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PubMed1991

VP4-specific intestinal antibody response to rotavirus in a murine model of heterotypic infection.

We have adapted a murine model of heterotypic rotavirus infection for the purpose of evaluating the intestinal antibody response to an infection that mimics human vaccination. Neonatal mice were infected with the rhesus rotavirus (RRV). The enzyme-linked immunospot assay was used in order to avoid common artifacts in the quantitation of intestinal immune responses inherent in measurements of luminal or serum immunoglobulins and to obtain easily quantifiable data in a flexible and convenient format. Functionally active lymphocytes were harvested from the spleen, small intestinal lamina propria, Peyer's patches, and mesenteric lymph nodes and processed into single-cell suspensions. Antibody-secreting cells (ASC) were quantitated from 5 to 50 days after infection for total, RRV-specific, baculovirus-expressed VP4-specific, and single-shell RRV-specific ASC secreting either immunoglobulin G (IgG), IgM, or IgA. The response to VP4 constituted less than 1.5% of the total virus-specific response, which was located almost exclusively in the gut and was 90% IgA. Intestinal ASC were directed overwhelmingly toward proteins incorporated in the single-shell particle, predominantly VP2 and VP6. We conclude that the antibody response to VP4, thought to be the site of the important neutralization sites conserved among several rotavirus serotypes, is an extremely small portion of the overall antibody response in the intestinal tract.

Animals↗

PubMed1996

Role of different lymphoid tissues in the initiation and maintenance of DNA-raised antibody responses to the influenza virus H1 glycoprotein.

Antibody responses in mice immunized by a single gene gun inoculation of plasmid expressing the influenza virus H1 hemagglutinin and in mice immunized by a sublethal H1 influenza virus infection have been compared. Both immunizations raised long-lived serum responses that were associated with the localization of antibody-secreting cells (ASC) to the bone marrow. However, the kinetics of these responses were 4 to 8 weeks slower in the DNA-immunized than in the infection-primed mice. Following a gene gun booster, the presence of ASC in the inguinal lymph nodes, but not in other lymph nodes, revealed gene gun responses being initiated in the nodes that drain the skin target site. Both pre- and postchallenge, the DNA-immunized mice had 5- to 10-times-lower levels of antibody and ASC than the infection-primed mice.

Animals↗

PubMed2001

Protective immunity and antibody-secreting cell responses elicited by combined oral attenuated Wa human rotavirus and intranasal Wa 2/6-VLPs with mutant Escherichia coli heat-labile toxin in gnotobiotic pigs.

Two combined rotavirus vaccination regimens were evaluated in a gnotobiotic pig model of rotavirus infection and disease and were compared to previously tested rotavirus vaccination regimens. The first (AttHRV/VLP2x) involved oral inoculation with one dose of attenuated (Att) Wa human rotavirus (HRV), followed by two intranasal (i.n.) doses of a rotavirus-like particle (2/6-VLPs) vaccine derived from Wa (VP6) and bovine RF (VP2) rotavirus strains. The 2/6-VLPs were coadministered with a mutant Escherichia coli heat-labile toxin, LT-R192G (mLT) adjuvant. For the second regimen (VLP2x/AttHRV), two i.n. doses of 2/6-VLPs+mLT were given, followed by one oral dose of attenuated Wa HRV. To compare the protective efficacy and immune responses induced by the combined vaccine regimens with individual rotavirus vaccine regimens, we included in the experiments the following vaccine groups: one oral dose of attenuated Wa HRV (AttHRV1x and Mock2x/AttHRV, respectively), three oral doses of attenuated Wa HRV (AttHRV3x), three i.n. doses of 2/6-VLPs plus mLT (VLP3x), three i.n. doses of purified double-layered inactivated Wa HRV plus mLT (InactHRV3x), mLT alone, and mock-inoculated pigs. The isotype, magnitude, and tissue distribution of antibody-secreting cells (ASCs) in the intestinal and systemic lymphoid tissues were evaluated using an enzyme-linked immunospot assay. The AttHRV/VLP2x regimen stimulated the highest mean numbers of intestinal immunoglobulin A (IgA) ASCs prechallenge among all vaccine groups. This regimen induced partial protection against virus shedding (58%) and diarrhea (44%) upon challenge of pigs with virulent Wa HRV. The reverse VLP2x/AttHRV regimen was less efficacious than the AttHRV/VLP2x regimen in inducing IgA ASC responses and protection against diarrhea (25% protection rate) but was more efficacious than VLP3x or InactHRV3x (no protection). In conclusion, the AttHRV/VLP2x vaccination regimen stimulated the strongest B-cell responses in the intestinal mucosal immune system at challenge and conferred a moderately high protection rate against rotavirus disease, indicating that priming of the mucosal inductive site at the portal of natural infection with a replicating vaccine, followed by boosting with a nonreplicating vaccine at a second mucosal inductive site, may be a highly effective approach to stimulate the mucosal immune system and induce protective immunity against various mucosal pathogens.

