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PubMed1979

The responsiveness of efferent lymph cells to phytohaemagglutinin during the response of the popliteal node to dinitrophenylated bovine serum albumin.

Cells, recovered from the efferent lymphatics of the popliteal nodes of sheep during in vivo responses to dinitrophenylated bovine serum albumin (DNP-BSA), were examined for their responsiveness to phytohaemagglutinin (PHA) in vitro during the first 4--5 days of the immune response. The response was almost totally depressed when cells collected throughout the response were cultured with supra-optimal doses of the mitogen. Optimal and suboptimal doses of PHA resulted in greatly enhanced responses in cells collected in the first two periods (0--6 h; 6--12h) of the response; the presence of high doses of DNP-BSA in the culture media prevented the enhancement in the second period but had no adverse effects on the cells collected during the first 6 h. Efferent cells collected after 12 h generally showed decreased responses, this depression being maximal in cells collected 2--3 days after antigenic stimulation. Later in the response the cells again exhibited enhanced responses. The possible interpretations of these results in terms of regulation of the response are discussed.

Animals↗
PubMed1993

Modification of the responses of hippocampal neurons in the monkey during the learning of a conditional spatial response task.

In order to analyze the function of the hippocampus in learning, the activity of single neurons was recorded while monkeys learned a task of the type known to be impaired by damage to the hippocampus. In the conditional response task, the monkey had to learn to make one response when one stimulus was shown, and a different response when a different stimulus was shown. It had previously been shown that there are neurons in the hippocampal formation that respond in this task, to, for example, a combination of a particular visual stimulus that had been associated in previous learning with a particular behavioral response. In the present study, it was found that during such conditional response learning, the activity of 22% of the neurons in the hippocampus and parahippocampal gyrus with activity specifically related to the task altered their responses so that their activity, which was initially equal to the two new stimuli, became progressively differential to the two stimuli when the monkey learned to make different responses to the two stimuli. These changes occurred for different neurons just before, at, or just after the time when the monkey learned the correct response to make to the stimuli. In addition to these neurons, which had differential responses that were sustained for as long as the recordings continued, another population of neurons (45% of those with activity specifically related to the task) developed differential activity to the two new stimuli, yet showed such differential responses transiently for only a small number of trials at about the time when the monkey learned. These findings are consistent with the hypothesis that some synapses on hippocampal neurons modify during this type of learning so that some neurons come to respond to particular stimulus-response associations that are being learned. Further, the finding that many hippocampal neurons started to reflect the new learning, but then stopped responding differentially (the transient neurons), is consistent with the hypothesis that the hippocampal neurons with large sustained changes in their activity inhibited the transient neurons, which then underwent reverse learning, thus providing a competitive mechanism by which not all neurons are allocated to any one learned association or event.

Action Potentials↗
PubMed1987

Automatic postural responses in the cat: responses of proximal and distal hindlimb muscles to drop of support from a single hind- or forelimb.

Cats respond to drop of the support from beneath a single limb with the "diagonal stance response" (Coulmance et al. 1979). They load the limbs on the diagonal opposite to the one containing the dropped limb and unload the third supporting limb in the diagonal containing the dropped limb. Characteristic biomechanical delays in limb motion and in vertical force changes imposed upon the limbs are observed. These delays range from 30 to 45 ms, depending upon the location of the dropped limb. This study describes the kinematics of the "diagonal stance response" and the activation of selected agonist-antagonist muscle pairs acting on the joints of the hindlimb during the response. Proximal and distal hindlimb muscles respond to perturbations in groups that are appropriate to the vertical forces imposed upon the limb. When the hindlimb containing the recording electrodes is loaded by drop of the contralateral hindlimb or the ipsilateral forelimb medium latency (25-45 ms) EMG responses occur in the extensors. This response serves to stiffen the limb against the increased vertical force of loading. A similar response is observed when the hindlimb is reloaded after being dropped. In this case, however, short latency responses precede the medium latency responses in muscles that are passively stretched by the limb drop. When drop of the diagonal forelimb unloads the hindlimb containing the electrodes, medium latency responses are observed in the distal hindlimb flexors, which indicates that the unloading is evoked in part by active lifting of the limb. In most cases, the medium latency responses precede or are coincident with the changes in force imposed on the limb, suggesting that the observed responses are centrally programmed.

