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Biomedical subjects

A J Stagg

Publications and source records attributed to A J Stagg.

16 recordsLinked to original sources
PubMed1998

Vaccines against Chlamydia: approaches and progress.

Infections of the eye and genital tract with the bacterium Chlamydia trachomatis are a major cause of morbidity worldwide and are costly to treat. Development of a vaccine capable of protecting against infection or severe disease presents special challenges but would be the most effective long-term option for control of chlamydial disease. Progress has been made in understanding protective and pathological immune mechanisms in these infections, and a number of potential vaccine candidates have been developed.

Animals↗
PubMed1998

Efficacy of doxycycline and ciprofloxacin against experimental Yersinia pestis infection.

The efficacies of ciprofloxacin and doxycycline prophylaxis and therapy were assessed against experimental pneumonic plague infections induced by two strains of Yersinia pestis in a mouse model. When exposed to an aerosol of Y. pestis strain GB, containing 8.39 x 10(5) +/- 4.17 x 10(4) cfu, the retained dose was 7.3 x 10(3) +/- 2.3 x 10(3) cfu. When exposed to an aerosol of Y. pestis strain CO-92, containing 1.86 x 10(5) +/- 7.4 x 10(3) cfu, the retained dose was 3.4 x 10(4) +/- 2.6 x 10(3) cfu. Both strains resulted in a respiratory and systemic infection closely resembling human pneumonic plague. Ciprofloxacin prophylaxis and therapy was successful against both strains for up to 24 h after challenge, but not after 48 h. Both doxycycline prophylaxis and therapy regimens were ineffective against both strains, although strain CO-92 was more susceptible in vitro to doxycycline than strain GB and supra-MIC levels were achieved in the serum and lungs of the animal.

Animals↗
PubMed1997

A sub-unit vaccine elicits IgG in serum, spleen cell cultures and bronchial washings and protects immunized animals against pneumonic plague.

In this study, the protection afforded against aerosolized Yersinia pestis by injection of an alhydrogel-adsorbed sub-unit vaccine has been compared with that given by an existing killed whole cell vaccine licensed for human use. The sub-unit vaccine protected mice against exposure to > 10(4) colony-forming units (c.f.u.) of virulent plague organisms (100 LD50 doses), whereas the whole cell vaccine provided only 50% protection against 1.8 x 10(3) c.f.u. In sub-unit vaccinees, IgG to each of the F1 and V antigens contained in the vaccine, was detected in serum, on direct secretion by spleen cells and in broncho-alveolar washings (BAL). In killed whole cell vaccinees, physiologically significant levels of IgG to F1 only were detectable in equivalent samples. Levels of F1-specific IgG in serum, secreted from spleen cells and in BAL were significantly higher (P < 0.01) in sub-unit compared with killed whole cell vaccinees. IgA was not detected in BAL from intra-muscularly dosed sub-unit vaccinees and thus the protection achieved against inhalational challenge with Yersinia pestis is attributed to the induction of systemic immunity to both the F1 and V antigens in the sub-unit vaccine. The enhanced protective efficacy of this sub-unit vaccine over an existing vaccine has been demonstrated in an animal model of pneumonic plague.

Animals↗
PubMed1997

Human blood dendritic cells: binding to vascular endothelium and expression of adhesion molecules.

To investigate the binding properties of dendritic cells (DC) to vascular endothelium, a comparative analysis was undertaken of DC, monocytes and lymphocytes isolated from the blood of 25 healthy subjects using monolayers of human umbilical vein endothelial cells as the adherence substrate. More blood DC (mean 24% adherence) were adherent to endothelial monolayers than monocytes (mean 18%; P < 0.001) and lymphocytes (mean 12%; P < 0.001). When the monolayers were pretreated with tumour necrosis factor-alpha (TNF-alpha) all leucocyte populations exhibited an increased attachment, but there was still greater binding of DC (mean 37% adherence) in comparison with monocytes (mean 23%; P < 0.001) and lymphocytes (mean 18%; P < 0.001). Flow cytometric analysis revealed that in relation to monocytes and lymphocytes the DC had a higher surface expression of the adhesion molecules CD11a (P < 0.05), CD11c (P < 0.005) and CD54 (P < 0.005) but a lower prevalence of cells bearing CD49d (mean 38%; P < 0.05) and the homing receptor CD62L (mean 14%; P < 0.001). CD1a was present on 22% of DC and virtually absent from the surface of monocytes and lymphocytes. The intensity of expression of the beta1-integrins, CD49c, CD49d and CD49e was greater on DC than lymphocytes and monocytes (P < 0.05). Antibody blocking studies demonstrated that DC binding to untreated and TNF-alpha-treated endothelium was dependent upon the expression of CD11a, CD18 and CD49d, and the simultaneous application of anti-CD18 and anti-CD49d antibodies produced an approximate 70% inhibition of adhesion (P < 0.001). Thus, the expression of both beta1- and beta2-integrins contributes to the adhesive interaction between DC and endothelium.

