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K W Beagley

Publications and source records attributed to K W Beagley.

At least 19 recordsLinked to original sources
PubMed2004

Genetic background affects susceptibility in nonfatal pneumococcal bronchopneumonia.

A nonfatal pneumococcal lung infection model was required to investigate immune responses during recovery, and the interaction of other diseases subsequent to infection. A murine model of nonfatal pneumococcal lung infection was developed and the effect of genetic background on susceptibility was determined in BALB/c and C57BL/6 mice. Bacteria colonised the lungs and mice developed mild clinical illness with pathophysiology similar to human bronchopneumonia. Recovery was associated with immune cell influx, which cleared bacteria but induced tissue damage characteristic of pneumococcal bronchopneumonia. After clearance, immune cell populations returned to normal and tissues appeared less inflamed. Although bacterial exposure and clearance were similar, the extent of immune cell influx and tissue damage differed significantly. Larger numbers of neutrophils and lymphocytes entered lung tissue and the affected area was greater in BALB/c compared with C57BL/6 mice. An inflammatory basis for differences was determined with greater levels of phagocytosis and oxidative burst observed in BALB/c mice. C57BL/6 mice cleared the low inoculum with a reduced immune response; however, C57BL/6 mice are more susceptible to larger inocula, which overwhelms the immune system. These different susceptibilities result from a greater inflammatory response in BALB/c compared with C57BL/6 mice.

Adult↗
PubMed2001

Effects of exogenous interleukin-6 during Pseudomonas aeruginosa corneal infection.

Lack of interleukin-6 (IL-6) during Pseudomonas aeruginosa corneal infection leads to more severe disease with changes in neutrophil recruitment. Exogenous IL-6 leads to increased efficiency of neutrophil recruitment and reduced bacterial loads in corneal infection in both IL-6 gene knockout and wild-type mice. This may be mediated by IL-6 increasing the production of corneal macrophage inflammatory protein 2 and intercellular cell adhesion molecule 1. We conclude that effective recruitment of neutrophils into the cornea is dependent on the production of IL-6 and that early augmentation of IL-6 may be protective in corneal infection.

Animals↗
PubMed2000

Transcutaneous immunization induces mucosal and systemic immunity: a potent method for targeting immunity to the female reproductive tract.

Female BALB/c mice were immunized with tetanus toxoid (TT) admixed with cholera toxin by direct application to shaved skin (Transcutaneous immunization, TCI). Tetanus toxoid-specific IgG and IgA in serum, saliva, vaginal lavage and fecal pellets were assayed by ELISA. Tetanus toxoid specific antibody-secreting cell (ASC) numbers were also determined by immunohistochemistry in sections of vagina, uterus, salivary gland and small intestine of immunized mice. TCI elicited significant levels of TT-specific IgG in serum, saliva and vaginal lavage, with the greatest increases over background seen in saliva (80-400 fold) and vaginal lavage (2-87 fold). TCI induced only modest levels of IgA in any of the samples tested (range 2-7 fold increase). In the absence of cholera toxin, application of TT alone did not result in detectable TT-specific antibodies in mucosal secretions. ASCs were found in all tissues following TCI. Cells were most frequent in uterus and vaginal tissues with ASC numbers less frequent in small intestine and salivary gland. This suggests that local production, rather than transudation from serum, is a major contributor of antibody in reproductive tract secretions. Further studies focussed on the role of sex hormones and immune induction following TCI. Animals immunized at the stage of oestrus cycle at which estrogen is abundant (Estrus), showed significantly lower levels of TT-specific IgG in vaginal lavage samples. Collectively, these data confirm the findings of Glenn and colleagues (1998), who showed TCI using cholera toxin can elicit high levels of serum IgG to both the toxin and co-administered antigen and further demonstrates that this route of immunization is particularly effective at eliciting humoral immunity in saliva and in the female reproductive tract.

Animals↗
PubMed2000

Chlamydia trachomatis infection: incidence, health costs and prospects for vaccine development.

