Tuberculosis (TB)

There have been no in-vivo clinical studies on the affects of Qina in the treatment of M.tuberculosis, however there have been hundreds of clinical anecdotal testimonial accounts of how Qina in conjunction with standard TB medication has reduced the cure rate from 6 months to just over three.
Based on the immunological explanations of TB (detailed below) and the accomplished clinical data on Qina we propose an explanation as to why this pathogenic effect is taking place.

By initially infecting the macrophage with TB, the normal immunologic function of the immune response of which the macrophage is the key controlling component, the rest of the immune mechanism is not activated in the correct sequencing and communication between cells is diminished. Qina has been proven to stimulate Macrophage activation within 24 hours, reducing TNFa production and increasing the activity of iNOS, consequently reducing ROS and NO respectively. Once induced, iNOS produces large amounts of NO which accounts for its microbicidal and tumoricidal activities. In addition Qina increases the CD+4 and CD8+ T cells in the correct ratio to each other, as well as the volume of cytokines.

The exact in-vivo mechanism of action as to why the NO production of macrophages is diminished in the presence of the Mycobacterium tuberculosis is not fully understood, AJRCCM (pp. 178–186) however with the use of Qina it emerges that one of the keys to a proper response is Macrophage activation resulting in the subsequent communication pathways to other immune components.

Immunological Aspects

M. tuberculosis initially infects macrophages. M. tuberculosis is surrounded by a lipid rich outer capsule which protects it from the toxic radicals and hydrolytic enzymes produced as a defense by macrophages. Pathogenic mycobacterium can spread into neighboring resting macrophages which serve as the preferred habitat for replication. Macrophages, activated by persistent exposure to inhaled particulates, possess potent microbicidal activity which can kill bacilli and arrest TB infection, but generally cannot eliminate infection entirely. Other essential mechanisms of anti-mycobacterial immunity include the destruction of infected cells by cytolytic T-lymphocytes.

Initial growth of M. tuberculosis results in a delayed type hypersensitivity response which is characterized by the formation of small necrotic lesions with solid caseous centers. M. tuberculosis multiplication is probably restricted while encapsulated in these granulomatous lesions. Granulomas (lesions) consist of T-lymphocytes and mononuclear phagocytes of different levels of maturation and activation. After initiation of delayed-type hypersensitivity (DTH) and tubercle formation, activation of macrophages by CD4+ TDTH cells enables the macrophages to destroy bacilli within the tubercle. Macrophage activation appears to be a central step of acquired resistance against M. tuberculosis.

Macrophage activation is achieved by T lymphocytes which are the principle mediator of cell mediated immune response against M. tuberculosis. CD4+ T cells are primarily helper T cells which secrete interleukins involved in the activation of macrophages. In the DTH response to M. tuberculosis, CD4+ T cells predominate over CD8+ T cells which are primarily cytolytic cells that lyse specific target cells.

Helper T cells are required to recruit and activate new monocytes and macrophages to the tubercle (lesion). CD4+ T cells are divided into TH1 and TH2 subsets depending on the type of cytokines produced. TH1 cells produce the cytokines interferon-gamma (IFN-gamma) and interleukin (IL-2), which are important for activation of anti-mycobacterial activities and essential for the DTH response. IFN-gamma specifically activates macrophages and stimulates them to ingest and kill mycobacterium more effectively.

Macrophage activation by cytokines provides only a partial explanation for immunity to M. tuberculosis. The presence of an MHC Class I-restricted response to mycobacterial infection has been shown in several T lymphocytes. CD8+ T lymphocytes contribute to macrophage activation by producing IFN-gamma. CD8+ T cells also may have cytolytic functions which enable them to recognize mycobacterial antigens presented by MHC Class I molecules on the surface of infected macrophages. CD8+ cytotoxic T-lymphocytes (CTLs) are thought to be required to release intracellular M. tuberculosis residing in infected macrophages.

CTLs with specificity for mycobacterial antigens have been identified in the murine model of tuberculosis. This has shown that exogenous antigen can gain access to the class I processing and presentation pathway, and elicit a CD8+ T cell response in vivo. M. tuberculosis has the ability to survive within macrophages, providing metabolic antigens for processing and presentation with Class I molecules on the macrophage surface. It has been suggested that mycobacteria may be able to avoid processing within the phagolysosomal environment and in doing so antigen may enter the endogenous antigen-processing pathway and be presented to CD8+ T cells. (Turner & Dockrell, 1996)

It has been proposed that CD4+ T-cells may also play a role in host defense against M. tuberculosis infection via cytolytic activity. CD4+ T cells may also be capable of lysing non-activated, infected macrophages and subsequently be taken up by activated macrophages which can destroy the mycobacterium. The presence of CD4+ T cells has been detected only in vitro human peripheral blood samples. (Mutis, Cornelisse, & Ottenhoff, 1993)

Gamma/Delta T cells are a minor population of T lymphocytes whose role in immune protection against M. tuberculosis remains unclear. They might have a role in the initial, innate immune response to M. tuberculosis because their population is expanded by mycobacterium and mycobacterial products in tissues. After subcutaneous and aerosol immunization of mice with mycobacterium, a significant proportion of the mycobacterium-reactive gamma/delta T cell population was stimulated. gamma/delta T cells also secrete IFN-gamma which may be an important trigger at initial stages of immune response.

Natural killer (NK) cells may also play an important part of the host response to M. tuberculosis. NK cells are capable of lysing host cells infected with mycobacterial pathogens indicating functional similarities with specific cytolytic T lymphocytes.

iNOS in Tuberculosis

Inducible Nitric Oxide Synthase in the Tuberculous Human Lung
The NOS2 isoform, often called iNOS, is a leading candidate to account for the incompletely successful bactericidal activity of macrophages toward M. tuberculosis. The designation "i" denotes that production of nitric oxide by iNOS is independent of elevated intracellular Ca2+ ,a biochemically distinctive and biologically important feature that explains how the enzyme can produce nitric oxide for days after its transcription is induced by immunologic and inflammatory stimuli.

Nitric oxide is the only molecule known to be produced by mammalian cells that can kill tubercle bacilli in vitro with a molar potency comparable to that of chemotherapy. That the primary product of iNOS is mycobactericidal provides one type of evidence consistent with a role for iNOS in controlling tuberculosis.