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Biomedical subjects

B Arnold

Publications and source records attributed to B Arnold.

At least 37 records · Page 2Linked to original sources
PubMed2000

Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance.

Myeloid antigen-presenting cells (APC) are known to cross-present exogenous antigen on major histocompatibility class I molecules to CD8+ T cells and thereby induce protective immunity against infecting microorganisms. Here we report that liver sinusoidal endothelial cells (LSEC) are organ-resident, non-myeloid APC capable of cross-presenting soluble exogenous antigen to CD8+ T cells. Though LSEC employ similar molecular mechanisms for cross-presentation as dendritic cells, the outcome of cross-presentation by LSEC is CD8+ T cell tolerance rather than immunity. As uptake of circulating antigens into LSEC occurs efficiently in vivo, it is likely that cross-presentation by LSEC contributes to CD8+ T cell tolerance observed in situations where soluble antigen is present in the circulation.

Animals↗
PubMed2000

[Use of auditory field measurement in patients with otosclerosis].

BACKGROUND: Middle ear surgery sometimes leads to unpleasant auditory impressions such as distortion or hyperacusis that cannot be detected by conventional audiometric testing. METHOD: Sixty-one patients with conductive hearing loss caused by otosclerosis underwent audiological evaluation, which included a questionnaire followed by testing of the audiometric threshold, speech audiometry, and assessment and quantification of loudness perception with a commercial system (WESTRA). This investigation includes the postoperative measurement of hearing improvement and the patients' subjective impressions regarding hearing increase, distortion of speech, and hyperacusis. RESULTS: Hearing improved in 88% of the patients. A quantification of this hearing increase was possible with pure tone audiometry and the Freiburg speech discrimination test. Reduced hearing threshold and lack of improvement in speech discrimination was confirmed by conventional hearing measurements. However, the presence of hyperacusis and distortion of speech could be determined by conventional audiometry in only 50% of cases. It was interesting to note that the subjects who reported speech distortion and hyperacusis in the questionnaire were identified by their increased loudness perception using the categorical loudness scaling. CONCLUSION: Category loudness scaling appears to be a valuable additional clinical test to characterize postoperative phenomena as distortion of speech and hyperacusis in patients undergoing stapes surgery.

Adult↗
PubMed2000

In vivo neutrophil recruitment by granulocyte chemotactic protein-2 is assisted by gelatinase B/MMP-9 in the mouse.

Granulocyte chemotactic protein-2 (GCP-2) of the mouse is a potent neutrophil chemotactic and activating factor in vitro and in vivo. Gelatinase B/matrix metalloproteinase-9 is released from neutrophils within 1 h after stimulation with GCP-2. In vitro neutrophil chemotaxis by GCP-2 was not impaired by specific inhibitory monoclonal antibodies (mAb) against gelatinase B, indicating that gelatinase B is not involved in chemotaxis of neutrophils through polycarbonate filters. To investigate if gelatinase B degranulation is involved in in vivo cell migration toward GCP-2, experiments were performed with gelatinase B knockout mice. When mouse GCP-2 was injected intradermally in mice, a dose-dependent neutrophil chemotactic response was observed, and this cell migration was significantly impaired in young mice by genetic gelatinase B knockout. In adult vs. young gelatinase B-deficient mice, such compensatory mechanisms as higher basal neutrophil counts and less impairment of chemotaxis toward local GCP-2 injection were observed. These experiments prove the concept that gelatinase B release under pressure of GCP-2 is a relevant, but not exclusive, effector mechanism of neutrophil chemotaxis in vivo and that known mechanisms, other than the release of gelatinase B, allow for a full-blown chemotactic response and compensate for gelatinase B deficiency in adult life in the mouse.

Aging↗
PubMed2000

In vitro and in vivo activities of SCH 56592 (posaconazole), a new triazole antifungal agent, against Aspergillus and Candida.

