Genetically susceptible mice remain proportionally more susceptible to tuberculosis after vaccination

DBA/2 mice are much more susceptible to infection with Mycobacterium tuberculosis than major histocompatibility complex-compatible BALB/c mice. It is shown here that, although vaccination provided mice of both strains with a capacity to reduce the level of infection in their lungs, vaccinated DBA/2 mice remained much more susceptible in this organ than vaccinated BALB/c mice. Consequently, the former mice developed more lung pathology and died much earlier than the latter. On the other hand, colony-forming unit counts and histology suggest that vaccination provided mice of both strains with an increased and equal ability to express immunity in the liver and spleen, thereby indicating that they possessed equal systemic levels of vaccine-induced immunity at the time of M. tuberculosis challenge. The results indicate that inefficient expression of immunity in the lungs is likely to prove an obstacle to successful vaccination against tuberculosis in resistant and susceptible mouse strains, but more so in the latter strains

HIV Alters Plasma and M. tuberculosis-induced Cytokine Production in Patients with Tuberculosis

To test the hypothesis that HIV infection brings about an alteration in the immune response to tuberculosis (TB), mycobacterial antigen-induced production and plasma levels of the inflammatory cytokine interferon-g (IFN-g) and its regulatory cytokines interleukin-12 (IL-12), IL-18, and IL-10 were determined in patients infected dually with HIV and TB and compared with individuals with either disease and with healthy controls. Peripheral blood mononuclear cells (PBMCs) of TB patients with HIV infection produced lesser amounts of IFN-g and IL-12 compared with TB patients without HIV infection after in vitro stimulation with mycobacterial antigens. There was no difference in antigen-induced IL-18 production in TB patients with or without HIV infection. The in vivo cytokine pattern did not correlate with that seen in vitro. Higher levels of IFN-g, IL-12, and IL-18 were detected in the plasma of TB patients infected with HIV compared with TB patients without HIV infection. The presence of significantly higher plasma levels of proinflammatory cytokines suggests a greater degree of immune activation in individuals with HIV and TB, particularly those with low CD4 counts. In vitro IL-10 production by HIV-positive TB patients was similar to that of the HIV-negative TB group and higher than in HIV-positive individuals without TB, but the plasma levels were similar. HIV infection downregulates the in vitro Th1 cytokine response to TB and simultaneously increases systemic levels of these cytokines

Lack of protection in mice and necrotizing bronchointerstitial pneumonia with bronchiolitis in guinea pigs immunized with vaccines directed against the hsp60 molecule of Mycobacterium tuberculosis.

&lt;p&gt;In this study, the hsp60 and hsp70 heat shock protein antigens of Mycobacterium tuberculosis were tested as potential vaccine candidates, using purified recombinant protein antigens or antigens encoded in the form of a DNA plasmid vaccine. Guinea pigs vaccinated with a mixture of the two proteins showed no evidence of resistance to low-dose aerosol challenge infection and quickly developed severe lung damage characterized by necrotizing bronchointerstitial pneumonia and bronchiolitis. As a result, we turned instead to a DNA vaccination approach using a plasmid encoding the hsp60 antigen of M. tuberculosis. Although immunogenic in mice, vaccination with plasmid DNA encoding hsp60 was not protective in that model or in the guinea pig model and again gave rise to similar severe lung damage. This study seriously questions the safety of vaccines against tuberculosis that target highly conserved heat shock proteins.&lt;/p&gt;</p

Induction of immunity by DNA vaccination: application to influenza and tuberculosis.

&lt;p&gt;DNA vaccination is an effective means of inducing both humoral and cell-mediated immunity in animal models of infectious disease. Presented here are data generated in two distinct disease models; one viral (influenza) and one bacterial (tuberculosis). Specifically, plasmid DNA encoding an influenza virus antigen (nucleoprotein; NP) and a Mycobacterium tuberculosis antigen (antigen 85; Ag85) were prepared and tested as DNA vaccines in mice. In both cases, high titer antibody responses and robust cell-mediated immune responses were induced against the respective antigens. With respect to the latter, lymphocyte proliferation, Th1-type cytokine secretion, and cytotoxic T lymphocyte responses were observed upon restimulation with antigen in vitro. Furthermore, protective efficacy in animal challenge models was demonstrated in both systems. The data support the hypothesis that DNA vaccination will prove to be a broadly applicable technique for inducing immunity against various infectious diseases.&lt;/p&gt;</p

Co-immunization with DNA vaccines expressing granulocyte–macrophage colony-stimulating factor and mycobacterial secreted proteins enhances T-cell immunity, but not protective efficacy against Mycobacterium tuberculosis

The development of more effective antituberculosis vaccines would assist in the control of the global problem of infection with Mycobacterium tuberculosis. One recent vaccination strategy is immunization with DNA plasmids encoding individual microbial genes. Using the genes for the M. tuberculosis-secreted proteins, MPT64 (23 000 MW) and Ag85B (30 000 MW) as candidate antigens, we previously prepared DNA vaccines and demonstrated their ability to stimulate T-cell responses and confer protection in a mouse model of aerosol tuberculosis (TB). The protective efficacy of the DNA vaccines was less than that promoted by the current vaccine Mycobacterium bovis bacille Calmette–Guèrin (BCG). To improve the immunogenicity and protective efficacy of these mycobacterial vectors, co-immunization of a plasmid expressing granulocyte–macrophage colony-stimulating factor (GM-CSF) was investigated. Intramuscular immunization with DNA expressing MPT64 or Ag85B and GM-CSF enhanced the antigen-specific cellular immune response, with increased proliferative response and production of interferon-γ (IFN-γ). The titre of antimycobacterial protein immunoglobulin G (IgG) antibodies was unchanged. Mice immunized with DNA vaccines showed reduced pulmonary bacterial load following an aerosol challenge of M. tuberculosis, but codelivery of the plasmid expressing GM-CSF did not increase the protective effect. Therefore, despite modifying the cellular immune response to DNA vaccines, GM-CSF does not improve their protective efficacy at the peak of infection after an aerosol challenge with 100 c.f.u. of M. tuberculosis