Chlamydia trachomatis infection is now the most common sexually transmitted disease worldwide. World Health Organisation figures estimated that 89 million new cases of genital Chlamydia infections occurred in 1995, highlighting the worldwide prevalence of infections and the economic burden on healthcare delivery. A number of methods have been developed for detection of chlamydial infection, which vary in sensitivity and specificity. No single method has yet gained general acceptance and in many countries Chlamydia infections are not reported, suggesting that the above figures may be an underestimate of the problem. As yet there is no consensus as to what constitutes a protective immune response against genital Chlamydia infection. Studies in animal models have shown that cell-mediated immunity, both Th1-driven macrophage activation and cytotoxic T cell responses, as well as antibody can mediate protection at different stages of the chlamydial life cycle. A successful vaccine would probably need to elicit both a systemic cell-mediated immune response to limit/resolve established infections and a mucosal IgA response to reduce bacterial shedding and the resulting spread of infection to partners of infected individuals. The immune response to Chlamydia, either through natural infection or following immunisation, also has the potential to enhance inflammation and to act as a driving force for constant mutation in the variable regions of the major outer membrane protein. As a result a constant prevalence of infection is maintained even in an immune population through the emergence of new allelic variants. Immune responses against antigens such as the 60 kDa heat shock protein can exacerbate inflammation through molecular mimicry and must not be elicited as a result of vaccination. Thus there are many challenges for the development of a successful vaccine which must elicit immunity against multiple serovars while at the same time minimising damaging pro-inflammatory immune responses.

Animals↗
PubMed2000

Interferon-gamma plays a critical role in intestinal immunity against Salmonella typhimurium infection.

Salmonella bacteria are a major cause of food-borne infectious diarrhoea and there is great interest in understanding the pathogenesis of Salmonella infection and in vaccine development. Potential vaccines include the aromatic mutants of S. typhimurium. Such non-lethal Aro mutants have also been useful for studying Salmonella infections in mouse models. Studies of systemic infection, using these Aro mutants, in both normal and cytokine gene knockout mice, indicate that interferon-gamma (IFN-gamma) plays a key role in the resolution of Salmonella infection. The present studies have investigated the outcome of oral infection in mice with attenuated Salmonella because this infection route mimics natural infection in humans. In IFN-gamma gene knockout (IFN-gamma-/-) mice, intestinal immunity was impaired and oral challenge resulted in disseminated septicaemia 2 weeks later. No dissemination of infection was seen in wild-type mice. In wild-type mice, both CD4 and CD8 cell numbers increased in the gut following Salmonella challenge, together with increased expression of major histocompatibility complex (MHC) II and vascular cell adhesion molecule-1 (VCAM-1). No such changes were seen in IFNgamma-/- mice. Following oral challenge, antilipopolysaccharide (LPS) and antiphosphoryl choline antibodies increased by more than 100-fold in both serum and faecal pellet extracts of IFNgamma-/- mice compared with wild-type mice. Our data show that IFN-gamma production is essential for resolution of enteric Salmonella infection and that antibody has little effect on this process.

Animals↗
PubMed1999

B1 B cell numbers and antibodies against phosphorylcholine and LPS are increased in IL-6 gene knockout mice.

Peritoneal cavity cells were isolated from IL6-gene knockout (IL6(-/-)) and wild-type mice and stained for expression of IgM, CD5, and CD23. B1 cell (IgM(+)/CD23(-), CD5(+)/IgM(+)) numbers were increased twofold in IL6(-/-) mice compared to normals while IgM(+)/CD23(+) (B2) cell numbers were reduced threefold. Intestinal antibody levels were also determined for both total immunoglobulin and phosphorylcholine (PC)-specific and LPS-specific antibody following oral challenge with attenuated Salmonella typhimurium. Total immunoglobulin levels (IgM, IgG, and IgA) were reduced 60-80% in intestinal secretions of IL6(-/-) mice compared to wild-type controls; however, PC-specific antibody was significantly higher in IL6(-/-) mice. Anti-LPS antibodies were also three- to sevenfold higher in IL6(-/-) mice compared to controls following Salmonella challenge. These data suggest that in IL6(-/-) mice the development of mucosal B2 cells is impaired but that intestinal B1 cells responding to microbial antigens such as PC and LPS develop normally and are fully functional.

Animals↗
PubMed1999

Analysis of the mucosal microenvironment: factors determining successful responses to mucosal vaccines.