SCH 56592 (posaconazole), a new triazole antifungal agent, was tested in vitro, and its activity was compared to that of itraconazole against 39 Aspergillus strains and to that of fluconazole against 275 Candida and 9 Cryptococcus strains. The SCH 56592 MICs for Aspergillus ranged from </=0.002 to 0.5 microg/ml, and those of itraconazole ranged from </=0.008 to 1 microg/ml. The SCH 56592 MICs for Candida and Cryptococcus strains ranged from </=0. 004 to 16 microg/ml, and those of fluconazole ranged from </=0.062 to >64 microg/ml. SCH 56592 showed excellent activity against Aspergillus fumigatus and Aspergillus flavus in a pulmonary mouse infection model. When administered therapeutically, the 50% protective doses (PD(50)s) of SCH 56592 ranged from 3.6 to 29.9 mg/kg of body weight, while the PD(50)s of SCH 56592 administered prophylactically ranged from 0.9 to 9.0 mg/kg; itraconazole administered prophylactically was ineffective (PD(50)s, >75 mg/kg). SCH 56592 was also very efficacious against fluconazole-susceptible, -susceptible dose-dependent, or -resistant Candida albicans strains in immunocompetent or immunocompromised mouse models of systemic infection. The PD(50)s of SCH 56592 administered therapeutically ranged from 0.04 to 15.6 mg/kg, while the PD(50)s of SCH 56592 administered prophylactically ranged from 1.5 to 19.4 mg/kg. SCH 56592 has excellent potential for therapy against serious Aspergillus or Candida infections.

Animals↗
PubMed1999

Selection of phenotypically distinct NK1.1+ T cells upon antigen expression in the thymus or in the liver.

Unlike the main TCR alphabeta T cell lineage in which deletion occurs at the CD4+ CD8+ double-positive (DP) stage upon TCR engagement by antigen in the thymus, some T cells appear to require such engagement for their selection, either in the thymus or extrathymically. We used a transgenic TCR (tgTCR) model which, as we previously showed, led to selection upon expression of the corresponding antigen H-2Kb (Kb) in the thymus, of tgTCR/CD3(lo) CD4- CD8- double-negative (DN) thymocytes that expressed the NK1.1 marker (NK T cells) (Curnow, S. J., et al., Immunity 1995. 3: 427). We now report that antigen expression on medullary epithelial cells of the thymus failed to select the NK T cells, whereas its expression on thymocytes did, although tgTCR DP thymocyte development was affected under both conditions. Antigen expression on hepatocytes (Alb-Kb mice) did not perturb tgTCR DP thymocyte development. No enrichment in tgTCR NK T cells was detected in the periphery, except for the liver of the Alb-Kb/tgTCR mice. When reconstitution of thymectomized and irradiated H-2k hosts expressing or not Kb was performed with bone marrow from tgTCR H-2k mice, an enrichment in tgTCR+ NK T cells was found in the liver, but not in the spleen, of the hosts which expressed Kb, either selectively on hepatocytes or ubiquitously. Surprisingly, the majority of the hepatic tgTCR+ NK T cells also expressed the CD8 alpha/beta heterodimer. These results indicate that thymus-independent NK T cells with unique phenotypic characteristics can be selected upon antigen encounter in the liver.

Animals↗
PubMed1999

Peripheral T-cell tolerance: the contribution of permissive T-cell migration into parenchymal tissues of the neonate.

T lymphocytes with self-destructive capacity are often found in healthy individuals, indicating efficient control mechanisms that prevent chronic autoimmune diseases. Since naive T lymphocytes do not circulate through extralymphoid tissues the concept has emerged that peripheral T cells ignore tissue-specific antigens unless they are presented by professional antigen-presenting cells in the lymphoid compartments. However, this view pays attention only to experiments performed in adult animals. This report reviews the evidence that tissues of neonatal mice, in contrast to adults, exhibit high accessibility for naive T cells, thereby allowing the direct contact with tissue-specific self-antigens on parenchymal cells during neonatal life and tolerance induction to such self-antigens. In mouse bone marrow chimeras generated at different ages, recent thymic emigrants were tolerized to a major histocompatibility class I antigen expressed on keratinocytes only during a neonatal period and not during adulthood. Blockade of T-cell migration neonatally prevented tolerance induction. The neonatally induced tolerance is maintained during adulthood, apparently by a dominant regulatory mechanism. Thus, parenchymal cells and T-cell migration in the neonate contribute to the control of autoreactive T cells.

Animals↗
PubMed1999

Autoaggression and tumor rejection: it takes more than self-specific T-cell activation.