Adjuvants, Immunologic↗

PubMed2002

Novel transcription coactivator complex containing activating signal cointegrator 1.

Human activating signal cointegrator 1 (hASC-1) was originally isolated as a transcriptional coactivator of nuclear receptors. Here we report that ASC-1 exists as a steady-state complex associated with three polypeptides, P200, P100, and P50, in HeLa nuclei; stimulates transactivation by serum response factor (SRF), activating protein 1 (AP-1), and nuclear factor kappaB (NF-kappaB) through direct binding to SRF, c-Jun, p50, and p65; and relieves the previously described transrepression between nuclear receptors and either AP-1 or NF-kappaB. Interestingly, ectopic expression of Caenorhabditis elegans ASC-1 (ceASC-1), an ASC-1 homologue that binds P200 and P100, like hASC-1, while weakly interacting only with p65, in HeLa cells appears to replace endogenous hASC-1 from the hASC-1 complex and exerts potent dominant-negative effects on AP-1, NF-kappaB, and SRF transactivation. In addition, neutralization of endogenous P50 by single-cell microinjection of a P50 antibody inhibits AP-1 transactivation; the inhibition is relieved by coexpression of wild-type P50, but not of P50DeltaKH, a mutant form that does not interact with P200. Overall, these results suggest that the endogenous hASC-1 complex appears to play an essential role in AP-1, SRF, and NF-kappaB transactivation and to mediate the transrepression between nuclear receptors and either AP-1 or NF-kappaB in vivo.

Amino Acid Sequence↗

PubMed2003

Activating signal cointegrator 2 belongs to a novel steady-state complex that contains a subset of trithorax group proteins.

Many transcription coactivators interact with nuclear receptors in a ligand- and C-terminal transactivation function (AF2)-dependent manner. These include activating signal cointegrator 2 (ASC-2), a recently isolated transcriptional coactivator molecule, which is amplified in human cancers and stimulates transactivation by nuclear receptors and numerous other transcription factors. In this report, we show that ASC-2 belongs to a steady-state complex of approximately 2 MDa (ASC-2 complex [ASCOM]) in HeLa nuclei. ASCOM contains retinoblastoma-binding protein RBQ-3, alpha/beta-tubulins, and trithorax group proteins ALR-1, ALR-2, HALR, and ASH2. In particular, ALR-1/2 and HALR contain a highly conserved 130- to 140-amino-acid motif termed the SET domain, which was recently implicated in histone H3 lysine-specific methylation activities. Indeed, recombinant ALR-1, HALR, and immunopurified ASCOM exhibit very weak but specific H3-lysine 4 methylation activities in vitro, and transactivation by retinoic acid receptor appears to involve ligand-dependent recruitment of ASCOM and subsequent transient H3-lysine 4 methylation of the promoter region in vivo. Thus, ASCOM may represent a distinct coactivator complex of nuclear receptors. Further characterization of ASCOM will lead to a better understanding of how nuclear receptors and other transcription factors mediate transcriptional activation.

