Julian K Ma

University of London, Londinium, England, United Kingdom

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Publications (2)6.28 Total impact

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    ABSTRACT: Protein subunit vaccines are an attractive mode of immunisation against infectious diseases but the approach is hampered by the lack of suitable adjuvants for human use. We investigated if antigen targeting to the endocytic cell receptor Dec-205 on dendritic cells (DCs) could induce a protective immune response to Mycobacterium tuberculosis (MTB) infection in the absence of conventional adjuvants. Dec-205 receptor expressed by several subsets of DC has been shown in previous studies to be an efficient endocytic receptor for inducing both humoral and cellular immune responses, but this immunisation approach has not been tested in an experimental model of infection. We therefore prepared chemical conjugates of an anti-mouse Dec-205 monoclonal antibody (mAb) and the highly immunogenic antigen 85B (Ag85B) of MTB and showed that they bound efficiently to bone-marrow derived DC. Moreover, DC stimulated in vitro with Dec-205 conjugates could induce proliferation of splenocytes from Ag85B-immunised mice, while the negative control conjugates failed to do so. Following immunisation of mice with the anti-Dec-205-Ag85B conjugates administered together with a co-stimulatory anti-CD40 mAb, antigen-specific humoral and cellular responses were detected. Although the conjugates induced a strong Ag85B-specific humoral response, T cell proliferation and interferon-γ production were observed only when the conjugates were used to boost BCG vaccine. Importantly though, the conjugate vaccine did not offer significant protection against MTB challenge when used on its own or as a boost to BCG. Therefore, we conclude that Ag85B-based vaccine targeting to Dec-205 alone is not a sufficiently robust vaccination strategy for tuberculosis, although this approach might be more successful with other antigens or infections.
    Vaccine 01/2011; 29(12):2279-86. · 3.77 Impact Factor
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    ABSTRACT: Macrophages are the target cells for mycobacterial infections. They are also largely responsible for intracellular killing of mycobacteria, which is dependent on the cytokine environment. Interferon-gamma (IFN-gamma) is chiefly responsible for macrophage activation and bactericidal capacity while Th2 cytokines have a contrasting effect. However, cytokines rarely act in isolation during an infection. Instead, multiple cytokines, both activating and inhibitory, are present and their concentration levels and mutual interactions are likely to determine the ultimate outcome of an infection. Here, we used an in vitro infection model of mouse macrophages to study the effect of cytokine interactions on the infection with Mycobacterium bovis strain BCG. We measured nitric oxide (NO) production and bacterial survival in cells following stimulation with various combinations of cytokines. The surprising finding was that high concentrations of IL-10 (i.e., above 16.5 ng/ml), which is generally considered to be a macrophage-suppressive cytokine, enhanced IFN-gamma-induced NO production. Furthermore, the simultaneous addition of either of the two Th2 cytokines IL-4 or IL-13, strongly inhibited IFN-gamma-mediated NO production and bacterial killing even at a low concentration of 0.62 ng/ml, but could not reverse the synergistic action of IFN-gamma and TNF-alpha, even when the Th2 cytokines were present at high concentrations (i.e., 50 ng/ml). Therefore, macrophage activity is heavily dependent on the cytokine micro-environment where the final outcome is determined in equal measures by the nature of cytokines present, the timing of their accumulation and their concentration levels.
    Cytokine 07/2010; 51(1):42-6. · 2.52 Impact Factor