Effects of inhaled ciclesonide on circulating T-helper type 1/T-helper type 2 cells in atopic asthmatics after allergen challenge

BACKGROUND: The predominance of T-helper type 2 (Th2) lymphocytes is thought to underlie the pathogenesis of asthma. Allergen inhalation challenge in atopic asthmatic subjects is associated with decreased interferon-gamma (IFN-gamma) positive CD4+ and CD8+ lymphocytes in peripheral blood and induced sputum. OBJECTIVE: This study examined the effects of an inhaled corticosteroid on these previously described allergen-induced changes in circulating Th1 and Th2 lymphocytes. METHODS: Subjects were randomized to 7 days of placebo, 40 or 80 micro g ciclesonide in a crossover study. Airway responses and peripheral blood were measured before and after treatment, and 24 h after allergen challenge. RESULTS: Ciclesonide 40 and 80 micro g significantly attenuated the late response and sputum eosinophils at 8 h post-allergen (P<0.05). Circulating IFN-gamma positive CD4+ lymphocytes decreased after allergen challenge with placebo (P<0.05), and this was inhibited by 40 micro g ciclesonide treatment (P<0.05). There was no effect of allergen inhalation or ciclesonide on IL-4-positive CD4+ lymphocytes or IFN-gamma and IL-4-positive CD8(high) lymphocytes. The allergen-induced change of IFN-gamma/IL-4 ratio on CD4+ cells correlated with the allergen-induced change of peripheral blood eosinophils. CONCLUSIONS: The results of this study suggest that attenuation of allergen-induced airway responses by ciclesonide may be mediated through regulation of IFN-gamma-positive CD4+ cells.     

Sister chromatid exchanges: A reexamination of the evidence for sex and race differences in humans

Published evidence for human sex and race differences in sister chromatid exchange (SCE) levels is reexamined. There is substantial support for the conclusion that women average approximately 0.5 SCE/cell higher than men among normal healthy adults. An index of heterogeneity for SCE counts for cells from a single subject is introduced, and this statistic is applied to the data of Butler [1981]. who compared Caucasians, Blacks, Native Americans, and Orientals with regard to SCE levels. There is evidence in Butler's data of differences in the heterogeneity index among these four racial groups, but this finding needs independent verification in a larger study.     

Regulation of interleukin-12/interleukin-23 production and the T-helper 17 response in humans

Summary: Interleukin-12 (IL-12) and IL-23 share a common chain. Yet, their production in response to pathogens is differentially regulated, and their functions are distinct and often antithetic. IL-12 is involved in the induction or amplification of the T-helper (Th) type 1 response, whereas IL-23 has been associated with the generation of the Th17 response and IL-17 production. Mycobacterium tuberculosis and yeast zymosan induce IL-23, but in the absence of other stimuli, no IL-12 is induced in human dendritic cells (DCs). The stimulation of IL-23 by M. tuberculosis was mostly explained by the triggering of Toll-like receptor (TLR2) and the cytoplasmic receptor nucleotide oligomerization domain (NOD)-containing protein 2, whereas zymosan induces IL-23 primarily by stimulating the β-glucan receptor dectin-1 alone or in combination with TLR2. IL-23, IL-6, transforming growth factor (TGF-β1), and IL-1β in supernatants from activated human DCs induce human naive CD4⁺ T cells to produce IL-17. These data are consistent with various recent reports that TGF-β is an inducer of IL-17 production both in human and in mouse cells. However, IL-1 is necessary in combination with some or all of the other cytokines to induce IL-17 production in human T cells. The ability of various stimuli to induce Th17 cells depends not only on their induction of IL-23, IL-6, and TGF-β production in DCs but also on their ability to activate directly or indirectly the inflammasome and to induce IL-1β.     

Nitric oxide inhibits the secretion of T-helper 1- and T-helper 2-associated cytokines in activated human T cells.