Amino Acid Motifs↗

PubMed1993

Characterization of amino acid transport in human endothelial cells.

The transport of amino acids has been studied in human umbilical vein endothelial cells. Neutral amino acids enter human umbilical vein endothelial cells through three distinct agencies endowed with the characteristics of systems A, ASC, and L. Each system has been studied by evaluating the influx of preferential substrates. The influx of L-proline and 2-methylaminoisobutyric acid occurs through an Na(+)-dependent adaptively regulated trans-inhibited agency identifiable with system A. L-Threonine influx occurs mainly through a distinct Na(+)-dependent trans-stimulated pathway corresponding to system ASC. System L accounts for Na(+)-independent influx of L-leucine. These systems cooperate for the transport of L-glutamine, which is due mainly to system ASC, whereas the component due to the operation of system A increases upon amino acid starvation. No clear evidence was found for a glutamine-specific system ("system N"). Two systems, one Na+ dependent (system XAG-) and the other Na+ independent (system xc-), transport anionic amino acids. L-Arginine influx exhibits a poor dependence on extracellular Na+, whereas it is sensitive to conditions known to change membrane potential and to trans-stimulation by intracellular amino acids. These features are consistent with a process mediated by system y+ and may be of significance for the regulation of the intracellular concentration of L-arginine.

Amino Acids↗

PubMed2006

Tumor suppressor BRCA1 inhibits a breast cancer-associated promoter of the aromatase gene (CYP19) in human adipose stromal cells.

Adipose tissue provides an important extragonadal source of estrogen. Obesity-associated elevation of estrogen production increases risk of breast cancer in postmenopausal women. Aromatase (CYP19), which converts androgen to estrogen, is a key enzyme in estrogen biosynthesis. In normal adipose tissue, transcription of the aromatase gene is initiated from a relatively weak adipose-specific promoter (I.4). However, in breast cancer, a switch of promoter utilization from I.4 to a strong ovary-specific promoter, PII, leads to increased aromatase expression and, hence, elevated estrogen production. Here, we report an intriguing relationship between the breast cancer susceptibility gene BRCA1 and aromatase expression in human adipose stromal cells (ASCs). Upon stimulation by phorbol ester or dexamethasone, increased aromatase expression in ASCs was accompanied by significant reduction of the BRCA1 level. In addition, adipogenesis-induced aromatase expression was also inversely correlated with BRCA1 abundance. Downregulation of BRCA1 expression in response to various stimuli was through distinct transcription or posttranscription mechanisms. Importantly, siRNA-mediated knockdown of BRCA1 led to specific activation of the breast cancer-associated PII promoter. Therefore, in addition to its well-characterized activities in breast epithelial cells, a role of BRCA1 in modulation of estrogen biosynthesis in ASCs may also contribute to its tissue-specific tumor suppressor function.

Adipose Tissue↗

PubMed1991

Neutral amino acid transport by isolated small intestinal cells from guinea pigs.