The predominance of IgA antibodies in mucosal sites reflects a combination of high rate IgA isotype switching among precursor cells in induction sites, their selective localisation in mucosal effector tissues and vigorous proliferation of these cells after extravasation. Each of these steps leading to IgA expression at the mucosa is under cytokine control. This paper will address the role of cytokines in induction and expression of IgA responses, the contribution of various precursor cell subsets and their differential responses to cytokine signals and strategies for manipulating cytokine expression. With respect to IgA antibody production in the gut whereas IL-4 and TGF-beta have been implicated in isotype switching of precursor cells to IgA commitment, their subsequent localisation, proliferation and effector activity expression is dependent on IL-5 and IL-6 expression locally. Most IgA plasma cells in the intestine derive from cells of the B2 lineage in the Peyer's patch, but a subpopulation of cells derived from the peritoneal cavity (B1 cells) also contribute to the IgA plasma cell population in the intestinal lamina propria. Whereas IgA+ cells of the B2 lineage are IL-6 dependent but IL-5 independent, B1-derived IgA+ cells are IL-5 dependent and IL-6 independent. On the other hand, cell mediated immune responses in the gut are highly dependent on IFN-gamma production by both Th1 CD4 cells and CD8 cells and in enteric Salmonella infection IFN-gamma production is essential but antibody has little effect on this process.Therapeutic interventions based on the information emerging from these studies will lead to improved vaccination responses and correction of immunodeficiencies especially in young animals.

Animals↗
PubMed1999

Increased severity of Candida vaginitis in BALB/c nu/nu mice versus the parent strain is not abrogated by adoptive transfer of T cell enriched lymphocytes.

The role of the host immune system in combating candidal infections in the vagina is poorly understood. A murine model of Candida vaginitis was used to elucidate the role of T cells in a candidal infection. Athymic BALB/c nu/nu mice or normal BALB/c mice were induced into estrus and then infected with 1 x 10(6) Candida albicans intravaginally. The infection was monitored over 1 week. Samples from blood, small intestine, tongue, kidney, spleen, liver, uterus and vagina were tested for recoverable C. albicans. Histology of the vagina was assessed for both inflammation and extent of infection. Results indicated that the BALB/c nu/nu mice had similar levels of vaginal yeast load to the normal BALB/c mice. In 25-30% of nude mice Candida was also recovered from extra vaginal sites (kidney, liver, small intestine), however, extra vaginal dissemination was not observed in any normal BALB/c animals. Histologically, both the nu/nu and control BALB/c had similar levels of vaginal inflammation; however, the nu/nu mice had more florid fungal growth in the vaginal epithelium. Adoptive transfer of either immune or non-immune BALB/c T cells into nude mice had no affect on either infection or vaginal inflammation. Immunohistochemical staining of vaginal tissues from normal BALB/c mice or nude mice adoptively transferred with either immune or non-immune T cells with anti-CD3 monoclonal antibody revealed no significant difference between groups in the numbers of CD3+ vaginal T cells. However, in mice receiving either immune or non-immune T cells no yeast was recovered from any tissues except the vagina. These data show that T cells have a limited role in protecting the vagina from C. albicans infection.

Animals↗
PubMed1999

Protection against Helicobacter pylori infection by intestinal immunisation with a 50/52-kDa subunit protein.

A mouse model of Helicobacter pylori infection was used to evaluate the vaccine antigen potential of the citrate synthase homologue protein purified from the H. pylori NCTC 11637 strain. Mice were immunised with the protein by intra-Peyer's patch immunisation. This route gives maximal intestinal immunisation and was used to screen oral vaccine candidate antigens without the added complication of simultaneously testing oral delivery systems. Two weeks post-immunisation mice were infected with Sydney strain H. pylori and 4 weeks after infection the mice were killed and the level of H. pylori infection in the stomach determined. Pre-immunisation with the 50/52-kDa protein led to a 84-91% reduction in H. pylori infection compared to unimmunised controls.

Animals↗
PubMed1998

Cytokine gene expression in murine fetal intestine: potential for extrathymic T cell development.

