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Biomedical subjects

P Ray

Publications and source records attributed to P Ray.

At least 91 records · Page 5Linked to original sources
PubMed1999

Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers.

OBJECTIVES: The objectives of this study were (1) to determine the safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate (PNCRM7) vaccine in infants and (2) to determine the effect of concurrent hepatitis B immunization during the primary series and the effect of concurrent diphtheria and tetanus toxoid and acellular pertussis [DTaP (ACEL-IMUNE)] and conjugate CRM197 Haemophilus influenzae type b [HbOC (HibTITER) immunization at time of the booster dose on the safety and immunogenicity of PNCRM7and these other concurrently administered vaccines. METHODS: This was a randomized double-blinded study in 302 healthy infants in the Northern California Kaiser Permanente (NCKP) Health Plan. Infants received either PNCRM7 vaccine or meningococcal group C conjugate vaccine as a control at 2, 4 and 6 months of age and a booster at 12 to 15 months of age. Study design permitted the evaluation of immunology and safety of concurrent administration of routine vaccines. Antibody titers were determined on blood samples drawn before and 1 month after the primary series and the booster dose. RESULTS: After the third dose of PNCRM7 geometric mean concentrations (GMCs) ranged from 1.01 for serotype 9V to 3.72 microg/ml for serotype 14. More than 90% of all subjects had a post-third dose titer of > or =0.15 microg/ml for all serotypes, and the percentage of infants with a post-third dose titer of > or =1.0 microg/ml ranged from 51% for type 9V to 89% for type 14. After the PNCRM7 booster dose, the GMCs of all seven serotypes increased significantly over both post-Dose 3 and pre-Dose 4 antibody levels. In the primary series there were no significant differences in GMCs of pneumococcal antibodies between the subjects given PN-CRM7 alone or concurrently with hepatitis B vaccine. At the toddler dose concurrent administration of PNCRM7 and DTaP and HbOC resulted in a near conventional threshold for statistical significance of a post-Dose 4 GMC for serotype 23F [alone 6.75 mirog/ml vs. concurrent 4.11 microg/ml (P = 0.057)] as well as significantly lower antibody GMCs for H. influenza polyribosylribitol phosphate, diphtheria toxoid, pertussis toxin and filamentous hemagglutinin. For all antigens there were no differences between study groups in defined antibody titers that are considered protective. CONCLUSION: We conclude that PNCRM7 vaccine was safe and immunogenic. When this vaccine was administered concurrently at the booster dose with DTaP and HbOC vaccines, lower antibody titers were noted for some of the antigens when compared with the antibody response when PNCRM7 was given separately. Because the GMCs of the booster responses were all generally high and all subjects achieved similar percentages above predefined antibody titers, these differences are probably not clinically significant.

Antibodies, Bacterial↗
PubMed1999

Postmarketing evaluation of the safety and effectiveness of varicella vaccine.

BACKGROUND: The Oka strain of live attenuated varicella virus was licensed for use in healthy children in the United States in March, 1995. We report a postmarketing evaluation of the short term safety of this vaccine within Kaiser Permanente. METHODS: After licensure varicella vaccination was introduced into the preventive care program of the Northern California Kaiser Permanente Medical Care Program. Potential adverse events after vaccination with varicella vaccine were identified from automated clinical databases of hospitalizations, emergency room visits and clinic visits. Deaths were identified from automated clinical databases at Kaiser as well as from the State death records for California. To evaluate safety, rates of diagnosis-specific events in the risk periods were compared with the rates of such diagnosis-specific events in two self control and one historical control period. RESULTS: During the study period of April 1, 1995, to December 31, 1996, a total of 89753 adults and children received varicella vaccine. A total of 3200 relative risks were calculated, and of these 5 hospital diagnostic categories, 9 emergency visit diagnostic categories and 30 outpatient diagnostic categories demonstrated at least 1 relative risk with a P value of <0.05 in 1 or more age groups and in comparisons with 1 control period or more. The p value for these tests was not adjusted for multiple comparisons. Of these categories 14 demonstrated an increased risk either in more than 1 age group or against more than 1 comparison group. These categories included elective procedures, febrile seizure, febrile illness, well child, acute gastroenteritis, varicella, congenital anomaly, "rule out sepsis," trauma, viral syndrome, apnea, back pain, congenital valvular heart disease and vision evaluation for glasses. Of these the outcomes of elective procedure, congenital anomaly, congenital valvular heart disease, well child and vision evaluation for glasses were judged not to have a biologically plausible association with vaccination. A second diagnostic grouping included febrile illness, viral illness, febrile seizure and "rule out sepsis." In an analysis of these events which adjusted for the concomitant administration of M-M-R(II) vaccine, none of the associations was statistically associated with receipt of varicella vaccine. The diagnostic category of "rule out sepsis" still had a relative risk of 1.95 with P = 0.02. None of the children in the "rule out sepsis" category had positive bacteriologic cultures from any other normally sterile site. Because of the large number of gastroenteritis cases, we reviewed a random sample of 100 exposed and 100 unexposed cases. From this review no consistent time association or clustering of any of these events was seen in the exposed follow-up time interval. Only gastroenteritis and negative evaluations for sepsis were thought to be possibly associated with receipt of varicella vaccine. Although there was a statistically significant increased risk over the entire 30 day-period, there was no clustering of these events within the 30-day window. CONCLUSION: In this study population of 89753 children and adults, the varicella vaccine (Oka strain, Merck) appeared to have a favorable safety profile. In addition rates of varicella-like rash and of breakthrough cases were both low and consistent with the rates observed in prelicensure studies.