Neutral amino acid transport was examined by using isolated enterocytes. Cells transport L-alanine by at least three different mechanisms: two Na(+)-dependent systems (A and ASC) and one Na(+)-independent mechanism (system L), in addition to passive entry. System A was characterized acterized by measuring the Na(+)-dependent alpha-(methylamino)isobutyric acid (MeAIB) uptake. Na(+)-dependent MeAIB uptake was concentrative and saturable. Vmax was obtained at 80mM Na+ in the incubation medium and Kt app for Na+ was 21.5 mM. Kt app for MeAIB was 6.75 +/- 0.37 mM and the Vmax was 14.2 +/- 0.3 nmol.mg-1.min-1. System ASC was studied by evaluating the Na(+)-dependent L-alanine uptake, insensitive to MeAIB and inhibitable by L-serine and L-cysteine. Uptake by this mechanism was also concentrative and saturable. Maximal uptake was obtained with 80 mM Na+ in the incubation medium and Kt app for Na+ was 29.7 mM. Kt app for L-alanine was 7.02 +/- 0.61 mM and Vmax was 5.44 +/- 0.19 nmol.mg-1.min-1. The Na(+)-independent system L was studied by measuring cycloleucine uptake in Na(+)-free medium. It had a saturable and a nonsaturable component. Only the saturable component was concentrative; it was inhibited by 2-amino-2-norbornanecarboxylic acid and was capable of mediating exchange diffusion. Kt app for cycloleucine was 4.05 +/- 0.72 mM and the Vmax was 31.9 +/- 1.3 nmol.mg-1.min-1. These results confirm the existence of Na(+)-dependent systems A and ASC and Na(+)-independent system L in isolated enterocytes.

Alanine↗

PubMed1993

Pressure diuresis and natriuresis in cirrhotic rats.

Arterial hypotension in liver cirrhosis has been proposed as a major mechanism contributing to renal sodium and water retention. To evaluate kidney excretory responses at different levels of arterial pressure (AP), we have characterized the relationships between renal perfusion pressure (RPP) and sodium and water excretion in carbon tetrachloride cirrhotic rats. Experiments were performed in anesthetized control (n = 9) and cirrhotic rats with (Asc, n = 6) and without ascites (Cir, n = 6) by mechanically adjusting vascular resistance in animals with renal denervation and infused with main systemic hormones. Control and Cir animals showed similar glomerular filtration rates (GFR), renal blood flows, hematocrits (Hct), and plasma proteins (PP). However, Hct, PP, and GFR were significantly lower in the Asc rats. For the same level of RPP, both cirrhotic groups excreted significantly less water and sodium than controls. Then, the pressure diuresis and natriuresis relationships of the Cir animals were significantly depressed, but those of the Asc animals were more reduced than those of the Cir rats. These results indicate that the cirrhotic kidney is not able to normally increase the sodium and water excretion in response to changes in AP. Intrarenal mechanisms, and not mainly RPP, are likely mediators of the renal alterations of liver cirrhosis.

Animals↗

PubMed2003

Thymulin evokes IL-6-C/EBPbeta regenerative repair and TNF-alpha silencing during endotoxin exposure in fetal lung explants.

Chorioamnionitis is associated with increased risks of perinatal respiratory failure; however, components of the inflammatory acute-phase response are known to actively promote lung maturation. To manipulate this relationship, we examined the effect of the thymic immunomodulator thymulin on fetal lung mesenchyme-epithelial differentiation during exposure to Escherichia coli lipopolysaccharide (LPS). Gestation day 14 fetal rat lung explants were cultured for 96 h at fetal (23 mmHg) or ambient (142 mmHg) Po(2). Airway surface complexity (ASC, perimeter/ radical area(2)) was greater at fetal vs. ambient Po(2); however, exposure to 0.1-50 microg/ml LPS significantly raised ASC at 2 microg/ml in ambient Po(2) explants. LPS (50 microg/ml) depressed ASC in both conditions to untreated ambient Po(2) control values without changes in necrosis or apoptosis. To manipulate LPS-evoked TNF-alpha and IL-6 release, we exposed explants and A549 cells to combinations of 50 microg/ml LPS, 10 microM ZnCl(2), and 0.1-1,000 ng/ml thymulin at either Po(2). Thymulin+Zn(2+) suppressed and potentiated LPS-evoked TNF-alpha and IL-6 release, yielding an IC(50(TNF-alpha)) of 0.5 +/- 0.01 ng/ml and EC(50(IL-6)) of 1.4 +/- 0.3 ng/ml in A549 cells. This was accompanied by activation of the p38 MAPKMAPKAP-K2 pathway with sustained expression of TNF-alpha and IL-6 transcripts at ambient Po(2). LPS+thymulin+Zn(2+)-treated explants showed proliferation of CCAAT-enhancer binding protein-beta (C/EBPbeta) and fibroblast growth factor-9 immunoreactive mesenchyme, which was abolished by IL-6 antisense oligonucleotides. The posttranscriptional suppression of immunogenic TNF-alpha synthesis coupled with raised IL-6 and C/EBPbeta-dependent mesenchyme proliferation suggests a role for bioactive thymulin in regulating regenerative repair in the fetal lung.