Animals↗
PubMed2002

Failure to inactivate CDK activity is responsible for the enhanced apoptotic response in U937 cells mediated by silencing ATM gene.

Silencing ATM gene gave rise to enhanced apoptotic response to irradiation and irradiation-like chemotherapy agents, this paper explored the crucial identities of the molecular elements responsible for the enhanced apoptotic response in U937 cells mediated by silencing ATM gene. Two U937 cell mutants named U937-ASPI3K (ATM, negative) and U937-pZeosv2(+) (ATM, wild-type) were used as a cell model system to identify the critical molecule(s) responsible for the varied apoptotic response in the absence or presence of ATM gene. Apoptosis was examined by measuring concentrations of free nucleosome in U937 cells. Western blot was employed to measure nuclear protein abundance of CDC25A, CDC25B, CDC25C, total p34cdc2, p34cdc2, (Thr 161) or p34cdc2 (Thr 14, Tyr 15). RT-PCR was used to estimate CDC25 transcript levels. U937-ASPI3K exhibited an enhanced apoptotic response to lower dosage of irradiation, which could not be blocked by protein synthesis inhibitor. Protein serine-threonine phosphatase inhibitor or cyclin-dependent kinase (CDK) inhibitors, on the other hand, abolished the enhancement indicated that protein phosphorylation/dephosphorylation modification and CDK activity are required for the enhanced apoptotic response in the absence of ATM gene. Upon irradiation, p34cdc2 in U937-pZeosv2(+) was maintained in an inactive state by phosphorylation on threonine 14 (Thr 14) and tyrosine 15 (Tyr 15), which was associated with a dramatic decrease of nuclear CDC25A, CDC25B and CDC25C proteins. In contrast, p34cdc2 in U937-ASPI3K maintained in an active state by dephosphorylation on threonine 14 (Thr 14) and tyrosine 15 (Tyr 15), which was associated with constant nuclear CDC25A, CDC25B and CDC25C protein abundance before and after irradiation. The responsive decrease of nuclear CDC25 proteins occurred at the post-transcription level. Silencing ATM gene blocks the responsive decrease of nuclear CDC25 proteins, which is responsible for failure to inactivate p34cdc2 after irradiation. Active p34cdc2 and CDK2, in turn, acts as the death executors to trigger apoptosis. In summary, aberrantly activated CDK activity is the critical molecular mechanism central to enhanced apoptotic responses in the absence of ATM gene.

Apoptosis↗
PubMed2002

A series of immune responses leading to the induction of T cell IL-12/IL-18 responsiveness in patients with relatively large tumor burdens.

The induction of interleukin-12 (IL-12) responsiveness in T cells depends on T cell receptor (TCR) triggering, and is regarded as a parameter of recently TCR-sensitized T cells. Here, we investigated whether IL-12 responsiveness could be detected in freshly prepared T cells from tumor-bearing patients, and if so whether such patients exhibited additional immunological parameters related to IL-12 responsiveness. CD4(+) and CD8(+) T cell populations from an appreciable proportion of tumor-bearing patients exhibited high levels of IL-12 responsiveness as evaluated by IL-12-stimulated interferon-gamma (IFN-gamma) production. T cell populations with high IL-12 responsiveness were observed in the group of patients with moderate to large tumor mass or tumor metastases rather than in patients with small tumors. The frequency of such a T cell population was also lower in post-surgery tumor-free patients, showing the correlation between IL-12 responsiveness and the presence of a certain extent of tumor burden. More importantly, a higher incidence of IL-12 responsiveness was observed in tumor-bearing patients exhibiting detectable plasma IL-12 levels, and correlated with IL-18 responsiveness. T cell IL-12 and IL-18 responsiveness is induced by TCR triggering and subsequent IL-12 stimulation respectively. Furthermore, TCR-triggered T cells stimulate antigen-presenting cells (APC) to produce IL-12. Therefore, the present observations suggest that an immune response loop from TCR sensitization to the induction of IL-12/IL-18 responsiveness via IL-12 production operates in tumor-bearing patients, particularly in those with relatively large tumor burdens.

