Abstract
New evidence has been emerging that antibodies can be protective in various experimental models of tuberculosis. Here, we report on protection against multidrug-resistant Mycobacterium tuberculosis (MDR-TB) infection using a combination of the human monoclonal IgA 2E9 antibody against the alpha-crystallin (Acr, HspX) antigen and mouse interferon-gamma in mice transgenic for the human IgA receptor, CD89. The effect of the combined mucosal IgA and IFN-γ; treatment was strongest (50-fold reduction) when therapy was applied at the time of infection, but a statistically significant reduction of lung bacterial load was observed even when the therapy was initiated once the infection had already been established. The protection involving enhanced phagocytosis and then neutrophil mediated killing of infected cells was IgA isotype mediated, because treatment with an IgG version of 2E9 antibody was not effective in human IgG receptor CD64 transgenic mice. The Acr antigen specificity of IgA antibodies for protection in humans has been indicated by their elevated serum levels in latent tuberculosis unlike the lack of IgA antibodies against the virulence-associated MPT64 antigen. Our results represent the first evidence for potential translation of mucosal immunotherapy for the management of MDR-TB.
Highlights
The evidence for a protective role of antibodies in tuberculosis (TB) has been strengthened significantly over the last decade or so, owing to a number of recent reports [1,2,3,4,5]
Using a transgenic mouse model expressing either human IgA (CD89) or IgG (CD64) receptors [20], we demonstrate effectiveness of IgA but not IgG and elucidate potential mechanisms involved in protection
The purified antibody migrated as a 160 kDa protein band under non-reducing conditions and as 55 kDa and 25 kDa protein bands under reducing conditions, as shown by Coomassie staining or Western blot (Figure 1A). 2E9IgA1 was fully functional as determined in direct antigen binding assay (Figure 1B) and bound to the surface of BCG as confirmed by flow cytometry (Figures 1D, G), while no binding could be observed with E. coli (Figures 1C, F)
Summary
The evidence for a protective role of antibodies in tuberculosis (TB) has been strengthened significantly over the last decade or so, owing to a number of recent reports [1,2,3,4,5]. Mucosal IgA Immunotherapy of Tuberculosis healthcare workers were more protective than those from TB patients, and this appears to be a common theme emerging from the most recent studies. Lu et al [3], reported that antibodies from individuals with latent M. tuberculosis infection were superior to those from active TB patients in their capacity to mediate intracellular killing of the bacteria by macrophages. This was associated with distinct glycosylation profiles of these antibodies which conferred superior functional properties and in particular enhanced interaction with the immunoglobulin Fc receptors on phagocytic cells
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