Mechanisms regulating the balance of T-helper 1 (Th1) and T-helper 2 (Th2) immune responses are of great interest as they may determine the outcome of allergic and infectious diseases. Recently, in mice, nitric oxide (NO), a powerful modulator of inflammation, has been reported to preferentially down-regulate Th1-mediated immune responses. In the present study, we investigated the effect of NO on the production of Th1- and Th2-associated cytokines by activated human T cells and human T-cell clones. Cytokine secretion was measured in the presence of the NO-donating agents 3-morpholinosydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP). Both NO-donors markedly inhibited the release of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-5, IL-10 and IL-4 by anti-CD3 activated T cells. A preferential inhibition of Th1-associated cytokines was not observed. Neither was nitrite found in the supernatants of activated T cells, nor was specific mRNA for inducible and constitutive NO synthase detectable, indicating that T cells themselves did not contribute to the observed effect of the NO donors. Costimulation with anti-CD28 monoclonal antibodies (mAb) prevented SIN-1/SNAP-mediated down-regulation of cytokine production only in part. In contrast, when T cells were stimulated by phorbol-ester and ionomycin, they were refractory to SIN-1-induced inhibition of cytokine production. When SIN-1 was added after the onset of anti-CD3 stimulation, the inhibitory effect was found to be less pronounced, indicating that SIN-1 may interfere with early signal transduction events. The addition of superoxide dismutase (SOD) and catalase did not restore the effects of SIN-1, demonstrating that the inhibition of cytokines was due to NO and not to oxygen intermediates. Furthermore, 8-Br-cGMP-mediated increase of intracellular cGMP caused the same pattern of cytokine inhibition as observed with SIN-1 and SNAP. Using a single cell assay, these agents were shown to reduce the frequency of IFN-gamma-producing T cells, suggesting that not all T cells are susceptible to SIN-1/SNAP. However, cytokine production by purified T-cell subpopulations (CD4+, CD8+, CD45RA+, and CD45RO+) was equally impaired by NO donors. In conclusion, in contrast to the murine system, our results do not provide evidence that NO preferentially inhibits Th1-cytokine secretion of activated human T cells in vitro.     

Extraversion-related differences in response organization: evidence from lateralized readiness potentials

Research utilizing a mental-chronometry approach to examine individual differences in extraversion suggests that extraversion-related individual differences may involve stimulus analysis, response organization, and peripheral motor processes. In a sample of 14 introverted and 14 extraverted female volunteers event-related potentials (ERP) and lateralized readiness potentials (LRPs) were recorded concurrently with reaction time (RT) measures as participants performed a two-choice go/no-go task. Although there were no extraversion-related differences in mean reaction time, introverts showed higher N1 amplitudes and shorter P3 latencies compared to extraverts. Furthermore, response-locked LRP latencies were reliably shorter for extraverts than for introverts. The latter finding provides first direct evidence for the contribution of central processes related to motor activation to account for extraversion-related individual differences.     

Limited T-cell receptor beta-chain diversity of a T-helper cell type 1-like response to Mycobacterium leprae.

Delayed-type hypersensitivity (DTH) is the standard measure of T-cell responsiveness to infectious organisms. For leprosy, the Mitsuda reaction, a local immune response to cutaneous challenge with Mycobacterium leprae, is considered to represent a measure of DTH against the pathogen. We analyzed the diversity of the T-cell receptor beta-chain repertoire in Mitsuda reactions to determine the breadth of the mycobacterial antigens involved. The polymerase chain reaction was used to compare V beta usage in the Mitsuda reaction T-cell lines established and unstimulated peripheral blood. These molecular analyses revealed a skewed T-cell receptor V beta gene usage in the Mitsuda reaction and in T-cell lines from lesions. To examine the reactivity of T cells from these lesions, T-cell lines were tested against the available native and recombinant antigens of M. leprae. T-cell lines derived from Mitsuda reactions responded more strongly to the 10-kDa M. leprae antigen, a homolog of GroES in Escherichia coli, than to other M. leprae proteins. T-cell lines were also shown to proliferate strongly in response to the 17- and 3-kDa proteins. The pattern of the lymphokine mRNA of these cells was reminiscent of the pattern of murine TH1 cells, positive for interleukin-2 and gamma interferon and weakly positive for interleukin-4. These data indicate that a limited array of T cells, perhaps recognizing stress proteins, secrete a type 1 lymphokine profile in the DTH response to mycobacteria.     

