Biomedical subjects

P J Hogarth

Publications and source records attributed to P J Hogarth.

13 recordsLinked to original sources

PubMed2006

Development of vaccines against bovine tuberculosis.

Bovine tuberculosis caused by Mycobacterium bovis remains an economically important problem in Great Britain with potential zoonotic consequences, and the incidence is rising exponentially. In 1997 an independent scientific review recommended that the best option for disease control in Great Britain was the development of a cattle vaccine. Bovine tuberculosis remains a significant problem in countries of the developing world. Indeed, more than 94% of the world's population live in countries in which the control of bovine tuberculosis in buffalos or cattle is limited or absent. Effective vaccination strategies would have a major impact in countries that cannot afford expensive test and slaughter-based control strategies. Here, we present a review of progress toward that goal, and discuss how this progress has shaped our research strategy for the development of a vaccine.

Animals↗

PubMed2004

Cloning and sequencing of badger (Meles meles) interferon gamma and its detection in badger lymphocytes.

The European badger (Meles meles) has been identified as a reservoir for Mycobacterium bovis and is implicated in the maintenance and transmission of tuberculosis in cattle. There is a need for a sensitive test of M. bovis infection in badgers and the current serodiagnostic test used for this purpose has low sensitivity. As observed for other species, assay of interferon-gamma (IFNgamma) produced in response to M. bovis antigens is a more sensitive test of tuberculosis. With this objective in sight, we report the first step in the development of an ELISA for badger IFNgamma. The badger IFNgamma gene was cloned and sequenced and used to generate a specific polyclonal antibody to the cytokine. The gene sequence demonstrated regions that were conserved within the IFNgamma genes of other mammals. The badger sequence was most similar to the canine, showing similar structural organisation of the gene and 88% amino acid identity. Rabbits were immunised with DNA encoding badger IFNgamma and the resulting polyclonal antiserum demonstrated specificity for canine IFNgamma by immunoblot of a commercial recombinant canine IFNgamma. The antiserum was used to detect intracellular badger IFNgamma by flow cytometry analysis of badger lymphocytes stimulated with mitogen.

Amino Acid Sequence↗

PubMed1999

Interleukin-12 modulates T-cell responses to microfilariae but fails to abrogate interleukin-5-dependent immunity in a mouse model of onchocerciasis.

Infection of mice with microfilariae of Onchocerca lienalis induces high levels of protective immunity to reinfection, which is dependent on interleukin (IL)-5 but not IL-4. Here, we have investigated the effect of exogenous IL-12 administration during either the priming or effector phases of the immune response. When administered during priming, IL-12 induced down-regulation of parasite-specific serum immunoglobulin (Ig)E and up-regulation of IgG2a. Antigen-specific IL-4 responses were strongly suppressed, whilst blood eosinophil levels were partially reduced. When administered during a challenge infection, IL-12 did not significantly influence the balance of antibody isotypes, but partially reduced eosinophil production. Antigen-specific IL-4 responses were again completely ablated. Unusually, interferon-gamma (IFN-gamma) responses were not significantly affected following IL-12 administration, either during priming or after challenge infections. Moreover, despite a fall in antigen-specific IL-5 production, the expression of IL-5-dependent immunity, as determined by reduction in worm recoveries, was fully maintained. These data demonstrate that parasite-induced IL-4 can be abrogated without affecting protective immunity to Onchocerca microfilariae in mice. In view of the established role of IL-4 in pathogenesis, this may have important implications for the development of immunoprophylaxis aimed at microfilariae and the alleviation of pathology in onchocerciasis.

Animals↗

PubMed1999

IL-5 dominates cytokine responses during expression of protective immunity to Onchocerca lienalis microfilariae in mice.

In a model of protective immunity against Onchocerca microfilariae (mf), it has been demonstrated previously that immunocompetent mice clear a primary infection and are highly resistant to re-infection. This immunity correlates with CD4+ Th2 cells, is dependent on IL-5 but not IL-4, and can be transferred adoptively with spleen cells. In the current investigation, high levels of spontaneous proliferation and of IFN gamma production were observed in splenocyte cultures from immune mice, compared with cells from naive controls. Antigen-specific proliferation also occurred in immune cells, being vigorous following stimulation with adult worm antigen, but not with antigens from developing embryos or mf. Levels of IL-4, IL-5 and IFN gamma induced by the various antigens was similar, indicating that activation of alternate T helper cell sub-sets was unlikely to explain the lack of cellular responsiveness. After a primary inoculation with mf, spleen cells from infected mice co-produced IFN gamma and IL-5. In contrast, IFN gamma production was downregulated while IL-5 levels remained high during active elimination of a challenge infection. Significant levels of IL-4 production occurred only once parasite clearance had begun. These data confirm the importance of IL-5 in protection against Onchocerca mf in mice and question the role of IFN gamma in the expression of immunity. Production of high levels of IL-5 correlated with blood and tissue eosinophil mobilization during the clearance of a challenge infection.