Adult↗
PubMed1999

Avalanches in breakdown and fracture processes.

We investigate the breakdown of disordered networks under the action of an increasing external-mechanical or electrical-force. We perform a mean-field analysis and estimate scaling exponents for the approach to the instability. By simulating two-dimensional models of electric breakdown and fracture we observe that the breakdown is preceded by avalanche events. The avalanches can be described by scaling laws, and the estimated values of the exponents are consistent with those found in mean-field theory. The breakdown point is characterized by a discontinuity in the macroscopic properties of the material, such as conductivity or elasticity, indicative of a first-order transition. The scaling laws suggest an analogy with the behavior expected in spinodal nucleation.

Journal Article↗
PubMed1998

Essential role of nuclear factor kappaB in the induction of eosinophilia in allergic airway inflammation.

The molecular mechanisms that contribute to an eosinophil-rich airway inflammation in asthma are unclear. A predominantly T helper 2 (Th2)-type cell response has been documented in allergic asthma. Here we show that mice deficient in the p50 subunit of nuclear factor (NF)- kappaB are incapable of mounting eosinophilic airway inflammation compared with wild-type mice. This deficiency was not due to a block in T cell priming or proliferation in the p50(-/-) mice, nor was it due to a defect in the expression of the cell adhesion molecules VCAM-1 and ICAM-1 that are required for the extravasation of eosinophils into the airways. The major defects in the p50(-/-) mice were the lack of production of the Th2 cytokine interleukin 5 and the chemokine eotaxin, which are crucial for proliferation and for differentiation and recruitment, respectively, of eosinophils into the asthmatic airway. Additionally, the p50(-/-) mice were deficient in the production of the chemokines macrophage inflammatory protein (MIP)-1alpha and MIP-1beta that have been implicated in T cell recruitment to sites of inflammation. These results demonstrate a crucial role for NF-kappaB in vivo in the expression of important molecules that have been implicated in the pathogenesis of asthma.

Animals↗
PubMed1998

Purification and characterization of protease activated by sulfur mustard in normal human epidermal keratinocytes.

A membrane-bound protease induced by sulfur mustard in cultured normal human epidermal keratinocytes (NHEK) was purified and partially characterized. Maximum enzyme stimulation occurred at 16 hr after normal human epidermal keratinocytes were exposed to 300 microM sulfur mustard. Purification to homogeneity of the protease was accomplished by Triton X-100 solubilization, ultracentrifugation, and dialysis, followed by ion-exchange chromatography through DEAE-cellulose and finally hydrophobic column chromatography through phenyl Sepharose. Analysis of the purified enzyme by SDS-PAGE revealed a single polypeptide at the 80 kDa region. Further investigation of biochemical properties showed that a synthetic serine-specific Chromozym TRY peptide and the physiological protein laminin were good substrates for this enzyme. Moreover, this enzyme was inhibited mostly by the serine-protease inhibitors leupeptin and di-isopropyl fluorophosphate and not by the cysteine protease inhibitor E-64 or the metalloprotease inhibitor 1,10-phenanthroline (Component H, CH), indicating the serine protease nature of this enzyme. This enzyme had a pH optimum in the range of 7.0 to 8.0. Amino acid sequencing of the purified enzyme revealed that this enzyme belongs to the endopeptidase family (serine protease), and is homologous with a mammalian-type bacterial serine endopeptidase that can preferentially cleave K-X, including K-P. These results suggest that serine-protease stimulation may be one of the mechanisms of mustard-induced skin blister formation, and that some specific serine-protease inhibitors may be useful for the treatment of this sulfur mustard toxicity.