Establishment of self-tolerance prevents autoaggression against organ-specific self-antigens. This beneficial effect, however, may in turn be responsible for tumor immune evasion. Thus, dissecting the mechanisms leading to the breakdown of self-tolerance in autoimmune diseases might provide insights for successful antitumor immune therapies. In a variety of animal models, organ- or tumor-specific immunity has been described, focusing on antigen-specific T-cell activation. Here, we discuss two transgenic mouse models which demonstrate that both autoaggression and tumor rejection require more than activated, self-reactive T cells. TCR transgenic mice, which are tolerant to a liver-specific MHC class I antigen, Kb, can be activated to reject Kb-positive grafts, but fail to attack Kb-expressing liver. However, autoaggression occurs when activated T cells are combined with "conditioning" of the target organ by irradiation or infection with a liver-specific pathogen. Similarly, in a mouse model of islet cell carcinoma, neither co-stimulatory tumor cells nor highly activated antitumor lymphocytes provoke an effective immune response against the tumor. Instead, a combination of activated lymphocytes and irradiation is required for lymphocyte infiltration into solid tumors. Both model systems provide evidence that although activated antigen-specific lymphocytes are a prerequisite for autoaggression, effector cell extravasation and appropriate interaction with the target organ/tumor are equally important. Thus, we propose that the organ/tumor microenvironment is a critical parameter in determining the effectiveness of an anti-self immune response.

Adenoma, Islet Cell↗
PubMed1999

Resistance of young gelatinase B-deficient mice to experimental autoimmune encephalomyelitis and necrotizing tail lesions.

Regulated expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) plays a role in various physiological processes. To determine in vivo how unbalanced expression of these factors can promote or affect the course of pathologies, we knocked out the mouse gelatinase B gene by replacing the catalytic and zinc-binding domains with an antisense-oriented neomycin resistance gene. Adult gelatinase B-deficient mice and wild-type controls could be induced to develop experimental autoimmune encephalomyelitis (EAE) with similar scores for neurologic disease, blood-brain barrier permeability, and central nervous system histopathology. However, whereas diseased control animals showed necrotizing tail lesions with hyperplasia of osteocartilaginous tissue, adult gelatinase B-deficient mice were resistant to this tail pathology. Gelatinase B-deficient mice younger than 4 weeks of age were significantly less susceptible to the development of EAE than were age matched controls and, even as they aged, they remained resistant to tail lesions. These data illustrate that gelatinase B expression plays a role in the development of the immune system and that, in ontogenesis, the propensity to develop autoimmunity is altered by the absence of this MMP.

Age Factors↗
PubMed1998

Control of neonatal tolerance to tissue antigens by peripheral T cell trafficking.

Self tolerance is acquired by the developing immune system. As reported here, particular properties of the neonatal tissue contribute to this process. Neonatal skin, but not adult skin, was accessible for naïve CD8 T cells. In mouse bone marrow chimeras generated at different ages, recent thymic emigrants were tolerized to a skin-expressed major histocompatibility complex class I antigen only during a neonatal period but not during adulthood. Blockade of T cell migration neonatally prevented tolerance induction. Thus, T cell trafficking through nonlymphoid tissues in the neonate is crucial for the establishment of self tolerance to sessile, skin-expressed antigens.

Animals↗
PubMed1998

Impaired fetal T cell development and perinatal lethality in mice lacking the cAMP response element binding protein.

CREB, the cAMP response element binding protein, is a key transcriptional regulator of a large number of genes containing a CRE consensus sequence in their upstream regulatory regions. Mice with a hypomorphic allele of CREB that leads to a loss of the CREBalpha and delta isoforms and to an overexpression of the CREBbeta isoform are viable. Herein we report the generation of CREB null mice, which have all functional isoforms (CREBalpha, beta, and delta) inactivated. In contrast to the CREBalpha delta mice, CREB null mice are smaller than their littermates and die immediately after birth from respiratory distress. In brain, a strong reduction in the corpus callosum and the anterior commissures is observed. Furthermore, CREB null mice have an impaired fetal T cell development of the alpha beta lineage, which is not affected in CREBalpha delta mice on embryonic day 18.5. Overall thymic cellularity in CREB null mice is severely reduced affecting all developmental stages of the alpha beta T cell lineage. In contrast gamma delta T cell differentiation is normal in CREB mutant mice.