Adult↗
PubMed2003

Unique transitions between stimuli and responses in SRT tasks: evidence for the primacy of response predictions.

The present experiments aimed at separating the impact stimulus and response predictions have on serial learning and performance in SRT tasks. In Experiment 1, a unique transition between two of four responses in an otherwise random response sequence was triggered by ambiguous stimulus transitions, allowing local response predictions but no stimulus predictions. The data indicated explicit transition knowledge and strong performance benefits. In Experiments 2 and 3, unique transitions between two of four stimuli in otherwise random stimulus sequences allowed local stimulus predictions under conditions of ambiguous response transitions. The data indicated fragmentary explicit transition knowledge but no performance effects. Experiments 4a and 4b reveal that the inefficacy of the unique stimulus transitions in Experiments 2 and 3 was presumably due to the fact that the stimuli differed with respect to conjunctions of response relevant and response irrelevant features which participants did not have to attend. However, although in Experiments 4a and 4b unique transitions between response relevant stimuli were applied, substantial explicit transition knowledge but only marginal performance effects resulted. It is argued i) that in SRT tasks learning mechanisms are addressed that primarily strive for reliable predictions of forthcoming responses and ii) that for these mechanisms to work the predictors have to be attended. Response transitions are easily learned and used because both criteria are fulfilled. In contrast, pure stimulus transitions are learned only if the predictive stimuli are attended, and learned stimulus transitions become effective only to the extent that the predicted stimuli specify the required responses.

Adult↗
PubMed1986

Differences in airway responsiveness to leukotriene D4 in allergic sheep with and without late bronchial responses.

Allergic sheep respond to inhaled Ascaris suum antigen with either acute and late bronchial obstructions (dual responders) or only acute bronchoconstriction (acute responders). In this study we tested the hypothesis that one factor which may distinguish between these two populations is the difference in sensitivity to a specific mediator of airway anaphylaxis, leukotriene (LT) D4 (a major component of slow reacting substance of anaphylaxis). We postulated that if the hypothesis was correct then dual responders should demonstrate increased airway responses to inhaled LTD4 and that this increased responsiveness should also be reflected by a more severe response to inhaled antigen. To test this we used animals from both groups with the same degree of non-specific airway responsiveness to carbachol and determined their airway responses to controlled inhalation challenges with synthetic LTD4 and Ascaris suum antigen. Airway responsiveness to carbachol was determined by measuring the change in specific lung resistance (SRL) to increasing concentrations of carbachol aerosol, and then identifying, by linear interpolation, the provocative carbachol concentration which produced a 150% increase (PC150) in SRL. Airway responses to LTD4, and antigen were determined by measuring the percentage change in SRL after a controlled inhalation challenge with either aerosol. Airway responsiveness to carbachol was not different between the two groups. There was, however, a difference (p less than 0.05) in the airway response to the same dose of LTD4 in the two groups. Dual responders showed a 297 +/- 72% increase in SRL as compared to a 90 +/- 13% increase in SRL in the acute responders. Dual responders also showed a greater immediate and more prolonged response to antigen than did acute responders. These results suggest that increased responsiveness to LTD4 may be one factor which may distinguish dual responders from acute responders.

Airway Resistance↗
PubMed1994

Sensory responsiveness of "broad-spike" neurons in the laterodorsal tegmental nucleus, locus coeruleus and dorsal raphe of awake rats: implications for cholinergic and monoaminergic neuron-specific responses.