Adenocarcinoma↗

PubMed2001

Hepatitis B virus genotype distribution among chronic hepatitis B virus carriers in Shanghai, China.

OBJECTIVE: Hepatitis B virus (HBV) genotype distribution is still unclear in China, where a high prevalence of HBV infection exists, although it is well known that HBV can be classified into six genotypes based on intergroup divergence. The aim of this study was to investigate the epidemiological distribution of HBV genotypes and to clarify further the genotype-related differences in the pathogenicity of HBV. METHODS: Seminested PCR and restriction fragment length polymorphism analysis were conducted in 97 asymptomatic HBV carriers (ASC) and 46 chronic hepatitis (CH), 37 liver cirrhosis (LC) and 44 hepatocellular carcinoma (HCC) patients in Shanghai, China. RESULTS: Two hundred and twenty samples (98.2%) were positive for HBV DNA, and of these, 3 (1.4%), 38 (17.2%) and 179 (81.4%) were classified as genotype A, B and C, respectively. There was a statistically significant difference in the distribution of genotypes B and C among various categories of liver diseases (p < 0.01). The distribution of genotype C showed an increasing trend from ASC, CH and LC to the HCC group; in contrast, the distribution of genotype B showed a decreasing trend in the same order. HBeAg positivity was higher in genotype C than in genotype B in all the subjects or in the ASC group alone (p < 0.05, p < 0.01, respectively). More severe liver damage and a higher mean age were observed in genotype C than in genotype B (p < 0.01, p < 0.05, respectively). CONCLUSIONS: These results indicate the following: (1) genotypes A, B and C of HBV exist in Shanghai, China; (2) genotype C is the major genotype in this area; (3) genotype C is associated with the development of severe liver diseases, and (4) genotype B has a relatively good prognosis.

Adolescent↗

PubMed2006

Sequential accumulation of the basal core promoter and the precore mutations in the progression of hepatitis B virus-related chronic liver disease.

OBJECTIVES: Despite the pathogenic role of the basal core promoter (BCP) and the precore mutations in chronic hepatitis B virus (HBV) infection, their role in the progression of liver disease is still controversial. We analyzed whether the accumulation of these mutations might enhance the progression of HBV-related chronic liver disease. METHODS: Forty consecutive patients at each clinical status were analyzed. Clinical statuses were as follows: HBeAg-positive asymptomatic carrier (HBeAg(+) ASC) (defined as HBeAg(+), anti-HBe(-), HBV-DNA(+) by hybridization, normal ALT); inactive HBsAg carrier; chronic hepatitis B; liver cirrhosis. The genotype and the BCP/precore regions were determined by PCR using genotype specific primers and direct sequencing, respectively. RESULTS: All patients except one were infected with genotype C. The A to T mutation at nucleotide 1762 and/or G to A mutation at nucleotide 1764 were found in 30% in HBeAg(+) ASC, 65.7% in inactive HBsAg carrier, 95% in chronic hepatitis B, and 90% in liver cirrhosis (p < 0.001). The prevalence of the G to A mutation at nucleotide 1896 was 5% in HBeAg(+) ASC, 22.5% in inactive HBsAg carrier, 32.5% in chronic hepatitis B, and 50% in liver cirrhosis, respectively (p < 0.001). The T to C/A mutation at nucleotide 1753 in the BCP and G to A mutation at nucleotide 1899 in the precore were more frequent in liver cirrhosis than in the other clinical statuses (p < 0.05). CONCLUSION: Sequential accumulation of mutations in the BCP/precore has an important role in the progression of HBV-related liver disease.

