Properties and protective value of the secondary versus primary T helper type 1 response to airborne Mycobacterium tuberculosis infection in mice

Abstract

Mice immunized against Mycobacterium tuberculosis (Mtb) infection by curing them of a primary lung infection were compared with naive mice in terms of the ability to generate a Th1 cell immune response and to control growth of an airborne Mtb challenge infection. Immunized mice generated and expressed Th1 cell immunity several days sooner than naive mice, as demonstrated by an earlier increase in the synthesis in the lungs of mRNA for Th1 cytokines and for inducible nitric oxide synthase, an indicator of macrophage activation. This Th1 cytokine/mRNA synthesis was accompanied by an earlier accumulation of Mtb-specific Th1 cells in the lungs and the presence of CD4 T cells in lesions. An earlier generation of immunity was associated with an earlier inhibition of Mtb growth when infection was at a 1-log lower level. However, inhibition of Mtb growth in immunized, as well as in naive, mice was not followed by resolution of the infection, but by stabilization of the infection at a stationary level. The results indicate that there is no reason to believe that the secondary response to an Mtb infection is quantitatively or qualitatively superior to the primary response.

Poor correlation between BCG vaccination-induced T cell responses and protection against tuberculosis

“…Rapid accumulation of specific IFN-␥-secreting CD8 ϩ T cells is in line with previous observations of accelerated accumulation of CD8 ϩ T cells and early IFN-␥ production in tissues of vaccinated or infected and cured mice (13)(14)(15)18). At later time points after challenge, nonvaccinated mice showed similar numbers of specific IFN-␥ secreting CD8 ϩ T cells when compared with vaccinated mice.…”

“…At the plateau phase of M. tuberculosis infection, frequencies of Ag85-specific IFN-␥ secreting CD4 ϩ T cells correlated with mycobacterial load in tissues rather than with protection. This lack of correlation of specific CD4 ϩ T cells with protection was unexpected, because CD4 ϩ T cell responses, in particular, IFN-␥ secretion, are considered pivotal for control of tuberculosis (14).…”

“…After challenge infection, the secondary immune response in vaccinated mice or mice previously cured of M. tuberculosis infection is characterized by accelerated accumulation of effector T cells in infected tissues and early production of Th1 cytokines (12)(13)(14)(15)(16)(17)(18). Consequently, mycobacterial growth is restricted more efficiently in the initial phase of infection, and growth reaches a plateau at a 10-fold-lower level as compared with nonvaccinated animals.…”

Antigen-Specific CD8+ T Cells and the Development of Central Memory during Mycobacterium tuberculosis Infection

“…Although immunological memory induced by M. tuberculosis can provide short-term protection as indicated by a reduction in the bacterial burden following rechallenge, some data suggest that long-term protective memory to M. tuberculosis does not efficiently develop in experimentally infected animals (20,42). The reinfection of patients previously treated for tuberculosis also challenges the notion that prior exposure to M. tuberculosis induces protective immunity (7,(43)(44)(45).…”

Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective responses against challenge with virulent Mycobacterium tuberculosis

“…This is known to be crucial for host protection against MTB infection [52][53][54]. Hwang, et al demonstrated in vitro that addition of lactoferrin on activated macrophages leads to increase IL-12 production while at the same time reducing IL-10 [25,33].…”