Although cholinergic neurons in the laterodorsal and pedunculopontine tegmental nuclei have been shown to have a pivotal role in neural mechanisms of paradoxical sleep, their function during wakefulness is less understood. To examine the latter, we have recorded from "broad-spike neurons", which were distinguished by their long spike duration, in the laterodorsal tegmental nucleus of undrugged, head-restrained rats, and examined their response properties to sensory stimuli such as light touch to the tail, air puff to the face, 2 kHz pure tone and flashes of light. Broad-spike neurons from the locus coeruleus and dorsal raphe nucleus were studied for comparison; these neurons have been demonstrated to be noradrenergic and serotonergic, respectively. The broad-spike neurons in the laterodorsal tegmental nucleus have also been suggested to be cholinergic. There were two kinds of responses: (1) a simple increase or decrease in firing, reflecting an elevated level of vigilance; and (2) a phasic response composed of a single spike or brief, high frequency burst, usually diminishing or disappearing upon repetition of the stimulus. When two or more types of stimuli were effective in a neuron, they evoked responses of the same quality. Most of the dorsal raphe neurons displayed only the simple increase of firing, whereas the locus coeruleus neurons gave a phasic response with rather weak attenuation upon repetition. Compared with these, the laterodorsal tegmental neurons were heterogeneous: about one-quarter showing only a simple change of firing (half increasing, half decreasing); and two-thirds displaying phasic responses. The latter response of many neurons attenuated strongly upon repetition. The laterodorsal tegmental neurons were classified into several groups according to their spontaneous firing behavior during sleep and wakefulness, but every neuron in a group did not show the same type of response. For example, some of the neurons which were most active during paradoxical sleep and essentially silent during wakefulness decreased or stopped firing upon sensory stimulation, while others in this group had strong phasic responses. These results suggest that putative cholinergic neurons in the laterodorsal tegmental nucleus have heterogenous properties not only with respect to their spontaneous activity during sleep and wakefulness but also with respect to their response to sensory stimulation. Some of these neurons may function to induce a global attentive state in response to a novel stimulus.

Acoustic Stimulation↗
PubMed2001

Does the antihypertensive response to angiotensin converting enzyme inhibition predict the antihypertensive response to angiotensin receptor antagonism?

To test the hypothesis that the antihypertensive response to angiotensin converting enzyme (ACE) inhibition can predict the response to angiotensin II type I receptor (AT1R) antagonism, 33 hypertensive patients were randomized to receive lisinopril (20 mg) or losartan (50 mg) for 5 weeks. Patients were then crossed-over to the alternative treatment for a second 5-week period. Twenty-four-hour ambulatory BP (ABP) was measured before randomization and on the final day of each period. The agreement in ABP response between the two drugs was assessed using the following approaches: Subjects were classified as responders and nonresponders using as a threshold an arbitrary level of response (ABP fall > or = 10 mm Hg systolic or > or = 5 mm Hg diastolic) or the median ABP response achieved by each of the drugs. Disagreement between the two drugs in the responders-nonresponders classification was expressed as the proportion of subjects whose ABP responded to one of the drugs only. Lisinopril was more effective than losartan in reducing ABP (mean difference 4.7+/-8.1/3.3+/-5.7 mm Hg, systolic/diastolic, P < .05). Disagreement in the antihypertensive response between the two drugs was found in 39%/33% of subjects for systolic/diastolic ABP using the arbitrary response criterion (33%/39% using the median response criterion). Significant correlations were found between the responses to lisinopril and losartan (r = 0.47/0.59, systolic/diastolic, P < .01). We conclude that in more than one third of hypertensive subjects, the BP response to ACE inhibition fails to predict the response to AT1R antagonism and vice versa. These data suggest that there are differences between these two drug classes that are not only of theoretical but also of practical significance.

Adult↗
PubMed1999

Choice and stimulus-response compatibility affect duration of response selection.

