Tuberculosis immune response

Although a humoral immune response is the primaiy protection against most viral and some bacterial diseases, protective defense against other pathogens such as HIV, Plasmodium and Mycobacterium tuberculosis requires a cytotoxic response mediated by CD8+ T-cells (CTL response). Since the introduction of the vaccination concept by Jenner almost 200 yeats ago, only few vaccines have been developed that are able to induce a CTL response. These vaccines are usually attenuated live vaccines that are accompanied by certain risks and are not readily available for most pathogens. The immense appeal of DNA vaccines can be attributed to a considerable part to the fact that they are able to induce... 

Mohan, V.P. et al., Effects of tumor necrosis factor alpha on host immune response in chronic persistent tuberculosis Possible role for limiting pathology, Infect. Immun., 69, 1847, 2001. 

In many instances, the unaided immune response to such infections can be inadequate, leading to prolonged and/or serious illness. Examples include the malaria and tuberculosis agents, the HIV virus (which has infected at least 14 million people worldwide), leishmaniasis (caused by the protozoan Leishmania, from which 12 million people suffer) and schistosomiasis, (caused by the Schistoma mansoni helminth, which currently infects approximately 250 million people worldwide). 

This vaccine is routinely given to infants and small children in countries where TB is common. This vaccine contains a live attenuated (weakened) strain of Mycobacterium tuberculosis, the bacterium which causes tuberculosis. The bacterium has been modified to produce a strain known as Bacille Calmette-Guerin, named after its discoverer. Killed vaccines (strain) can not be used to protect against tuberculosis infection since they do not produce the necessary cellular immune response. 

BCG is a viable strain of Mycobacterium bovis that has been used for immunization against tuberculosis. It has also been employed as a nonspecific adjuvant or immunostimulant in cancer therapy but has been successful only in intravesical therapy for superficial bladder cancer. BCG appears to act at least in part via activation of macrophages to make them more effective killer cells in concert with lymphoid cells in the cellular efferent limb of the immune response. Lipid extracts of BCG as well as nonviable preparations of Corynebacterium parvum may have similar nonspecific immunostimulant properties. A chemically defined derivative of the BCG cell wall, [Lys18]-muramyl dipeptide, has been licensed in Japan to enhance bone marrow recovery after cancer chemotherapy. 

IFN-y, a 20 to 25 kDa lymphokine, is synthesized naturally by activated T cells, and is critical in the immune response against Mycobacterium tuberculosis. Beck et al. [94] have demonstrated the efficacy of aerosol-administered murine IFN-y in pneumocystis-infected mice, while the results of studies in rodents have indicated an antitumor effect [95] and anti-infective potential of IFN-y [96]. Deposition studies indicated that aerosolized IFN-y can be effectively delivered to the lower respiratory tract, and that IFN-y given by this route does not reach the systemic... 

PCR can provide valuable diagnostic information in medicine. Bacteria and viruses can be readily detected with the use of specific primers. For example, PCR can reveal the presence of human immunodeficiency virus in people who have not mounted an immune response to this pathogen and would therefore be missed with an antibody assay. Finding Mycobacterium tuberculosis bacilli in tissue specimens is slow and laborious. With PCR, as few as 10 tubercle bacilli per million human cells can be readily detected. PCR is a promising method for the early detection of certain cancers. This technique can identify mutations of certain growth-control genes, such as the ras genes (Section 15.4 2). The... 

The most popular and successful adjuvants have been the water in oil emulsions developed by Freund. The basic ingredients of light mineral oil (Bayol) and emulsifying agents mixtures such as Arlacel (A or C) are available commercially. The reagents are emulsified with either solutions or suspensions of the immunogen (incomplete Freund s adjuvant). The addition of mycobacteria (Mycobacterium butyricum, M. tuberculosis) in small amounts to the suspension (complete Freund s adjuvant) leads to a further enhancement of the immune response. This has been attributed to the increased local inflammatory response caused by the mycobacteria. ... 

Live Attenuated Organisms. Live attenuated bacteria and viruses have been used not only as vaccines but also as a delivery system that elicits humoral, mucosal, and cellular immune responses against exogenous antigens. Since the success with live attenuated oral vaccines against tuberculosis and polio more than 3 decades ago, a number of live attenuated microorganisms have been used as antigen-delivery systems. Live vaccines are relatively easy and cheap to manufacture, because they do not require purification of... 

M. tuberculosis bacteria persist in the harsh environment of the host s alveolar macrophages. These bacteria are able to survive by downregulating the host s immune response. Specifically, M. tuberculosis prevents activation of the infected macrophages. Macrophage activation would lead to production of pro-inflammatory cytokines, such as IL-12, IL-18 and tumor necrosis factor a (TNF-a), and to production of interferon-y producing T cells, allowing the host to combat the infection [303]. Both the LAMs and the mycolic acids of M. tuberculosis are able to modulate the host s immune response. 

ManLAM and PILAM seem to have opposite effects on the immune response [262,264]. Man-LAM was shown to inhibit macrophage activation, the production of the pro-inflammatory cytokines IL-12 and TNF-o and, M. tuberculosis -induced macrophage apoptosis. PILAM, in contrast, induces the release of pro-inflammatory cytokines. By suppressing the immune response, ManLAM thus promotes survival of pathogenic mycobacteria, while PILAM promotes killing of non-pathogenic mycobacteria. ManLAM and PILAM were also shown to interact with different cell-surface receptors on phagocytic cells [262,264]. 

In contrast to contact hypersensitivity, tuberculin-type hypersensitivity reactions are primarily dermal and result from intradermal injections into the skin. In people that have had tuberculosis or have been exposed to the bacterium through infection or BCG immunization, a cell-mediated immune response to the bacterium develops. When small amounts of tuberculin (a complex mixture of antigenic material derived from Mycobacterium tuberculosis) are subsequently injected into the skin, a localized T cell-dependent inflammatory response develops in the dermis. Within 24-72 h of injection, individuals with prior exposure to the bacterium display a raised, red, indurated area on the skin at the injection site. The lack of a response suggests no prior exposure to the bacterium. 

TNFa is classically associated with septic shock and diverse infectious pathological conditions. It is involved in the development of a protective immune response in tuberculosis. Measurable serum TNFa levels have been detected in 10.5% of children with pulmonary tuberculosis, all of whom belonged to the group with active disease. Results suggest a protective role for TNFa in respiratory syncytial virus infection. In patients with chronic hepatitis C during treatment with IFNa, elevated production of TNFa by PBMCs may be due to host response to the virus. In HIV infection, TNFs and IL-6 stimulate viral replication. 

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