Beneficial effect of anti-interleukin-4 antibody when administered in a murine model of tuberculosis infection.

There remains much controversy surrounding the role of Th2 cytokines, such as interleukin-4 (IL-4), in tuberculosis infection. Here we demonstrate that anti-IL-4 antibody, administered as a pulse during the early or late stages of murine infection, can provide significant reductions in the bacterial burden. The fact that substantial benefit can be achieved when treatment is administered during established infection strengthens the view that clinical interventions aimed at suppressing the IL-4 component of the host immune response seen in tuberculosis patients may be beneficial.

Current strategies in TB immunotherapy.

Currently available chemotherapy for the treatment of pulmonary tuberculosis (TB) is far from ideal, requiring multiple anti-tuberculous drugs to be taken in combination for extended time periods. This long duration of therapy, coupled with the side effects of current regimens, often results in poor patient adherence, treatment failure and the associated emergence of drug resistance with major financial implications. Thus, the development of novel, shorter treatment regimens is an urgent objective of anti-tuberculous drug discovery. Immunotherapy is an area that merits more consideration than it has previously received, not least, as it could potentially avoid the problem of pathogen resistance. However, this must be undertaken with caution, as at least part of the disease pathology is a consequence of the host immune response. Thus, the protective, and not the harmful, aspects of immunity must be stimulated. Various attempts at utilizing immunotherapy as an adjunct to chemotherapy are reviewed with particular emphasis on the evidence from human studies, including the modulation of cytokine levels, administration of environmental mycobacteria and antibody therapy, in order to modulate or enhance the host immune response to Mycobacterium tuberculosis.

Induction of high levels of protective immunity in mice after vaccination using dendritic cells infected with auxotrophic mutants of Mycobacterium tuberculosis.

Adoptively transferred dendritic cells presenting antigens derived from different pathogens have been shown to elicit specific T cell responses and to induce protective antibacterial immunity. We describe here the induction of high levels of protective immunity in mice using dendritic cells infected with auxotrophic mutants of Mycobacterium tuberculosis. We provide evidence that protection is superior to BCG and that it is associated with increased priming of CD4+ and CD8+ T cells specific for mycobacterial antigens. This method for generating high levels of anti-bacterial protective immunity could be helpful in the design of novel vaccines against tuberculosis and other intracellular pathogens.

Therapeutic efficacy of high-dose intravenous immunoglobulin in Mycobacterium tuberculosis infection in mice.

Intravenous immunoglobulin (IVIg) is used to treat patients with primary antibody deficiencies and, at high doses, to treat a range of autoimmune and inflammatory disorders. With high-dose IVIg (hdIVIg), immunomodulatory mechanisms act on a range of cells, including T cells, B cells, and dendritic cells. Here, we demonstrate that the treatment of M. tuberculosis-infected mice with a single cycle of hdIVIg resulted in substantially reduced bacterial loads in the spleen and lungs when administered at either an early or late stage of infection. Titration of the IVIg showed a clear dose-response effect. There was no reduction in bacterial load when mice were given equimolar doses of another human protein, human serum albumin, or maltose, the stabilizing agent in the IVIg preparation. HdIVIg in vitro had no inhibitory effect on the growth of M. tuberculosis in murine bone marrow-derived macrophages. In addition, the effect of hdIVIg on bacterial loads was not observed in nude mice, suggesting the involvement of conventional T cells. Analysis of T cells infiltrating the lungs revealed only small increases in CD8(+) but not CD4(+) T-cell numbers in hdIVIg-treated mice. The mechanism of action of hdIVIg against tuberculosis in mice remains to be determined. Nevertheless, since hdIVIg is already widely used clinically, the magnitude and long duration of the therapeutic effect seen here suggest that IVIg, or components of it, may find ready application as an adjunct to therapy of human tuberculosis.