In general, for movements to visual targets, response times increase with the number of possible response choices. However, this rule only seems to hold when an incompatibility exists between the stimulus and response, and is absent when stimulus and response are highly compatible (e.g., when reaching toward the location of the stimulus). Stimulus-response (S-R) compatibility can be manipulated either at the level of stimulus and response characteristics, or at the level of the mapping between elements of the stimulus and response sets. The current study was undertaken to determine the extent of the interaction between choice and each of these two levels of S-R compatibility. Subjects used a joystick to move a cursor in response to two, four or eight possible cues, with S-R compatibility manipulated along two dimensions (type of stimulus, and mapping between stimulus and response sets) in separate blocks of trials. Choice effects were absent when S-R relationships were highly compatible, moderate when incompatible in either of the two dimensions, and greatest when incompatible in both dimensions. These results indicate that choice affects response selection at each stage in the decoding of S-R relationships. Similar but smaller effects were seen for trials in which the stimulus was the same as that presented in the immediately preceding trial, suggesting that repeated stimulus-response transformations are faster and more efficient due to the priming effects of previous trials.

Adult↗
PubMed2004

Do CA125 response criteria overestimate tumour response in second-line treatment of epithelial ovarian carcinoma?

Recent studies indicate that cancer antigen 125 (CA125) response criteria tend to overestimate a tumour reduction measured by standard WHO response criteria in recurrent epithelial ovarian carcinoma. The aim of the study was to validate the recently introduced GCIG (The Gynaecological Cancer Intergroup) CA125 response criteria in predicting a tumour response measured by WHO (World Health Organization) criteria. Changes in CA125 levels (GCIG criteria) were retrospectively compared with alterations in the tumour load (WHO criteria) during second-line chemotherapy with topotecan or paclitaxel-platinum in 124 consecutive patients with recurrent or refractory disease. In patients assessable by both response criteria (n=72), the overall response rate using GCIG CA125 criteria was 57% (95% confidence interval (CI): 45-69%) and significantly higher than the response rate of 39% (95% CI: 28-51%) using WHO response criteria (P=0.045). The GCIG CA125 criteria had a sensitivity of 96% (95% CI: 82-100%), a specificity of 68% (95% CI: 52-81%) and an accuracy of 79% (95% CI: 68-88%) in predicting a response measured by WHO criteria. In conclusion, the GCIG CA125 response criteria seem to overestimate a tumour response by WHO criteria when monitoring the efficacy of second-line chemotherapy with topotecan or paclitaxel-platinum in patients with epithelial ovarian carcinoma.

Adult↗
PubMed2003

Effects of bisphenol A on antigen-specific antibody production, proliferative responses of lymphoid cells, and TH1 and TH2 immune responses in mice.

1. We investigated the effect of bisphenol A (BPA), which binds estrogen receptors, on immune responses including production of antigen-specific antibodies, proliferative responses of lymphoid cells, and Th1 and Th2 responses. 2. For this investigation, mice were p.o. given varying doses including 3, 30, 300, and 3000 micro g kg(-1) of BPA immediately after immunization with hen egg lysozyme (HEL) (day 0) and then daily by day 20. On day 21, anti-HEL IgG antibodies in sera and proliferative responses of spleen cells to the antigen were measured. Anti-HEL IgG2a antibodies and IFN-gamma secreted from splenic lymphocytes were also measured as indicators of Th1 immune responses, while anti-HEL IgG1 antibodies and IL-4, as those of Th2 responses. 3. The results showed that treatment with 3000 micro g kg(-1) of BPA was followed by a significant increase in anti-HEL IgG as well as the antigen-specific cell proliferation. Anti-HEL IgG2a production and IFN-gamma secretion were significantly enhanced in mice treated with 300 and 30 micro g kg(-1) of BPA, respectively, while anti-HEL IgG1 production and IL-4 secretion were augmented in animals given 3000 and 300 micro g kg(-1) of the chemical, respectively. 4. Augmentation of these immune responses was also observed in mice exposed to 0.3-30 micro g kg(-1) of estradiol, although Th1 responses appeared to be more sensitive to the sex hormone than Th2 responses. 5. These results suggest that BPA may play a role in augmenting immune responses, especially Th1 responses.

Animals↗
PubMed1999

The late asthmatic response is associated with baseline allergen-specific proliferative responsiveness of peripheral T lymphocytes in vitro and serum interleukin-5.