Amino Acid Sequence↗
PubMed1998

Effector-sensitive cross-linking of phosphorylase b kinase by the novel cross-linker 4-phenyl-1,2,4-triazoline-3,5-dione.

The dienophile 4-phenyl-1,2,4-triazoline-3,5-dione (PTD) was identified as a novel protein cross-linker, and utilized as a conformational probe of phosphorylase b kinase (PhK), a hexadecameric enzyme with the subunit composition (alphabetagammadelta)4. In its reaction with this enzyme, PTD produced five major cross-linked conjugates as resolved by denaturing gel electrophoresis: alphabeta, betagammagamma, alphagamma and a doublet of differently migrating homodimers, betabeta1 and betabeta2. Cross-linking in the presence of six different activators of the kinase targeted to its various subunits caused substantial changes in the amounts of three of the conjugates. The formation of alphagamma was increased by all of the activators but the largest enhancement was caused by exogenous Ca2+/calmodulin. All except one of the activators decreased the amount of betagammagamma formed, with Mg2+ having the greatest effect, and all except two increased the amount of betabeta1, with Mg2+ again having the largest influence. From the overall similarity of the changes in cross-linking by PTD induced by the various activators, we conclude that, even though they are targeted to different sites and subunits, they induce activated conformations of PhK that have certain structural features in common. Regarding the mechanism of cross-linking by PTD, its reaction with a model nucleophile suggests that its initial reaction with a side chain nucleophile of PhK involves a 1,4-conjugate addition to form a urazole adduct, with the secondary cross-linking reaction occurring through an as yet unknown pathway.

Animals↗
PubMed1998

Safety and efficacy of stripping of membranes at term.

OBJECTIVES: To assess the efficacy of stripping of membranes in initiation of labor and to study its effect on maternal and perinatal morbidity. METHOD: One-hundred primigravidae with certain gestational dates were randomized at 38 weeks gestation to either receive stripping of membranes or only gentle cervical examination. Cervical swabs were taken before pelvic examination at 38 weeks and again at the onset of labor. Placental membranes were sent for bacteriological study after delivery in all patients. RESULTS: The mean gestational age, parity and Bishop score were similar in both groups at recruitment. Gestational age at delivery was lower in the study group (38.70 +/- 0.63) compared to the control group. Seventy-two percent of the study group and 8% of the control group had spontaneous onset of labor within 7 days of examination. Labor was induced in one patient (2%) of the study group and 16 patients (32%) of the control group. No statistically significant difference was noted in incidence of premature rupture of membranes (PROM), mode of delivery, intrapartum events and perinatal outcome. No increase in neonatal morbidity was seen in association with this procedure. No patient in the study group had clinical evidence of chorioamnionitis. There was no statistically significant difference in the microbiological flora of both groups. CONCLUSION: Stripping of the fetal membranes is a safe and efficacious procedure for induction of labor. It decreases the incidence of induction of labor with no increase in incidence of maternal and neonatal morbidity.

Adult↗
PubMed1998

Comparison of serum prostate-specific antigen levels and PSA density in African-American, white, and Hispanic men without prostate cancer.

OBJECTIVES: To determine the influence of race or ethnicity on serum prostate-specific antigen (PSA) levels and PSA density (PSAD) in a population of healthy men without clinically evident prostate cancer. METHODS: This retrospective study was conducted between January 1988 and January 1993. The serum PSA levels were measured in 859 men (586 African Americans, 142 whites, and 131 Hispanics) who were participants in a prostate cancer screening program or had urinary symptoms suggestive of prostate gland pathology. All men underwent a detailed clinical examination, including digital rectal examination, serum PSA determination, and transrectal ultrasound (TRUS). None of the subjects included had clinical or TRUS evidence of prostate cancer (furthermore, 283 men were pathologically proved to be cancer-free by prostate biopsies). Serum PSA levels and PSA densities as a function of each individual's ethnic background were determined. RESULTS: The mean serum PSA level in African Americans was 2.1 ng/mL, which was significantly higher than that of whites (mean PSA of 1.53 ng/mL) and Hispanics (mean PSA of 1.83 ng/mL) (P = 0.003). Similar differences among the three groups were observed in PSA density (the mean PSAD was 0.078, 0.057, and 0.065 for African Americans, whites, and Hispanics, respectively). A separate analysis for the biopsy-negative men was performed, and the findings were consistent with the observations for the entire study group. After adjustment for age and prostate volume, the differences remained statistically significant. CONCLUSIONS: Among men without evidence of prostate cancer, African Americans have higher serum PSA levels and PSA densities than do whites or Hispanics. Race or ethnicity was an independent factor that affected serum PSA levels even after adjustment for age and prostate volume.