An increasing body of evidence suggests that certain T cell subsets mature extrathymically in the epithelium of the intestine. In the studies reported here, the authors have analysed cytokine/growth factor gene expression, recombinase-activating gene RAG-1 and RAG-2 gene expression and terminal deoxynucleotidyl transferase (TdT) gene expression in mouse fetal intestine and fetal thymus and liver, two known haematopoietic tissues. Stem cell factor (SCF) and interleukin 7 (IL-7) message was abundant in all three tissues during fetal development. IL-2 and IL-4 were not expressed in fetal gut but IL-4 was weakly detected in fetal liver and thymus. IL-9 and IL-13 mRNA was detected in all fetal tissues and IL-15 mRNA was abundant in fetal intestine but only weakly expressed in fetal liver and thymus. mRNA for SCF, IL-7, IL-13 and IL-15 was also detected in fibroblast-like cell lines derived from fetal intestine. RAG-1 and RAG-2 mRNA was detected in all three fetal tissues. TdT mRNA was not detected in fetal gut or liver but was weakly expressed in (fetal day) fd19-20 fetal thymus. Long-term (> 6 weeks) in vitro growth of IEL was achieved by coculturing intraepithelial lymphocytes (IEL) with IL-7-secreting fibroblasts in the presence of SCF and IL-2. The data show that the fetal mouse gut provides a suitable environment for lymphocyte development and receptor rearrangement, similar to fetal thymus and liver, even though expansion of intestinal IEL is delayed until 2-3 weeks after birth.

Animals↗
PubMed1998

Cellular immunity in recurrent vulvovaginal candidiasis.

Impaired T cell function has been reported to predispose women to recurrent vulvovaginal candidiasis, but conflicting results have been noted in the literature. Most clinical episodes occur in the late luteal phase, suggesting hormonal influence on host resistance. The present study assesses the cellular immune responses of 28 women with recurrent vaginal candidiasis (patients) and 25 control women (controls), noting results in relation to whether the women were in the follicular or luteal phase of the menstrual cycle at the time of sampling. Candida-stimulated peripheral blood lymphocyte proliferation was significantly reduced in patients compared with controls. Interferon-gamma (IFN-gamma) production in response to both Candida and purified protein derivative (PPD) stimulation was significantly lower in patients compared with controls. Skin test responses were comparable in both groups. A significant reduction in Candida-stimulated IFN-gamma production was seen in patients but not controls in the follicular phase compared with those in the luteal phase. There was also a trend towards lower proliferation in response to Candida in patients but not controls in the follicular phase compared with patients in the luteal phase. These results suggest that there is a partial T cell dysregulation in recurrent vaginal candidiasis which may be exacerbated by the hormonal balance present during the follicular phase, correlating with the risk of clinical infection.

Adult↗
PubMed1998

Intestinal IgA plasma cells of the B1 lineage are IL-5 dependent.

Two lineages of B cells, designated B1 and B2 cells, have been identified based upon their origins, anatomical distribution, cell surface markers, antibody repertoire and self-replenishing potential. B1 cells are maintained by self-renewal of cells resident in the peritoneal cavity (PerC) and they utilize a limited repertoire of germline V-region genes, mostly directed against ubiquitous bacterial antigens such as phosphoryl choline (PC). B2 cells are replenished from bone marrow precursors and use a larger repertoire of immunoglobulin V-region genes. Whereas most immunoglobulin A (IgA) plasma cells in the intestine derive from B2 lineage precursors in the Peyer's patch, a subpopulation of Per C-derived B1 cells populate the intestinal lamina propria where they mature into IgA plasma cells. In previous in vivo studies we have shown that whereas IgA+ B2 cells are interleukin (IL)-6 dependent, B1 cells are IL-6 independent. In view of the in vitro evidence that IL-5 is also involved in IgA expression, in the studies reported here we have used IL-5-deficient mice to evaluate the role of IL-5 in vivo in IgA expression in the gut. The results demonstrate that although total IgA cell numbers are only marginally depressed in IL-5-deficient mice, there is a marked selective depletion of IgA+ cells of the B1 lineage in the gut and a corresponding depression in the capacity of these mice to mount an intestinal response to a B1 antigen (PC) but not to a B2 antigen (oralbumin; OVA), reflecting intact B2-derived IgA cell function but a defect in the B1 cell contribution to IgA responses in IL-5 deficient mice. Collectively these data demonstrate differential cytokine regulation of subsets of IgA+ cells in the gut in that IgA+ cells of the B2 lineage are IL-6 dependent but IL-5 independent, but B1-derived IgA+ cells are IL-5 dependent and IL-6 independent.

Animals↗
PubMed1998

Exogenous IL-6 promotes enhanced intestinal antibody responses in vivo.