Animals↗

PubMed1998

Intestinal intraepithelial lymphocytes include precursors committed to the T cell receptor alpha beta lineage.

The majority of T cells develop in the thymus and exhibit well characterized phenotypic changes associated with their maturation. Previous analysis of intestinal intraepithelial lymphocytes (IEL) from nude mice and a variety of experimentally manipulated models led to the view that at least a portion of these cells represent a distinct T cell population that matures extrathymically. The IEL that are postulated to mature within the intestine include both T cell receptor (TCR) alpha beta- and gamma delta-bearing subpopulations. They can be distinguished from conventional thymically derived T cells in that they express an unusual coreceptor, a CD8alpha homodimer. In addition, they can utilize the Fc receptor gamma-chain in place of the CD3-associated zeta-chain for TCR signaling and their maturation depends on the interleukin 2 receptor beta-chain. Moreover, TCRalpha beta+CD8alpha alpha+ IEL are not subject to conventional thymic selection processes. To determine whether CD3(-)CD8alpha alpha+ IEL represent precursors of T cells developing extrathymically, we examined IEL from knockout mice lacking the recombination activating gene-1 (rag-1), CD3epsilon, or both Lck and Fyn, in which thymic T cell development is arrested. CD3(-)CD8alpha alpha+CD16(+) IEL from all three mutant strains, as well as from nude mice, included cells that express pre-TCRalpha transcripts, a marker of T cell commitment. These IEL from lck-/-fyn-/- animals exhibited TCR beta-gene rearrangement. However, CD3(-)CD8alpha alpha+CD16(+) IEL from epsilon-deficient mice had not undergone Dbeta-Jbeta joining, despite normal rearrangement at the TCRbeta locus in thymocytes from these animals. These results revealed another distinction between thymocytes and IEL, and suggested an unexpectedly early role for CD3epsilon in IEL maturation.

Animals↗

PubMed1998

IL-5-dependent immunity to microfilariae is independent of IL-4 in a mouse model of onchocerciasis.

Th2 lymphocyte responses under the control of IL-4 and IL-5 are frequently associated with protective responses to parasitic helminths. Studies on the role of these cytokines in acquired resistance to parasitic nematodes indicate that, in the case of gastrointestinal nematodes, immunity is mediated by IL-4, while immunity to tissue-dwelling nematodes is dependent on IL-5. Here we investigate the role of IL-5 and eosinophils in protective immunity to Onchocerca microfilariae in IL-4-deficient mice. In the absence of IL-4, and despite the up-regulation of Th1-type responses, immunity remains dependent on IL-5 and eosinophils. Protection was unaffected by the absence of Ab in B cell-deficient mice, confirming that IL-5 is not acting via either B cell differentiation, Ag presentation, or isotype switching mechanisms. These data demonstrate the dissociation of IL-4 and IL-5 in a functional model of protective immunity to a tissue dwelling nematode and cast doubt on the role of IL-4 in the generation of CD4+ T cell-mediated, IL-5-dependent immunity to Onchocerca microfilariae. Importantly, they also segregate T cell-mediated mechanisms of protective immunity from those characterized in ocular pathologic responses in onchocerciasis, which are dependent on IL-4.

Animals↗

PubMed1996

Eosinophils are the major effector cells of immunity to microfilariae in a mouse model of onchocerciasis.

Mice inoculated with microfilariae of the filarial nematode Onchocerca lienalis clear their parasites over a period of 3-4 months and are highly resistant to re-infection. We have investigated the comparative roles of the eosinophil, macrophage and neutrophil in effecting this parasite clearance, employing agents specifically to perturb cell function in vivo. Using the anti-IL-5 monoclonal antibody TRFK-5, we show that eosinophils are of primary importance in effecting resistance to re-infection. Ablation of macrophages (with carbon) and neutrophils (with the monoclonal antibody NIMP-R14) had no effect on parasite clearance following re-infection. Neutralization of these 3 cell types during a primary infection showed that while the removal of both eosinophils and macrophages caused a small but significant delay in parasite clearance, the depletion of neutrophils had no effect. This report describes the first direct evidence for eosinophil-mediated killing of microfilariae in vivo, and is consistent with Th-2 cell responses previously described in this model.

Animals↗

PubMed1995

Accelerated clearance of Onchocerca microfilariae and resistance to reinfection in interleukin-4 gene knockout mice.

Immunity to Onchocerca microfilariae (mf) in mice is associated with CD4+ Th2 cells and is dependent on IL-5. In view of the role of IL-4 in the development of Th2 cells, we have utilized IL-4 gene knockout mice (IL-4-/-) to investigate microfilarial clearance and resistance to reinfection. Paradoxically, in the absence of IL-4 there is accelerated clearance of microfilariae during a primary infection and unimpeded expression of resistance to reinfection. IL-4-/- mice showed a lack of an IgE response although peripheral eosinophilia was equivalent to wildtype controls. The data presented here suggest that elimination of mf can occur independent of IL-4 and that in this model it may even be detrimental to the host.

Animals↗

PubMed1973