Adult↗
PubMed1998

Predictive factors of tumor response and prognostic factors of survival during lung cancer chemotherapy.

The aim of this study was (i) to determine predictive factors of a complete response to chemotherapy in small cell lung cancer (SCLC) and predictive factors of an objective response in non-small cell lung cancer (NSCLC) and (ii) to determine whether prognostic factors are different with regard to treatment response and survival. Ninety-nine patients with SCLC and two hundred and two patients with NSCLC received chemotherapy. The following variables were recorded prior to treatment: tumor, node, metastasis status, performance status, body weight loss, blood leukocyte count, serum sodium, serum albumin, lactate dehydrogenase (LDH), alkaline phosphatase, serum NSE, serum TPS, and serum CYFRA 21-1. Tumor response was analyzed at the 10th week. Analysis of survival were done using the landmark method. Hazard ratios of the significant prognostic variables of survival were calculated using the Cox's model. Odds ratios of the significant predicting factors of response were calculated by stepwise logistic regression. In SCLC, the significant determinants of poor survival were: lack of complete response (HR: 2.04), weight loss (HR: 1.76), high serum LDH level (HR: 1.64), and high serum TPS level (HR: 2.47). A high serum TPS level was the only factor among those studied able to predict lack of achievement of complete response (OR: 0.39). In NSCLC, significant determinants of poor survival were: no objective response (HR: 2.28), poor performance status (HR: 2.52), presence of metastases (HR: 1.51), and high serum CYFRA 21-1 level (HR: 1.84). On the other hand, a high serum TPS level (OR: 0.50), the presence of metastases (OR: 0.45), and a leukocyte blood count over 10,000/microl (OR: 0.43) were independent determinants for a patient not to achieve an objective response. We concluded that the predictive factors of complete response in SCLC remain to be defined. On the other hand, in NSCLC three variables contribute to the prediction of an objective response. Finally, determinants of survival differ from predictive factors of response.

Analysis of Variance↗
PubMed1998

Characterization of lymphocytic subsets and cytokine production in gastric biopsy samples from Helicobacter pylori patients.

BACKGROUND: This study characterized the phenotypic subsets of isolated gastric lymphocytes and the cellular immune response in cultured gastric biopsy specimens. METHODS: Endoscopy specimens from 40 Helicobacter pylori-positive and 40 H. pylori-negative patients were studied. a) Isolated gastric lymphocytes were analysed for CD4+, CD8+ T-lymphocyte subsets, activated T cells, and natural killer cells on a fluorescence-activated cell sorter, using monoclonal antibodies. b) The supernatant of cultured gastric biopsy specimens were assayed for interleukin (IL)-2, IL-4, and IL-6 levels. RESULTS: In H. pylori-positive patients there was (a) a decrease in CD4+/CD8+ T cells, no change in activated T cells, and an increase in natural killer cells, and (b) no change in IL-2 levels and a significant increase in IL-4 and IL-6 levels. CONCLUSIONS: There is an increase in CD8+ lymphocytes and natural killer cells, and the observed increase in IL-4 and IL-6 might be important in H. pylori-associated gastritis.

Adult↗
PubMed1998

Varicella serology among school age children with a negative or uncertain history of chickenpox.