BACKGROUND: Increasing insights into the mechanism underlying the allergen-induced late asthmatic response (LAR) have been gained with implication of activated eosinophils and CD4+ T lymphocytes. However, the patient characteristics that indicate the individual capacity to develop a LAR are not well-defined. METHODS: In 22 subjects with mild to moderate house dust mite-allergic asthma, we investigated the relationship between the LAR and two other models of late-phase allergic inflammation, i.e. the allergen-specific proliferative response of peripheral blood T lymphocytes in vitro and the late cutaneous response. Non-specific bronchial responsiveness (PC20histamine), lung function (FEV1), peripheral blood eosinophil count, early phase allergic skin sensitivity, and levels of total and specific immunoglobulin E (IgE) were determined prior to bronchial allergen challenge. Serum levels of interleukin-5 (IL-5) were measured before and at several time points after allergen inhalation. RESULTS: A significant correlation was found between the magnitude of the LAR and the allergen-specific proliferative response of peripheral T lymphocytes (r = 0.44, P = 0.04) but not the late cutaneous response. Stepwise-multiple linear regression of the magnitude of the LAR on the parameters analysed at baseline, resulted in a model combining PC20 histamine, early phase allergic skin sensitivity, and the allergen-specific proliferative response of peripheral T lymphocytes (R2 = 0.84, P<0.001). No contribution of the late cutaneous response to the prediction of the LAR was found. Serum levels of IL-5 increased significantly at 6 h (P = 0.01) and 24 h (P = 0.003) after bronchial allergen challenge and correlated with the allergen-specific proliferative response of peripheral T lymphocytes in vitro (rho = 0.48, P = 0.02). CONCLUSIONS: The findings in this study point to a role of TH2-lymphocyte responses in the development of the allergen-induced LAR. In allergic asthmatic patients, allergen-specific responsiveness of peripheral T-lymphocytes in vitro may serve as a model to determine the individual capacity to develop a LAR after allergen inhalation.

Adolescent↗
PubMed1998

Effects of adjuvants on the immune response to allergens in a murine model of allergen inhalation: cholera toxin induces a Th1-like response to Bet v 1, the major birch pollen allergen.

Based on the fact that type I allergies are frequently elicited by inhalant allergens, we have established a model of aerosol inhalation leading to allergic sensitization in BALB/c mice. Using this model we studied the effects of aluminium hydroxide (Al(OH)3), known to enhance IgE antibody responses, compared with cholera toxin (CT), a potent mucosal adjuvant, on the immune response to birch pollen (BP) and its major allergen Bet v 1. Two groups of BALB/c mice were either systemically immunized with recombinant Bet v 1 in Al(OH)3 and subsequently aerosol exposed to BP allergen, or aerosolized with BP and CT. IgE-mediated skin reactions were only elicited in the mice which had received Bet v 1/Al(OH)3. Allergen-specific serum IgE and IgG1 antibodies dominated in the Al(OH)3 group, IgG2a antibody levels to BP and rBet v 1 were markedly higher in the sera of mice exposed to CT with the allergen. IgA antibodies were only detected in the bronchial lavage of the CT-treated group. Moreover, the latter group displayed consistently higher T cell proliferative responses to BP and interferon-gamma production in vitro. Thus, the systemic immunization with rBet v 1 in Al(OH)3 before inhalation of the BP extract promoted a Th2-like immune response, while CT mixed with the aerosolized BP extract rather induced a Th1-like immune response. In an attempt to reverse these ongoing immune responses we could achieve a shift towards a Th0 response. Immunization with BP extract without adjuvant treatment led to undetectable antibody or cellular immune responses. We conclude from the present study that the induction of an immune response to BP allergen after aerosol inhalation can be directed towards a Th1- or a Th2-like response. Once established, the immune response can be modulated.

Adjuvants, Immunologic↗
PubMed2002

Polyclonal and allergen-induced cytokine responses in adults with asthma: resolution of asthma is associated with normalization of IFN-gamma responses.