LKM512 yogurt consumption improves the intestinal environment and induces the T-helper type 1 cytokine in adult patients with intractable atopic dermatitis

BACKGROUND: In atopic dermatitis (AD) patients, the intestinal mucosal barrier function is weakened, permiting frequent invasion by antigens. Polyamines and short-chain fatty acids (SCFA) produced by intestinal bacteria are involved in the promotion of intestinal mucosal barrier functions. AIM: Our aim was to investigate the effect of pro-biotic yogurt containing Bifidobacterium animalis subsp. lactis LKM512 (LKM512 yogurt) on subjective symptoms, intestinal microbiota, intestinal bacterial metabolites (polyamines and SCFA), and T-helper type 1 (Th1)/Th2 balance in intractable AD patients. METHODS: In a double-blind, placebo-controlled, crossover study, LKM512 yogurt was given for 4 weeks to 10 adult AD patients who were diagnosed with moderate AD (four males and six females; average age, 22.1 years). The subjective symptoms were recorded after each intervention. The dynamics of fecal microbiota were analysed by the terminal-restriction fragment length polymorphism method. The effects of LKM512 yogurt on fecal polyamines, SCFA, and serum cytokines were evaluated. RESULTS: Scores of itch and burning tended to improve to a greater extent by LKM512 yogurt consumption than by placebo consumption. LKM512 yogurt (P<0.005) and placebo consumption (P<0.05) significantly increased the serum IFN-gamma concentration by six- and threefold, respectively. Fecal microbiota was altered dynamically by LKM512 yogurt consumption, in particular, the bacterial species and phylotypes of Bifidobacterium, Clostridium cluster IV and subcluster XIVa were increased in number. In addition, fecal spermidine concentration was significantly (P<0.05) increased, while fecal butyrate also tended to be increased by LKM512 yogurt consumption. CONCLUSION: We conclude that LKM512 yogurt consumption may be effective against intractable adult-type AD and this effect depends on the recovery of the intestinal mucosal barrier function and the induction of the Th1-type cytokine by polyamines and SCFA, particularly, butyrate, produced by the altered intestinal microbiota.     

Place and response learning in human virtual navigation: behavioral measures and gender differences

Two experiments examined the use of place and response strategies by humans navigating virtual multiple T mazes. In Experiment 1, probe trials revealed that participants commonly used place and response strategies, and place strategies were more frequent early in training, whereas response strategies were more frequent late in training. Compared with women, men learned the correct path through the maze more quickly and developed a more stable route through the maze. In Experiment 2, participants were trained to locate 2 targets. One target required participants to use either a place or response strategy, whereas the other target could be found using either strategy. Accuracy improved faster for place training compared with response training, and women outperformed men in both groups. Probe trials testing transfer of the imposed strategy to the other target found faster transfer for place training than for response training and that women demonstrated faster transfer than men. Accuracy on probe trials was correlated with poor route stability in the place-trained group and with good route stability in the response-trained group, indicating that navigation strategy use may be related to measures of improvement in performance on normal trials.     