BACKGROUND: Clinicians who offer varicella vaccination to school age children face the dilemma of whether to serotest or vaccinate presumptively. Varicella seroprevalence among 7- to 12-year-old children with negative or uncertain histories has not previously been studied. Our main objective was to describe varicella seroprevalence among children ages 7 to 12 years with a negative or uncertain history of chickenpox. METHODS: This was a cross-sectional study of children whose clinicians had ordered varicella serotesting. Guidelines from the medical group's regional pediatric infectious disease specialists recommended obtaining varicella serology on all children 7 to 12 years old with a negative or uncertain history. Parents were interviewed by telephone about the child's history of chickenpox before test results were completed. RESULTS: Varicella seroprevalence ranged from 9% among 7-year-olds whose parents said they had definitely not had chickenpox to 68% among 11-year-olds whose parents were not sure whether they had had chickenpox. Among children whose parents were uncertain about their chickenpox history, almost one-half (48%) were seropositive. Twenty-five percent of children whose parents said they definitely had not and 32% of children whose parents said they had probably not had chickenpox were seropositive. Of parents whose children had experienced serotesting, 73% said they would prefer to have the blood test first rather than presumptive vaccination. For a large health maintenance organization, it was projected to be most cost-effective (in terms of cost per chickenpox case prevented) to recommend testing for children 9 to 12 years old with uncertain histories of chickenpox. CONCLUSIONS: We conclude that among children 7 to 12 years old with negative or uncertain histories of chickenpox, varicella seroprevalence ranges from 9 to 68% depending on age and clinical history. Parents are generally receptive to serotesting, although individual preferences vary. In the population we studied it would be most cost-effective to recommend testing before deciding about vaccination for children 9 to 12 years old with uncertain histories of chickenpox.

Chickenpox↗
PubMed1998

Inhibitory effect of amiloride on the urokinase plasminogen activators in prostatic cancer.

The diuretic drug amiloride (AMLD), which competitively inhibits the catalytic activity of urokinase plasminogen activators (UPA), was used to study its effects on the proteolytic enzymes implicated in the invasiveness and metastases in a prostatic tumor model carrying two different sublines of adenocarcinoma of the prostate. Our data showed that UPA activity was significantly higher, both in the cytosol and pellet of R3327-AT3, a fast-growing highly metastatic and androgen-insensitive tumor, as compared to the G3327-G subline, a slow-growing nonmetastatic tumor of the prostate. The UPA activity in AT3 tumor dropped when the rats were treated with AMLD for 3 weeks. The UPA activity in the sera and tumor effusions from rats with AT3 tumor was significantly higher as compared to those with G subline tumor. The number of pulmonary metastatic foci was the same in untreated rats as compared to those treated with AMLD. The lymph node inspection after 3 weeks revealed no secondary tumor in the AMLD-treated group. The role of UPA in the metastases of prostate cancer is discussed.

Adenocarcinoma↗
PubMed1998

AIDS-related primary pulmonary lymphoma.

We describe 12 cases of AIDS-related primary pulmonary lymphoma occurring between 1986 and 1996 in a large French cohort of HIV-infected patients. Diagnostic criteria were: (1) histologically proven lymphomatous pulmonary involvement; (2) absence of mediastinal and/or hilar adenopathy on chest radiography; (3) absence of extrathoracic lymphoma extension. All patients were severely immunodeficient at the time of diagnosis. All but one patient presented with B and/or nonspecific respiratory symptoms. Chest radiography showed one or more marginated nodule(s) or large mass. CT scan showed a cavitary lesion in five patients. No lymph node enlargement or specific pleural effusion was detected. Transthoracic needle biopsies were performed in 10 patients and avoided open-lung biopsy for the diagnosis of lymphoma in five patients. All but one of the primary pulmonary lymphoma were high-grade B-cell non-Hodgkin's lymphomas. Using antilatent membrane protein-1 antibodies and an Epstein-Barr-Virus-encoded RNA transcript-specific probe, latent EBV infection of tumor cells was demonstrated in every case. All but one of the patients received chemotherapy. The median survival time was 4 mo, and no patient was still alive at the cut-off date for this analysis. Progessive pulmonary lymphoma was the main cause of death, but infections were also frequent.

AIDS-Related Opportunistic Infections↗
PubMed1998

Protease in normal human epidermal keratinocytes.

An in vitro normal human epidermal keratinocytes (NHEK) model was used to study and to characterize the protease stimulated by the mustards 2-chloroethyl ethyl sulphide (CEES), 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (nitrogen mustard, HN2), and Bis-2-chloroethyl sulfide (sulfur mustard, HD). The results obtained by using a chromozym (TRY) peptide substrate protease assay showed the optimum mustard concentration and time for protease stimulation to be about 200 microM CEES, 100 microM HN2 or HD, and 16 hours. The mustard-stimulated protease was membrane-bound, and was inhibited by adding a Ca2+ chelator EGTA (2 mM), BAPTA AM (50 microM) or a serine protease inhibitor diisopropyl fluoro-phosphate DFP (1 mM), or a protein synthesis inhibitor cycloheximide (10 microM) in the extracellular medium. These results suggest that one of the mechanisms of mustard toxicity is via the stimulation of a trypsin/chymotrypsin like serine protease, which is dependent on Ca2+ and new protein synthesis. Sodium dodecyl sulfate polyacrylamide gel electrophoresis revealed a mustard-stimulated approximately equal to 70-80 KDa protein band that was associated with protease activity which was inhibitable by EGTA, BAPTA, DFP or cycloheximide. This mustard-stimulated protein (protease) may serve as a diagnostic tool for mustard exposure as well as an assay for screening prospective antivesicant protease inhibitor drugs.