Animals↗
PubMed1998

Failure to induce organ-specific autoimmunity by breaking of tolerance: importance of the microenvironment.

Peripheral tolerance is considered to be a safeguard against autoimmunity. Using a TCR-transgenic mouse system displaying peripheral tolerance against a liver-specific MHC class I Kb antigen, we investigated whether the breaking of tolerance would result in autoimmunity. Reversal of tolerance was achieved by simultaneous challenge with cells expressing the Kb autoantigen and IL-2. Tolerance could not be broken with IL-2 alone or when Kb- and IL-2-expressing cells were applied to different sites of the mice. However, despite the presence of activated autoreactive T cells that were able to reject Kb-positive grafts no autoaggression against the Kb-positive liver was observed. These results indicate that breaking of tolerance per se is not sufficient to cause liver-specific autoimmunity. However, when in addition to breaking tolerance the mice were infected with a liver-specific pathogen, autoaggression occurred. Thus, in this system at least two independent steps seem to be required for organ-specific autoimmunity: reversal of peripheral tolerance resulting in functional activation of autoreactive T cells and conditioning of the liver microenvironment which enables the activated T cells to cause tissue damage.

Animals↗
PubMed1998

A two-step model for the induction of organ-specific autoimmunity.

Peripheral tolerance is considered to be a safeguard against autoimmunity but the mere existence of anergic T cells renders them potentially dangerous. Using transgenic mice that were tolerant to a foreign MHC class I antigen (Kb) exclusively expressed in the liver, we investigated whether reversal of tolerance in vivo would directly result in autoimmunity. Breaking of tolerance was achieved by application of tumour cells expressing both Kb and interleukin 2. Despite the fact that the respective mice were now able to reject Kb-positive grafts, the reversed T cells did not infiltrate and attack the Kb-positive liver. However, when the liver was 'conditioned' through an inflammatory reaction either by irradiation or by infection with Listeria, massive T cell infiltration and liver damage were observed in the reversed mice. The results show that at least two steps are required for autoimmunity: (1) activation of antigen-specific T cells, and (2) conditioning of the target organ. It will be important to determine the factors leading to conditioning but it is likely that adhesion molecules are involved. These experiments are not only of relevance for treatment of autoimmune disease but also for tumour therapy.

Animals↗
PubMed1998

Tolerance induction in mature T lymphocytes.

T lymphocytes with self-destructive capacity are often found in healthy individuals, indicating efficient control mechanisms that prevent autoimmunity. Recently, we were able to demonstrate the existence of peripheral tolerance in double-transgenic mice expressing the foreign histocompatibility antigen H-2Kb exclusively outside the thymus and a T cell receptor (Des.TCR) directed against the Kb molecule. In mice expressing Kb only on keratinocytes anti-Kb T cells were still present but failed to reject Kb-positive tissue grafts. This observation would imply a continuous migration of naïve T cells exported from the thymus into non-lymphoid tissues where these fresh thymic emigrants would need to be tolerized. However, this is in contrast to the view that migration to peripheral tissues is restricted to activated T cells. To investigate whether there is a continuous process of tolerization of naïve T cells in adult DES.TCR x 2.4Ker-Kb mice, 2.4Ker-Kb mice were crossed with Rag-2-deficient mice and reconstituted with bone marrow cells of Des.TCR transgenic mice (Des.TCR x 2.4Ker-Kb.Rag-2-). Tolerance was not observed in these chimeric mice. We conclude from these results that in contrast to the neonate the adult physiological environment does not allow tolerance induction to antigens expressed on keratinocytes in T cells newly exported from the thymus. Furthermore, we have to postulate regulatory events responsible for the maintenance of peripheral tolerance in the adult Des.TCR x 2.4Ker-Kb animals.

Animals↗
PubMed1998

Clinical effects and pharmacokinetics of the fusion protein PIXY321 in children receiving myelosuppressive chemotherapy.

UNLABELLED: A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited, and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels. PURPOSE: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with myelosuppressive chemotherapy. METHODS: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered once or twice daily by subcutaneous injection in total doses of 500 to 1000 microg/m2 per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule only). RESULTS: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose studied (1000 microg/m2 per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m2 (range 77 1804 ml/min per m2) and the median half-life was 3.7 h (range 2.1-20.8 h). On day 14, clearance increased in all patients studied (median increase 63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were < 1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent activity in vitro. CONCLUSIONS: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients.