Age differences in task switching and response monitoring: evidence from ERPs

This study investigates age differences in the flexible adaptation to changing demands on task switching and conflict processing. We applied a cued task-switching version of the Stroop task and manipulated the ratio of conflict trials. During task preparation, the P300 varied as a function of conflict ratio and a later positive component was larger for switch than non-switch trials. Stimulus-related conflict processing as indicated by a negativity for incompatible trials (Ni) was delayed for older adults. Moreover, the Ni varied as a function of conflict ratio and was larger for switch than for non-switch trials. Age differences were also obtained in the correct response negativity (CRN). CRN was larger on incompatible trials and this CRN-compatibility effect was enhanced when incompatible trials were infrequent in younger, but not in older adults. Our findings suggest impairments of older adults primarily in response-related conflict processing and in the flexible adaptation to changing task contexts.     

Mannoprotein from Cryptococcus neoformans promotes T-helper type 1 anticandidal responses in mice

We previously demonstrated that mannoprotein (MP) from Cryptococcus neoformans (CnMP) stimulates interleukin-12 production by human monocytes, thus fostering a T-helper type 1 (Th1) protective anticryptococcal response. In this paper we show that CnMP was also able to induce a Candida albicans-directed protective Th1 response. This was demonstrated for mice immunized with CnMP by induction of a delayed-type hypersensitivity (DTH) reaction to C. albicans MP (CaMP) as well as induction of gamma interferon production by CD4(+) and CD8(+) splenic T cells stimulated in vitro with CaMP. CnMP-immunized mice were also partially protected from lethal systemic challenge with C. albicans, as shown by prolonged median survival times and decreased fungal burden in the kidney. Much evidence supports the validity of these cross-reactive and functional Th1 responses: (i) a non-cross-reactive C. albicans antigen, such as enolase, did not produce a DTH response to CaMP; (ii) passive adoptive transfer of T cells primed with CnMP induced a DTH reaction; (iii) C. neoformans extract elicited a DTH response to CaMP; and (iv) a monoclonal antibody (7H6) directed against a major and immunodominant T-cell-stimulatory 65-kDa MP (MP65) of C. albicans also recognized discrete 100-kDa constituents of C. neoformans extracts, as well as secretory constituents of the fungus. These results suggest the presence of common Th1 antigenic determinants in the mannoproteic material of C. neoformans and C. albicans epitopes, which should be considered in devising common strategies for immunoprophylactic or immunotherapeutic control of the fungi.     

Eosinophils contribute to IL-4 production and shape the T-helper cytokine profile and inflammatory response in pulmonary cryptococcosis

Susceptibility to infection with Cryptococcus neoformans is tightly determined by production of IL-4. In this study, we investigated the time course of IL-4 production and its innate cellular source in mice infected intranasally with C. neoformans. We show that pulmonary IL-4 production starts surprisingly late after 6 weeks of infection. Interestingly, in the lungs of infected mice, pulmonary T helper (Th) cells and eosinophils produce significant amounts of IL-4. In eosinophil-deficient ΔdblGATA mice, IL-33 receptor-expressing Th2s are significantly reduced, albeit not absent, whereas protective Th1 and Th17 responses are enhanced. In addition, recruitment of pulmonary inflammatory cells during infection with C. neoformans is reduced in the absence of eosinophils. These data expand previous findings emphasizing an exclusively destructive effector function by eosinophilic granulocytes. Moreover, in ΔdblGATA mice, fungal control is slightly enhanced in the lung; however, dissemination of Cryptococcus is not prevented. Therefore, eosinophils play an immunoregulatory role that contributes to Th2-dependent susceptibility in allergic inflammation during bronchopulmonary mycosis.     

Hemodynamic response patterns: responder type differences in reactivity and recovery

We examined whether responder type groups reflecting patterns of hemodynamic reactivity might also differ in recovery responses. Cardiac output (CO), total peripheral resistance (TPR), systolic and diastolic blood pressure, heart rate, and Heather index were assessed at rest and during speech and cold pressor tasks in young adults. Participants (n = 152) were classified as myocardial, vascular, or mixed-mild responders based on CO and TPR responses to speech presentation. Vascular responders exhibited slower CO and TPR speech recovery than the myocardial and/or mixed-mild groups. Responder type differences in reactivity showed limited task-generalizability. The sustained vascular response pattern of the vascular group is consistent with that seen in hypertension. In light of associations of heightened TPR with markers of disease risk, this suggests potentially negative health implications for vascular responders.     

