A mAb recognizing a surface antigen ofMycobacterium tuberculosisenhances host survival

Abstract

Murine mAbs reactive with the surface of Mycobacterium tuberculosis were assayed for their ability to affect the course of infection in mice challenged with virulent organisms. An IgG3 mAb (9d8) specific for arabinomannan and reactive with purified antigen from a clinical isolate of M. tuberculosis conferred partial protection on mice after respiratory challenge (30-60% survival >75 days; P < 0.05). Control mice pretreated with an irrelevant mAb of the same isotype succumbed to tuberculosis within 30 days. Mice with gene disruptions in interferon ␥ and major histocompatibility complex Class II also were partially protected from challenge. The protective mAb was neither bactericidal nor inhibitory of infection or bacterial replication. Nevertheless, it profoundly altered the nature of the granulomas in the infected lungs. Mice treated with mAb 9d8 and challenged with M. tuberculosis localized the pathogen within granuloma centers, suggesting that the mAb conferred protection by enhancing a cellular immune response.

Human NKT Cells Express Granulysin and Exhibit Antimycobacterial Activity

“…IFN-␥ can activate phagocytes to kill intracellular organisms through upregulation of nitrogen-radical production (49), and NKT cell-derived IFN-␥ might be particularly beneficial in the setting of mycobacterial infection because the virulence of strains of M. tuberculosis from human clinical isolates varies inversely with the ability to induce a Th1 response (50). Recent data also indicates that humoral responses can also contribute to host defense because Abs directed against mycobacterial Ags confer protection by directing organisms to granulomas (51). A role for NKT cell-derived IL-4, a mediator of humoral immunity, is suggested by studies demonstrating that NKT cells are necessary for the formation of granuloma-like lesions in mice exposed to mycobacterial cell walls (19).…”

“…Target cells were pulsed with ␣GalCer for 16 h, then washed and labeled with 100 Ci of 51 Cr (ICN Biomedicals) for 1 h and plated in a 96-well V-bottom plate at a final concentration of 5000 targets/100 l. T cells were then added at indicated E:T ratios for 4 h. Supernatants were collected and target cell lysis was calculated by quantifying 51 Cr release. The spontaneous 51 Cr release by monocytes or MoDCs in the absence of T cells was Ͻ10%. Results are expressed as percent specific lysis and are calculated as follows: 100 ϫ (experimental release Ϫ spontaneous release)/(maximum release Ϫ spontaneous release).…”

Latently and uninfected healthcare workers exposed to TB make protective antibodies against Mycobacterium tuberculosis

“…Furthermore, as an intracellular pathogen, it has been argued that Mtb would not be within the therapeutic reach of antibodies. Nonetheless, multiple studies have shown the efficacy of mAbs in ameliorating murine models of TB infection (6)(7)(8)(9)(10)(11)(12), and antibodymediated immunity to several intracellular pathogens, including Cryptococcus neoformans and typhoid Salmonella, has been documented (13), raising the possibility that antibody-mediated immunity may also exist for TB. Pooled Igs from human donors have been shown to protect mice against Mtb (14), but it was not known if this was caused by a generalized immunomodulatory effect (15) targeting the inflammatory component of the disease or whether protective antibodies directly targeting critical mycobacterial antigens could be isolated from individuals.…”

The Pathology ofMycobacterium tuberculosisInfection

“…Antibody-opsonized mycobacteria are more efficiently internalized and killed by neutrophils and macrophages 49 and more effectively processed for antigen presentation by DCs. 198 Interestingly, although antibody production is typically associated with a shift to a Th2 response, BCG-induced antibodies were shown to enhance proliferation of IFN-g production in mycobacteriumspecific CD4þ and CD8þ T cells. 49 Unfortunately, diagnostic testing for antibody responses to Mtb components has poor sensitivity and specificity, rendering these tests relatively ineffective.…”