Cells, Cultured↗
PubMed1998

Race and serum prostate-specific antigen levels: current status and future directions.

Prostate cancer (PC) is a serious public health problem in the United States, especially in African-American men (AAs). AAs have higher incidence and mortality rates and present with higher stage and grade of PC than other racial/ethnic groups. Given the importance of serum prostate-specific antigen level (PSA) as a screening tool for PC and its prognostic value among patients with PC, exploring the relationship between PSA and race has gained enormous interest lately. The number of studies addressing such relationships has increased tremendously over the past few years. Most of these studies indicate a higher PSA in AAs than whites in men with or without PC even after adjustment for patients' age and prostate volume (in men without PC) and for PC grade and stage (in men with PC). The etiology of higher PSA levels in AAs is not completely understood and might be secondary to biological, environmental/socioeconomic reasons, or both. Studying serum PSA dynamics among AAs may help in elucidating the epidemiological features of PC in AAs.

Biomarkers, Tumor↗
PubMed1997

Regulated overexpression of interleukin 11 in the lung. Use to dissociate development-dependent and -independent phenotypes.

Standard overexpression transgenic approaches are limited in their ability to model waxing and waning diseases and frequently superimpose development-dependent and -independent phenotypic manifestations. We used the clara cell 10-kD protein (CC10) promoter and the reverse tetracycline transactivator (rtTA) to create a lung-specific, externally regulatable, overexpression transgenic system and used this system to express human interleukin 11 (IL-11) in respiratory structures. Gene induction could be achieved in utero, in neonates and in adult animals. Moreover, gene expression could be turned off by removal of the inducing stimulus. When gene activation was initiated in utero and continued into adulthood, subepithelial airway fibrosis, peribronchiolar mononuclear nodules, and alveolar enlargement (emphysema) were noted. Induction in the mature lung caused airway remodeling and peribronchiolar nodules, but alveolar enlargement was not appreciated. In contrast, induction in utero and during the first 14 d of life caused alveolar enlargement without airway remodeling or peribronchiolar nodules. Thus, IL-11 overexpression causes abnormalities that are dependent (large alveoli) and independent (airway remodeling, peribronchiolar nodules) of lung growth and development, and the CC10-rtTA system can be used to differentiate among these effector functions. The CC10-rtTA transgenic system can be used to model waxing and waning, childhood and growth and development-related biologic processes with enhanced fidelity.

Aging↗
PubMed1997

Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene.

Interleukin-5 (IL-5), which is produced by CD4(+) T helper 2 (Th2) cells, but not by Th1 cells, plays a key role in the development of eosinophilia in asthma. Despite increasing evidence that the outcome of many diseases is determined by the ratio of the two subsets of CD4(+) T helper cells, Th1 and Th2, the molecular basis for Th1- and Th2-specific gene expression remains to be elucidated. We previously established a critical role for the transcription factor GATA-3 in IL-5 promoter activation in EL-4 cells, which express both Th1- and Th2-type cytokines. Our studies reported here demonstrate that GATA-3 is critical for expression of the IL-5 gene in bona fide Th2 cells. Whereas mutations in the GATA-3 site abolished antigen- or cAMP-stimulated IL-5 promoter activation in Th2 cells, ectopic expression of GATA-3 in Th1 cells or in a non-lymphoid, non-IL-5-producing cell line activated the IL-5 promoter. During the differentiation of naive CD4(+) T cells isolated from T cell receptor transgenic mice, GATA-3 gene expression was up-regulated in developing Th2 cells, but was down-regulated in Th1 cells, and antigen- or cAMP-activated Th2 cells (but not Th1 cells) expressed the GATA-3 protein. Thus, GATA-3 may play an important role in the balance between Th1 and Th2 subsets in immune responses. Inhibition of GATA-3 activity has therapeutic potential in the treatment of asthma and other hypereosinophilic diseases.

Animals↗