It is well documented that IL-6 plays a critical role in B cell terminal differentiation, and in mucosal sites it stimulates proliferation and large-scale secretion of immunoglobulin by B cells, especially those committed to IgA production. The close juxtaposition of IL-6 mRNA+ cells to plasma cells in the intestinal lamina propria supports the proposition that IL-6 production in situ is an important factor determining the outcome of antibody responses at that site. However, it has not been established previously whether exogenous IL-6 could boost antibody responses in the intestine if administered with a challenge antigen. Using a resected gut loop (Thiry-Vella loop) model, we have been able to demonstrate that in mice with double loops, antibody containing cell responses to lumenal administration of ovalbumin were 50% greater in loops given intralumenal recombinant IL-6 with the challenge antigen, than in loops challenged with antigen alone. This demonstrates the efficacy of IL-6 in promoting accumulation of antibody secreting cells in the gut, and suggests a potential therapeutic role for IL-6 to enhance responses to mucosal vaccines.

Animals↗
PubMed1998

Dendritic cells from Peyer's patch and spleen induce different T helper cell responses.

The role of antigen-presenting cells (APC) in regulating the balance of T helper type 1 (Th1) and T helper type 2 (Th2) responses and cytokine production is unclear. Dendritic cells (DC), the most potent APC for naive T cell activation, were found to regulate Th1 and Th2 cytokine profiles in a manner dependent on their tissue of origin. Using whole tissues or purified cell mixtures, spleen (systemic) DC were found to induce mainly Th1 cytokines, and Peyer's patch (mucosal) DC were found to induce predominantly Th2 cytokines. Spleen DC induced high levels of interferon-gamma (IFN-gamma) or interleukin-2 (IL-2) or both, and Peyer's patch DC induced IL-4 or IL-6 or both in spleen and Peyer's patch T cells, allogeneic mixed leukocyte reactions, or antigen-specific Th0 clones. These data suggest that the tissue of origin of DC has a significant impact on subsequent T cell development.

Animals↗
PubMed1998

Acute neutropenia decreases inflammation associated with murine vaginal candidiasis but has no effect on the course of infection.

We have used a mouse model of vaginal candidiasis to determine the effect of neutrophil depletion on (a) the clearance of Candida albicans and (b) the degree of inflammation associated with infection. No differences in recoverable yeast number or rate of clearance were observed between normal and neutrophil-depleted mice; however, vaginal inflammation was significantly decreased in neutrophil-depleted animals.

Acute Disease↗
PubMed1998

Intraepithelial lymphocytes: origins, distribution, and function.

Intraepithelial lymphocytes (IEL) are associated with the intestinal tract, respiratory tract, genitourinary tract epithelium, and the skin and are the first immune system cells to encounter pathogens that have invaded an epithelial surface. IEL are predominantly T cells (CD3+) with CD8+ cells predominating at most, but not all, sites. Both TCR alphabeta+ and TCR gammadelta+ cells are found within IEL populations and an increasing body of evidence suggests that some IEL may arise extrathymically. The presence within intestinal IEL of cells expressing potentially self-reactive TCR suggests that T cell selection within epithelia may differ from thymic T cell selection although recent evidence suggests that these cells may in fact be nonresponsive. IEL exhibit various cytotoxic activities including alloreactive and virus-specific CTL activity, NK activity and spontaneous cytotoxicity, activities consistent with an immune surveillance or first line of defence role. IEL also appear activated in vivo and secrete a variety of cytokines. Subsets of IEL have been shown to provide B cell help, to play a role in the maintenance of oral tolerance and to regulate epithelial cell function. In this review the morphology, distribution and phenotype of IEL, the potential for extrathymic development and possible functions of this unique lymphoid population are discussed.

Cell Movement↗
PubMed1998

Immune responses in the epididymis: implications for immunocontraception.

In recent years the need to develop vaccines against a variety of sexually transmitted diseases, the desire to treat male infertility and interest in developing alternative contraceptive methods have focused research interest on the immunology of the male reproductive tract. This paper reviews the current state of knowledge of immunity in the male tract. Both physical and immune mechanisms that operate to maintain the blood-testis barrier are discussed with regard to (i) their importance in preventing autoimmune responses against spermatozoa and (ii) how these can be overcome to induce specific immunity in the testis and efferent ducts. The role of both the systemic and mucosal arms of the humoral immune response are discussed both in terms of immune-mediated infertility and the induction of specific immunity. Finally some novel approaches to elicit immunity in the male reproductive tract are discussed.

Animals↗