Adult↗

PubMed1979

Further studies on the adjuvant effect of silica on IgE antibody production in mice.

The effects of amorphous silica (Aerosil) and of aluminium hydroxide on anti-DNP IgE antibody production were studied in Swiss mice preimmunized with Ascaris protein and then challenged 7 days later with DNP-ASC. Aerosil exerted an adjuvant effect especially when it was injected together with the DNP-ASC conjugate. Al(OH)3 had a weaker adjuvant effect than that produced by Aerosil and then only when it was injected with the DNP-ASC conjugate. Al(OH)3 given with Ascaris extract 7 days before complete antigen had an inhibitory effect on the anti-DNP IgE antibody production.

Adjuvants, Immunologic↗

PubMed1987

Inhibitory immunization using complete Freund's adjuvant on ongoing eosinophilia induced by repeated antigen-stimulations in guinea pigs.

Ongoing eosinophilia, in guinea pigs repeatedly sensitized with dinitrophenylated (DNP)-Ascaris antigen (DNP-Asc) into the peritoneal cavity, was suppressed significantly by complementary immunizations with a heterologous antigen, e.g., ovalbumin (OA) or bovine gamma-globulin (BGG) emulsified in complete Freund's adjuvant (CFA). Challenge injections of DNP-OA or DNP-BGG elicited peritoneal eosinophilia in animals that were sensitized repeatedly with DNP-Asc. Under these conditions, antigen specificity in suppressive immunization was studied. Eosinophilia, induced by DNP-OA challenge, was suppressed by immunization with either OA in CFA or BGG in CFA. However, Asc (homologous carrier of sensitizing antigen) elicited no suppression. Additionally, CFA, used as an adjuvant, played an important role in suppressive immunization, but CFA alone had no effect in suppressing peritoneal eosinophilia. Anti-DNP antibody, detected by hemagglutination test or passive cutaneous anaphylaxis, was not affected by complementary immunization. These results suggested that peritoneal eosinophilia was suppressed concomitantly by a supplemental immunization in an antigen-nonspecific manner. Eosinophilia in the bone marrow also was suppressed significantly by complementary immunization, but the pattern was quite different from that shown in the peritoneal cavity. The first nuclear cell response peak after challenging, including eosinophils, was stanched completely by CFA itself. The second nuclear cell peak, on day 5, recovered, but eosinophil response continued to be suppressed.

Animals↗

PubMed1992

L-ascorbic acid 2-phosphate enhances the production of type I and type III collagen peptides in cultured rabbit keratocytes.

We studied the effect of L-ascorbic acid 2-phosphate (P-Asc), a long-acting phosphate derivative of L-ascorbic acid, on the production and secretion of type I and type III collagen peptides in cultured rabbit keratocytes using immunohistochemistry and enzyme immunoassay. P-Asc enhanced production and secretion of these collagen peptides. Our observations support a therapeutic role for P-Asc in the repair of corneal stromal damage such as caused by corneal chemical burn.

Animals↗

PubMed1978

'Positive and 'negative' aspects of the 'altered states of consciousness' induced by autogenic training, Zen and yoga.

As practices of altered states of consciousness (ASC) have become more widely used among psychotherapists who have become aware of the limitations of psychoanalytic, educational and behavioral approaches, negative aspects ('Makyo') of ASC have drawn their special attention. For the purpose of controlling or preventing these side-effects, (1) the problem of indication is most important, (2) and evaluation of the patient's personality is indispensable, (3) preparatory education about ASC methods and (4) guidance by experienced leaders are most helpful, (5) appropriate use of tranquilizers and (6) the mere presence of a supportive therapist at the place of practice can also be helpful.

