passive protection with immunoglobulin a antibodies against tuberculous early infection of the lungs

6
Passive protection with immunoglobulin A antibodies against tuberculous early infection of the lungs ANN WILLIAMS,* RAJKO RELJIC,y IRENE NAYLOR,* SIMON O. CLARK,* GUSTAVO FALERO-DIAZ,z MAHAVIR SINGH,§ STEPHEN CHALLACOMBE,y PHILIP D. MARSH* & JURAJ IVANYIy *Health Protection Agency, Porton Down, Centre for Applied Microbiology and Research (CAMR), Salisbury, UK, yDepartment of Oral Medicine & Pathology, Guy's Campus of Kings College London, UK, zDepartment of Monoclonal Antibodies, Finlay Institute, Havana, Cuba, and §Department of Biochemistry, Technical University, Braunschweig, Germany SUMMARY We report on a new approach toward protection against tuberculosis, based on passive inoculation with immunoglobulin A (IgA) antibodies. In a mouse model of tuberculous lung infection, intranasal inoculations of mice with an IgA monoclonal antibody (mAb) against the a-crystallin antigen of Mycobacterium tuberculosis reduced up to 10-fold the lung bacterial counts at nine days after either aerosol- or intranasal challenge. This effect involved synergism between mAb inoculations shortly before and 3 days after infection. Monomeric IgA reduced the colony-forming unit counts to the same extent as the polymeric IgA, suggesting antibody targeting to Fca, rather than poly-immunoglobulin receptors on infected lung macrophages. The protective effect was of short duration, presumably due to the rapid degradation of the intranasally applied IgA. Our results provide evidence of an alternative approach which could be further developed toward immunoprophylaxis against tuberculosis in immunocompromised subjects. INTRODUCTION According to currently established concept, immune resistance against tuberculosis (TB) is mediated exclusively by T cells, involving cytokine (mainly interferon-g)-mediated activation or cytotoxicity of infected macrophages, and this view determines all current strategies of TB vaccine research. However, active tuberculosis develops in the majority of patients despite the presence of abundant T helper 1 immunity 1 and T-cell targeted vaccination does not always induce optimal protection either in humans or in experimental animals. Therefore, it is desirable to investigate alternative immune mechanisms of protection. Recently, the potential protective role of antibodies against tuberculosis was re-appraised 2 and data demonstrating a pro- tective effect were reported using an immunoglobulin G3 (IgG3) monoclonal antibody (mAb) against lipoarabinomannan (LAM) 3 and with antibodies against the heparin-binding hae- magglutinin. 4 Passive antibody-mediated protection has recently been demonstrated also in respect of a number of non-tuberculous intracellular bacterial infections. 5±7 Further indirect supportive data in humans associated serum IgG anti- body levels to LAM with milder manifestation of child tuber- culosis 8 and salivary IgA antibody levels with protection against leprosy. 9 Most recently, protection of mice and guinea pigs against TB challenge by vaccination with mycobacterial arabi- nomannan±protein conjugates, was attributed at least partly to IgG antibodies interfering with the deleterious effects of LAM. 10 We focused attention in this study to mAbs of the IgA isotype, in view of a capacity of the poly-IgR-mediated trans- cytosis of polymeric IgA antibodies to interact with intracellular pathogens 11 and of the potent Fca mediated activation of mononuclear cells for bacterial clearance. 12 Interest in the IgA isotype was stimulated also by the ®nding, that protection against pulmonary tuberculous infection in protein antigen vaccinated mice was associated with elevated IgA antibody forming cells in the lungs. 13 Therefore, we recently gene- rated IgA mAbs against surface expressed antigens of Immunology 2004 111 328±333 328 # 2004 Blackwell Publishing Ltd Received 24 September 2003; revised 28 October 2003; accepted 28 November 2003. Abbreviations: LAM, lipoarabinomannan; polyIgR, polyIg receptor; RLU, relative luminescence units; PBS, phosphate-buffered saline; CFU, colony-forming units; mAbs, monoclonal antibodies. Correspondence: Dr J. Ivanyi, Department of Oral Medicine and Pathology, Guy's Tower Floor 28, Guy's Hospital, London SE1 9RT, UK. E-mail: [email protected] doi: 10.1111/j.1365-2567.2004.01809.x

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