Cell Adhesion↗
PubMed1996

Antigen-presenting cells but not lymphocytes in the joint may indicate the cause of reactive arthritis.

T cells and antigen-presenting cells (APC) accumulate in the joint in reactive arthritis and there are reports that the T cells are a population selected for responsiveness to the causative agent. In this work, the latter view is questioned by detailed studies of the antigen specificities of the lymphocytes within the joint (SFMC) and peripheral blood (PBMC) of patients with reactive arthritis triggered by infection with Chlamydia trachomatis. Using a hanging-drop microculture system. SFMC displayed enhanced responses not only to antigens from the triggering organism, but also to other antigens, including PPD and tetanus toxoid, to which the patients were likely to have had prior exposure. No evidence was obtained for a dominant cross-reactive T-cell response to epitopes common to these antigen preparations, confirming the polyclonal nature of the infiltrate. In contrast to the broad specificity of the T-cell infiltrate, two experimental approaches indicated that APC within the joint carried chlamydial antigen. The failure of antigen-bearing APC to interact with T cells at this site may underlie the inability to clear microbial antigen from the joint.

Antigen Presentation↗
PubMed1995

A comparison of Plague vaccine, USP and EV76 vaccine induced protection against Yersinia pestis in a murine model.

The median lethal dose (MLD) of a pathogenic strain of Yersinia pestis was established by three routes of administration in three strains of mouse. There was no significant difference between the MLDs in the different strains of mouse. The MLD by the subcutaneous route in Balb/C and an outbred line was approximately 1 c.f.u.; the MLD following intraperitoneal administration was tenfold higher. There were significant differences in the mean times to death after administration of the challenge by different routes. The relative efficacy of a live attenuated vaccine strain of Y. pestis (EV76) was compared with that of the formaldehyde-killed vaccine (Plague vaccine, USP). EV76 protected against high challenge doses (up to 5.75 x 10(6) MLD), though immunized animals showed side effects of varying severity. The killed vaccine was less effective in terms of dose-protection (deaths occurred after challenge with 4000 MLD) and several of the vaccinated animals suffered sub-lethal, plague-related sequelae to the challenge.

Animals↗
PubMed1994

Failure in antigen responses by T cells from patients with common variable immunodeficiency (CVID).

Antigen-driven responses by T cells from patients with CVID and normal subjects have been assessed. Low-density cells enriched for antigen-presenting dendritic cells were cultured with T cells using a 20-microliters hanging drop system. T cells from all subgroups of CVID patients showed markedly reduced responses to the recall antigens purified protein derivative (PPD) or tetanus toxoid, whereas responses by cells from patients with X-linked agammaglobulinaemia, used as a disease control, were in the normal range. However, primary allo-stimulation of CVID T cells was normal. CVID cells from two patients failed to respond to stimulation with a neoantigen, an HIV env peptide, under conditions where normal T cells did respond. These data illustrate a profound defect in antigen-stimulated T cell proliferation in vitro in all groups of CVID patients, but do not distinguish whether the defect is in the presenting cell or in the T lymphocyte. In vivo, germinal centre B cells are thought to present antigen to primed T cells to obtain essential signals (e.g. CD40 ligand and IL-2) for B cell survival and progression to immunoglobulin secretion. A failure of antigen-specific T cell function in vivo in CVID would thus not provide the primed T cells needed for B cell rescue, and could be the primary defect leading to the low immunoglobulin production in this condition.

Antigen-Presenting Cells↗
PubMed1993

Antigen-presenting cell types.

Different antigen-presenting cells elicit responses in different T-cell populations for primary activation, secondary stimulation and cytotoxic effector functions. Maturing bone marrow derived dendritic cells may acquire and process antigens, transport them to lymph nodes and activate naive T cells located there. By contrast, follicular dendritic cells, acquiring antigen-antibody complexes, maintain 'memory' via B-cell activation. Effector memory T cells recognize various tissue cells bearing antigen and we speculate that they may also target specialized antigen-presenting dendritic populations.

Animals↗
PubMed1993

Primary human T-cell responses to the major outer membrane protein of Chlamydia trachomatis.

