of IL-10 in serum were not significantly increased at day 0 and day 3 (306.6 ± 200.4 pg/ml and 56.6 ± 38.4 pg/ml, respectively; controls, 17.4 ± 9.0 pg/ml). In contrast, levels of IL-4 in serum were not increased on admission (3.4 ± 1.2 pg/ml; controls, 2.4 ± 0.8 pg/ml), but at day 3 a moderate and significant increase of IL-4 levels was observed (4.5 ± 1.7 pg/ml). In conclusion, the increase of Th1 cytokine IL-12 and IFN-γ levels during the acute phase of uncomplicated P. falciparum malaria may reflect an early and effective immune response regulated by proinflammatory Th1 cytokines, and in particular IFN-γ may play a role in limiting progression from uncomplicated malaria to severe and life-threatening complications.     

Th9 and allergic disease

Helper CD4⁺ T-cell subsets have improved our understanding of adaptive immunity in humans and in animal models of disease. These include T helper type 1 (Th1), Th2 and the interleukin-17 (IL-17) -producing population ‘Th17’. Th2 cells have been described as orchestrating the immune response in allergic disease based on studies with patient samples and animal models. The cytokine IL-9 has largely been regarded as a Th2 cytokine that makes multifocal contributions to allergic disease. Recent data suggest that under certain conditions relevant to chronic disease (IL-4 and transforming growth factor-β), a distinct population of IL-9-producing ‘Th9’ helper T cells can exist. The contribution of Th9 cells in allergic disease is currently unknown, and this review will propose a model for how these cells may regulate chronic allergic inflammation.     

Effects of cytokine milieu secreted by BCG-treated dendritic cells on allergen-specific Th immune response

Bacillus Calmette-Guerin (BCG) is reported to suppress Th2 response and asthmatic reaction. Dendritic cells (DCs), the major antigen-presenting cells, infections with BCG are known to result in inducing various cytokines. Thus, DCs are likely to play a role in the effects of BCG on asthma. This study aims at investigating that cytokine milieu secreted by BCG-treated DCs directly enhances allergen-specific Th1 response and/or suppresses Th2 response in allergic asthma. DCs and CD3+ T cells were generated from Dermatophagoides farinae-sensitive asthmatics. DCs were cultured with and without BCG and subjected to flow cytometric analysis. IL-12 and IL-10 were determined from the culture supernatants. Some DCs were cocultured with T cells in the presence of D. farinae extracts after adding the culture supernatants from BCG-treated DCs, and IL-5 and IFN-gamma were determined. BCG-treated DCs enhanced significantly the expressions of CD80, CD86, and CD40, and the productions of IL-12 and IL-10. Addition of culture supernatants from BCG-treated DCs up-regulated production of IFN-gamma by T cells stimulated by DCs and D. farinae extracts (p<0.05), but did not down-regulate production of IL-5 (p>0.05). The cytokine milieu secreted by BCG-treated DCs directly enhanced allergen-specific Th1 response, although did not suppress Th2 response.     

Kinetics and functional implications of Th1 and Th2 cytokine production following activation of peripheral blood mononuclear cells in primary culture

The importance of cytokine production in some disease processes is now widely recognized. To investigate temporal relationships between cytokines, we stimulated peripheral blood mononuclear cells (PBMC) in vitro using the T cell mitogen phytohemagglutinin (PHA) and various antigens chosen to induce predominantly Th1 (streptokinase: streptodornase or purified protein derivative) or Th2 (Dermatophagoides pteronyssinus, bee or wasp venom: allergens in sensitive subjects) responses. Cytokine production was measured by sensitive bioassays or enzyme-linked immunosorbent assays. Of the 30 subjects studied, 10 were normal and 20 individuals were allergic to either D. pteronyssinus (n = 10) or bee venom (n = 10) (examined before specific allergen immunotherapy). We examined the temporal profiles of a panel of cytokines produced in prmary culture. In PHA-driven cultures, cytokines were found to be sequentially produced in the order interleukin (IL)-2, IL-4, IL-5, IL-3, interferon (IFN)-γ, IL-10, IL-6, IL-12 and tumor necrosis factor (TNF)-α. The response to allergen in allergic patients was predominantly Th2 in nature, with the production of IL-4, IL-5, IL-6 and IL-10, but little or no IFN-γ. IL-2, IL-3, TNF-α and IL-12 were also produced in low amounts. The response of both atopic and normal subjects to recall bacterial antigens was predominantly Th1, with high levels of IFN-γ, IL-2 and TNF-α. The relevance of the order, amount and speed of production, characteristic kinetics (production, consumption, homeostatic regulation) and the cell source of the cytokines are discussed.