BACKGROUND: Atopic disease is associated with skewing of immune responses away from a T(H)1 toward a T(H)2 profile. Previous studies have implicated this cytokine imbalance in the development of disease. However, it is not known whether normalization of this imbalance is conversely associated with disease resolution. OBJECTIVE: To further delineate the role of reduced T(H)1 and increased T(H)2 cytokine production in the pathogenesis of atopic disease and to determine whether disease resolution is associated with alteration of cytokine profiles, we investigated cytokine responses in a cohort of adult patients with asthma followed from childhood. METHODS: A cohort of wheezy children and control subjects aged 7 to 10 years were recruited from 1964 to 1967. Subjects were reevaluated every 7 years to monitor the outcome of childhood asthma. At the 42-year follow-up, 89 subjects from this cohort were evaluated for mitogen and house dust mite (HDM)-induced T(H)1 (IFN-gamma) and T(H)2 (IL-4, IL-5, and IL-13) cytokine responses. Cytokine responses were compared in patients with ongoing asthma, patients with resolved asthma, and control subjects. RESULTS: Patients with severe ongoing asthma had significantly reduced HDM-induced IFN-gamma production compared with that of control subjects and patients with resolved asthma. In contrast, HDM-induced IFN-gamma production in patients with resolved asthma was equivalent to that seen in control subjects. Patients with ongoing and resolved asthma produced significantly higher levels of IL-5 in response to HDM compared with that seen in control subjects, with levels being equivalent in patients with active and resolved asthma. HDM-induced IL-13 production was significantly increased in the patients with resolved asthma when compared with that seen in the control subjects. PHA-induced cytokine responses did not parallel HDM-induced responses. CONCLUSION: Patients with persistent and severe atopic asthma have a reduced HDM-induced T(H)1 response, whereas those with resolved asthma do not. This suggests that reduced HDM-induced IFN-gamma production might be an important factor contributing to ongoing severe asthma and that normalization of allergen-induced T(H)1 responses might be important for disease resolution. The finding that all subjects with a history of asthma displayed increased HDM-induced T(H)2 (IL-5 and IL-13) cytokine responses, irrespective of the presence or absence of asthma, suggests that increased T(H)2 responses reflect the presence of the atopic state per se rather than being specifically linked to asthma.

Adult↗
PubMed2003

Survey of naturally occurring CD4+ T cell responses against NY-ESO-1 in cancer patients: correlation with antibody responses.

NY-ESO-1 is one of the most immunogenic proteins described in human cancers, based on its capacity to elicit simultaneous antibody and CD8+ T cell responses in vivo. Although HLA class II restricted epitopes from NY-ESO-1 have been identified, no broad survey has yet established the status of natural CD4+ T cell responses in cancer patients in relation to CD8+ and antibody responses. We used a recently developed general strategy for monitoring CD4+ responses that overcomes the need for prior knowledge of epitope or HLA restriction to analyze a series of 31 cancer patients and healthy donors for the presence of CD4+ T cells to NY-ESO-1, and related this response to NY-ESO-1 expression in tumor cells and serum antibodies to NY-ESO-1. None of the 18 patients that tested seronegative for NY-ESO-1 had detectable CD4+ T cell responses. On the contrary, 11 of 13 cancer patients with serum antibodies to NY-ESO-1 had polyclonal CD4+ T cell responses directed against various known and previously undescribed NY-ESO-1 epitopes. NY-ESO-1 peptide 80-109 was the most immunogenic, with 10 of 11 patients responding to this peptide. We show here that 12-mer determinants from NY-ESO-1 eliciting a CD4+ T cell response were peptide 87-98 with promiscuous HLA class II presentation, peptide 108-119 restricted by HLA-DP4, and peptides 121-132 and 145-156, both shorter epitopes from previously described HLA-DR4 peptides, also presented by HLA-DR7. This study represents the next step in compiling a comprehensive picture of the adaptive immune response to NY-ESO-1, and provides a general strategy for analyzing the CD4+ T cell response to other tumor antigens eliciting a humoral immune response.