The major outer membrane protein (MOMP) of Chlamydia trachomatis is the main candidate antigen for a synthetic vaccine against chlamydial infection. Antibodies to surface-exposed epitopes on MOMP neutralize chlamydial infectivity but little is known about T-cell recognition of the molecule. We have measured primary human T-cell responses to recombinant fragments of MOMP as well as to the whole organism and synthetic MOMP peptides. Using antigen-pulsed low density cells (LDC) we were able to stimulate proliferative responses with T cells from most naive individuals. This response was antigen dose dependent and displayed an absolute requirement for dendritic cells in the antigen-presenting cell (APC) population. Several T-cell epitopes were identified in MOMP and one which stimulated T cells from 80% of donors was resolved as a 12 amino acid synthetic peptide. Dual cell surface labelling and cell cycle analysis by FACS revealed that both CD4+ and CD8+ T cells were stimulated in these cultures. The fact that we were able to obtain proliferative responses and interferon-gamma (IFN-gamma) production to MOMP using cells from cord bloods confirmed that these are genuine primary responses. These experiments have identified a region on MOMP, to which T cells from most humans make a primary response, which may be useful in a chlamydial vaccine. The approach is useful for vaccine development in general.

Amino Acid Sequence↗
PubMed1991

The distribution and functional properties of dendritic cells in patients with seronegative arthritis.

Dendritic cells (DC), potent antigen-presenting cells, are known to be increased in numbers in inflammatory lesions in rheumatoid arthritis and juvenile chronic arthritis. In this study, patients with seronegative arthritis were studied; the distribution and functional properties of DC enriched low density cells (LDC) from peripheral blood (PB) and synovial fluid (SF) were compared. The composition of LDC from both sources was similar, comprising approximately 30% DC, 60% monocytes with few T lymphocytes. SF was significantly enriched for LDC compared with paired peripheral blood (P less than 0.0001) or peripheral blood from healthy controls (P less than 0.001). In contrast, patient PB contained fewer LDC (P less than 0.05) overall than healthy controls. LDC from both sources were potent simulators of allogeneic PB T cells in a mixed leucocyte reaction (MLR), but in four out of 10 patients SF LDC were significantly more stimulatory. In autologous MLRs (AMLRs) SF T cells were not stimulated by either LDC population. This anergy of T cells was confined to the joint as patient PB T cells showed an AMLR response to PB LDC which was similar to that seen in cells from healthy controls. PB T cells also responded to SF LDC; in a minority of patients SF LDC caused significantly greater stimulation in AMLR than PB LDC and the possibility is discussed that this may represent presentation of antigen acquired in vivo.

Arthritis↗
PubMed1991

Peripheral blood and synovial fluid T cells differ in their response to alloantigens and recall antigens presented by dendritic cells.

Properties of T cells from inflammatory lesions were analysed by comparing the response of peripheral blood (PB) and synovial fluid (SF) T cells from 19 patients with a range of arthropathies to enriched allogeneic dendritic cells (DC) in a primary mixed leucocyte reaction (MLR). In 17 patients the proliferative response of SF T cells was significantly (P less than 0.05) less than that of PB lymphocytes. The reduced response of SF T cells was observed in all disease categories studied and could not be attributed to differences in cell number requirements or response kinetics. Addition of recombinant interleukin-2 enhanced the response of SF T cells in a dose-dependent manner. Cell mixing experiments suggested that active suppression was not the underlying mechanism of the poor MLR response of SF T cells. In contrast to the MLR response. SF T cells were able to mount vigorous proliferative responses to recall antigen presented by autologous antigen-presenting cells. The possibility is discussed that T cells compartmentalized at inflammatory lesions are a unique population with a diminished ability to interact with DC and respond to primary stimuli but an ability to respond to secondary antigenic challenge.

Arthritis↗
PubMed1986

Investigation of antigen cross-reactivity of Mycobacterium leprae-reactive murine T-cell lines and clones.

Inguinal lymph node lymphocytes from BALB/c mice immunized intradermally with 10(8) 60Co-irradiated Mycobacterium leprae were cloned by limiting dilution culture. In general, cloned T-cell lines exhibited helper type activity producing interleukin-2, macrophage activation factor and gamma-interferon and lines were further characterized in terms of their cross-reactivities with other species of mycobacteria. M. leprae clones derived after a period of in vitro restimulation were found to cross-react with other species of mycobacteria probably recognizing non-specific or closely related common cell wall associated mycobacterial determinants. On the other hand, lines established by cloning directly from immune mice appeared more M. leprae-specific, exhibiting antigen-dependent lymphokine production and proliferation in vitro.

Animals↗
PubMed1982

Anthrax island.

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Animals↗