Adolescent↗
PubMed1998

Comparative activity of ciprofloxacin, ofloxacin, levofloxacin, and erythromycin against Legionella species by broth microdilution and intracellular susceptibility testing in HL-60 cells.

Animal lung macrophages or human peripheral blood mononuclear cells have been used for testing intracellular activity of anti-Legionella antibiotics; such studies are labor intensive such that comparative antibiotic studies for the many Legionella species are few. We evaluated a human monocyte cell line (HL-60) as an alternative model. HL-60 (1.5 x 10(6) cells/well) was differentiated into adherent cell and infected with 1.5 x 10(7) CFU of Legionella pneumophilia (L. pneumophilia). Erythromycin and quinolones, ciprofloxacin, ofloxacin, and levofloxacin were added to cells at 1 and 8 x MIC. Percent (%) inhibition ratios equal to total L. pneumophila with agent divided by L. pneumophila without agent x 100 were determined at 48 h; lower ratios implied greater potency. By broth dilution in buffered yeast extract broth, the most potent agents against L. pneumophila were (MIC): ciprofloxacin (0.015-0.03), ofloxacin (0.015-0.03), levofloxacin (0.015-0.03), erythromycin (0.125-1.0 microgram/mL). In the intracellular model, the most potent inhibitors of L. pneumophila multiplication at 8 x MIC were (in order of potency) levofloxacin (24.2%), ciprofloxacin (30.6%), ofloxacin (37.1%), and erythromycin (55.0%). All the quinolones were highly active and significantly more potent against L. micdadei and L. bozemanii when compared to L. pneumophila.

Anti-Bacterial Agents↗
PubMed1998

Activity of azithromycin, clarithromycin, roxithromycin, dirithromycin, quinupristin/dalfopristin and erythromycin against Legionella species by intracellular susceptibility testing in HL-60 cells.

We evaluated a human monocyte cell line (HL-60) as a model for testing the intracellular activity of anti-Legionella antibiotics; 1.5 x 10(6) HL-60 cells/well were differentiated into adherent cells and infected with 1.5 x 10(7) cfu of Legionella pneumophila. The most active agents against L. pneumophila as judged by broth dilution MICs were (in order of activity) azithromycin, clarithromycin, roxithromycin, quinupristin/dalfopristin, erythromycin and dirithromycin. The most active inhibitors of L. pneumophila intracellular multiplication were (in order of activity) azithromycin, erythromycin, quinupristin/dalfopristin, roxithromycin, dirithromycin and clarithromycin. All the agents were highly active against Legionella micdadei and Legionella bozemanii when compared with L. pneumophila.

Anti-Bacterial Agents↗
PubMed1997

Enforced Bcl-2 expression inhibits antigen-mediated clonal elimination of peripheral B cells in an antigen dose-dependent manner and promotes receptor editing in autoreactive, immature B cells.

The mechanisms that establish immune tolerance in immature and mature B cells appear to be distinct. Membrane-bound autoantigen is thought to induce developmental arrest and receptor editing in immature B cells, whereas mature B cells have shortened lifespans when exposed to the same stimulus. In this study, we used Emu-bcl-2-22 transgenic (Tg) mice to test the prediction that enforced expression of the Bcl-2 apoptotic inhibitor in B cells would rescue mature, but not immature, B cells from tolerance induction. To monitor tolerance to the natural membrane autoantigen H-2Kb, we bred 3-83mudelta (anti-Kk,b) Ig Tg mice to H-2(b) mice or to mice expressing transgene-driven Kb in the periphery. In 3-83mudelta/bcl-2 Tg mice, deletion of autoreactive B cells induced by peripheral Kb antigen expression in the liver (MT-Kb Tg) or epithelia (KerIV-Kb Tg), was partly or completely inhibited, respectively. Furthermore, Bcl-2 protected peritoneal B-2 B cells from deletion mediated by acute antigen exposure, but this protection could be overcome by higher antigen dose. In contrast to its ability to block peripheral self-tolerance, Bcl-2 overexpression failed to inhibit central tolerance induced by bone marrow antigen expression, but instead, enhanced the receptor editing process. These studies indicate that apoptosis plays distinct roles in central and peripheral B cell tolerance.

Animals↗