395회 Immunity to tuberculosis: On the limited protective value of anti…

395회  

일시: 2006. 09. 21

연사: 정유진, 강원대학교 자연과학대학

제목: Immunity to tuberculosis: On the limited protective value of anti-tuberculosis immunity in a susceptible host.

Abstract

Only 5-10% of immunocompetant humans are susceptible to tuberculosis (TB), and of those who become infected more than 85% develop the disease exclusively in the lungs. In immunocompromise humans, by contrast, the disease can be systemic, involve multiple organs and result in much earlier death. This indicates that most susceptible, immuunocompetent humans generate an anti-TB immune response that exerts a growth inhibitory influence on Mycobacterium tuberculosis (Mtb) and acts to confine infection-induced disease to the lungs. It is now established that humans with active TB generate Th1-mediated anti-Mtb immunity.

Mice are also susceptible to tuberculosis, and like most susceptible humans develop disease exclusively in the lungs. Mice also generate Th1-mediated anti-Mtb immunity that is capable of inhibiting Mtb growth in the lungs at about day 20 on infection, and of holding infection at a stationary level. However, stationary level infection induces progressive lung pathology that is eventually lethal. It can be argued, therefore, that immunity to mouse TB is like immunity to the disease in susceptible humans, and that the reason for failure of immunity to resolve infection in mice will prove to be the same as that for failure of immunity to resolve infection in humans.

The purpose of vaccination is to enable susceptible hosts to mount a successful Th1 immune response, and it seems reasonable to propose that the requirements for successful vaccination of mice will apply to susceptible humans. Research in many laboratories is aimed at developing vaccines that are more protective than the vaccine currently in use, the attenuated BCG strain of M.bovis that is considered of limited value in protecting humans. It is clear, however, that attempts to vaccinate mice against Mtb infection with a variety of recently developed vaccines have proved no more successful than vaccinating with BCG. In all cases vaccination provided about 1 log of protection against an Mtb challenge infection.

The purpose of this presentation is to discuss the meaning of the 1 log of protection afforded by vaccination, and to argue that the protection afforded by any one vaccine will prove to be wholly attributable to its ability to enable the host to generate an earlier Th1 immune response that serves to inhibit Mtb growth at an earlier stage of infection when the number of Mtb is about 1 log lower. It will be argued further that earlier expression of immunity does not enable mice to resolve the lower level of infection, but enables them, instead, to hold infection at a lower stationary level that is disease inducing. The inability of naive and vaccinated mice to resolve infection may not be the result of an inadequate number of Mtb-specific T cells, but a consequence of functional limitations of macrophages that are transcriptional activated by Th1 cytokines to express immunity. If inhibition of Mtb growth is part of a metabolic counter response on the part of pathogen that enables it to survive the antimicrobial defenses acquired by activated macrophages, then, the earlier that Th1 immunity mediates macrophage activation the earlier the pathogen will defend itself by entering a state of nonreplicating persistence. It is apparent that Mtb has evolved to survive in susceptible humans in a nonreplicating state that, with the aid of Th1 immunity, enables it to induce lung pathology of a chronic type that favors its long-term transmission to new hosts.