Differential cytokine secretion and early treatment response in patients with pulmonary tuberculosis

Biomarkers for treatment response would facilitate the testing of urgently needed new anti‐tuberculous drugs. The present study investigated the profiles of 30 proinflammatory, anti‐inflammatory and angiogenic factors [epidermal growth factor, eotaxin, fractalkine, granulocyte colony‐stimulating factor, granulocyte–macrophage colony‐stimulating factor, interleukin (IL)‐1α, IL‐1β, IL‐1ra, IL‐2, IL‐4, IL‐5, IL‐6, IL‐7, IL‐8, IL‐10, IL‐12p40, IL‐12p70, IL‐13, IL‐15, IL‐17, interferon‐γ, interferon‐inducible protein‐10, Krebs von den Lungen‐6, monocyte chemotactic protein‐1, macrophage inflammatory protein (MIP)‐1α, MIP‐1β, sCD40L, transforming growth factor‐α, tumour necrosis factor‐α and vascular endothelial growth factor] in the plasma of 12 healthy tuberculin skin test‐positive community controls and 20 human immunodeficiency virus‐negative patients with active tuberculosis (TB) and identified potential biomarkers for early treatment response. We showed differences in the level of circulating cytokines between healthy controls and TB patients, but also between fast responders and slow responders to anti‐tuberculosis treatment. The general discriminant analysis based on pre‐treatment and week 1 measurements identified 10 sets of three‐variable models that could classify fast and slow responders with up to 83% accuracy. Overall, this study shows the potential of cytokines as indicators of anti‐tuberculosis treatment response.     

Classification of individual differences in cardiovascular responsivity: The contribution of reactor type controlling for race and gender

Classification of 150 normotensive or mildly hypertensive men and women into myocardial, vascular, or mild reactors was accomplished using a regression-based approach. The method was based on the participants’ cardiac output (CO) and total peripheral resistance (TPR) reactivity to the speech presentation task. This task purportedly can elicit both myocardial and vascular responses. Cut-scores were based on the v-intercept from the linear regression of the CO reactivitv on TPR reactivity and vice versa. A greater percentage of Black men were classified as vascular responders as compared to Black women and White participants. Groups were found to differ on cardiovascular reactivity to the speech preparation, cold pressor, and mirror tracing tasks in predictable ways, after controlling for gender and ethnicity. Groups were also differentiated by ambulatory blood pressure and hypertensive status. The study supports the classification of homogeneous groups of participants based on the relative extent to which myocardial or vascular mechanisms dominate the reactivity to stress.     

Absent gender differences of hippocampal atrophy in amnestic type mild cognitive impairment

Hippocampus displayed progressively gender-associated damage in Alzheimer's disease. However, gender effects have been largely neglected in studies of amnestic type mild cognitive impairment (aMCI) patients who were believed to represent an early stage of this disease. The goal of this study was to use in vivo neuroimaging techniques to determine whether there were any evidences of gender differences in hippocampal atrophy in aMCI. A region of interest-based magnetic resonance imaging approach was used to compare hippocampal volume between aMCI patients (22 male, 17 female) and normal aging controls (12 male, 11 female). Independent of group, male hippocampal volumes were larger than female volumes and right hippocampal volumes were typically smaller than left volumes. Hippocampal volumes were significantly reduced in the clinical group but no gender differences were noted in terms of degree of atrophy present. However, female patients showed more impaired cognitive function than male patients despite this apparent equivalence in atrophy. The absence of a gender difference suggested that early neuropathological progression might be independent of gender. However, the data also suggested female aMCI patients had an increased vulnerability to cognitive impairment earlier in the illness course.