Autogenic Training↗

PubMedDate not supplied

Human papillomavirus testing with a liquid-based system: feasibility and comparison with reference diagnoses.

OBJECTIVE: To validate the utilization of cervical specimens collected in the fixative liquid used in the CYTO-screen System (SEROA, Monaco) for oncogenic human papillomavirus (HPV) DNA detection by the Hybrid Capture II technique (HCII) (Digene, Gaithersburg, Maryland, U.S.A) by reference to cytologic and/or histologic results. STUDY DESIGN: A technical feasibility study was conducted on 3 modalities of sample preparation before HCII technique, 1 with a proteinase digestion, I with PBS washing and I using the Digene sample conversion kit recommended for ThinPrep medium preparation (Cytyc Corp., Boxborough, Massachusetts, U.S.A.). The stability of cells after storage at days 28, 60 and 90 was tested on 26 positive samples (13 with high initial indices and 13 with low initial indices). Results of HPV testing were compared to cytologic and histologic results on a sample of 98 smears already identified as high grade squamous intraepithelial lesion (HSIL) (48) or low grade squamous intraepithelial lesion (LSIL) (50). A retrospective analysis was then performed on 995 HPV tests perfornmed routinely in 2003 in terms of comparison with the corresponding cytologic and/or histologic results. RESULTS: The HCII technique after direct treatment by proteinase K appeared to be as effective as the Digene sample conversion kit. By using the first technique, all 26 positive cases remained positive at 60 days, but 4 of 13 (30%) with low indices became negative at 90 days. The sensitivity of HPV testing for detecting biopsy- proven cervical intraepithelial neoplasia (CIN) 2 or worse was 100% in the 50 LSIL and 98% in the 48 HSIL samples. In the retrospective study (n = 995), the cytologic diagnoses of atypical squamous cells of undetermined significance (ASC-US) (n=278), LSIL (n = 137) and HSIL (n = 28) were associated with a positive HPVtest in 44%, 75% and 96% of cases, respectively. On a subsample of 156 patients among 278 with a diagnosis of ASC- US, the sensitivity of HPV testingfor detecting CIN 2 or worse was 88%, specificity 57%, positive predictive value 10% and negative predictive value 99%. Performing HPV testing by the HCII technique for cervical specimens collected in the fixative liquid used in the CYTO-screen System is feasible in the context of an ASC-US cytologic diagnosis.

Adolescent↗

PubMed2003

A role for CD44 in an antigen-induced murine model of pulmonary eosinophilia.

Previous studies established that IL-5-producing CD4(+) T cells play a pivotal role in allergic respiratory inflammation. It was also reported that CD4(+) T cells express higher levels of CD44 in the airway than in peripheral blood of patients with allergic respiratory diseases. We have used experimental pulmonary eosinophilia induced in mice by Ascaris suum (Asc) extract to investigate the role of CD44 in the development of allergic respiratory inflammation. Intraperitoneal administration of anti-CD44 mAb prevented both lymphocyte and eosinophil accumulation in the lung. Anti-CD44 mAb also blocked antigen-induced elevation of Th2 cytokines as well as chemokines (CCL11, CCL17) in bronchoalveolar lavage fluid (BALF). Treatment with anti-CD44 mAb inhibited the increased levels of hyaluronic acid (HA) and leukotriene concentrations in BALF that typically result from antigen challenge. Anti-CD44 mAb also blocked antigen-induced airway hyperresponsiveness. An anti-CD44 mAb (IM7) inhibited the HA-binding ability of splenocytes associated with decreased levels of CD44. Soluble CD44 levels in serum were increased in Asc-challenged IM7-treated mice, but not in KM201-treated mice, compared with Asc-challenged rat IgG-treated mice. Ab's that block CD44-HA binding reduced allergic respiratory inflammation by preventing lymphocyte and eosinophil accumulation in the lung. Thus, CD44 may be critical for development of allergic respiratory inflammation.

Animals↗