Amino Acid Sequence↗
PubMed2001

Monitoring virological responses to interferon-ribavirin and interferon monotherapy of chronic hepatitis C re-treated due to relapse or non-response.

Adding the nucleoside analog ribavirin (RBV) to interferon (IFN) for treatment of HCV has improved the sustained response rates, but the mechanism by which RBV mediates viral clearance is not fully understood. In this study, a highly sensitive method (Codes Amplicor HCV Monitor) was used to monitor the early (first 12 weeks of therapy) and long-term virological response in 20 patients who were treated first with IFN and later, due to non-sustained response, with IFN-RBV. All 10 IFN relapsers displayed a prompt virological response at week 4 to both IFN and IFN-RBV therapy; nine of them showed a sustained response to IFN-RBV. Out of 10 IFN non-responders, five showed a sustained response to IFN-RBV. Four of these were HCV RNA-negative at week 4 of IFN-RBV therapy and two of them had a transient early virological response (RNA-negative at weeks 4-8) to IFN alone. Overall, of the 14 patients (nine IFN relapsers, five IFN non-responders) with a sustained response to IFN-RBV, 11 and 13 had HCV RNA below 2000 copies/ml at week 4 of IFN and IFN-RBV, respectively, as compared with one and one of six patients without a sustained response to IFN-RBV (p < 0.02). Thus, addition of RBV to IFN increased both viral clearance during the first 12 weeks of therapy and the rate of sustained response. Loss of viremia at week 4 of IFN was associated with a sustained response to IFN-RBV and was seen in 11 of 13 patients (85%) with genotypes 2 or 3, as compared with one of seven patients (14%) with genotype 1 (p = 0.0044).

Adult↗
PubMed1973

Hapten-specific IgE antibody responses in mice. II. Cooperative interactions between adoptively transferred T and B lymphocytes in the development of IgE response.

The present studies have established conditions for the demonstration of cooperative interactions between specific T and B lymphocyte populations in the development of IgE antibody responses in vivo in mice. This has been accomplished by utilizing a system which permits the successful adoptive transfer to irradiated recipients of DNP-specific secondary IgE responses with spleen cells from suitably primed syngeneic donor mice. Thus, adoptively transferred DNP-KLH or DNP-ASC-primed spleen cells produced high levels of anti-DNP antibodies of both IgE and IgG antibody classes in response to challenge with the appropriate homologous priming conjugate but failed to develop more than meager responses to the reciprocal heterologous conjugate. However, when spleen cells from donors primed to the second carrier were concomitantly transferred with hapten-primed lymphocytes, secondary IgE ant-DNP responses were consistently obtained upon challenge with the heterologous conjugate. Moreover, we have been able to elicit augmented primary IgE anti-DNP antibody responses to either DNP-ASC or DNP-KLH after adoptive transfer of spleen cells from donors primed only to the carrier, ASC or KLH, respectively. This adoptive transfer system has enabled us to provide direct proof for the participation of theta-bearing T lymphocytes in antibody responses of the IgE class. Thus, the capacity of ASC-primed spleen cells to effectively cooperate with the DNP-KLH-primed lymphocytes in the adoptive secondary response to DNP-ASC could be abolished by in vitro treatment of such cells with anti-theta serum plus complement. This was true not only for the anti-DNP response of the IgG antibody class, but for the IgE antibody class as well. These studies have, furthermore, demonstrated the capacity to stimulate secondary anti-DNP antibody production in vivo by the concomitant administration of the DNP and relevant carrier determinants on separate molecules. This was more readily seen in the IgE than in the IgG antibody class. Thus, DNP-ASC-primed cells developed significant IgE, but more variable IgG, anti-DNP responses upon challenge with DNP-KLH plus unconjugated ASC. Antibody responses of both classes elicited in this manner were appreciably improved by the transfer of additional carrier (ASC)-primed cells. These and other results presented herein suggest that IgE B lymphocyte precursors may be inherently more sensitive than IgG B cells to at least certain of the functions of T lymphocytes concerned with regulatory mechanisms involved in antibody production.

Adjuvants, Immunologic↗