Several explanations for the immunologic effects of DNCB in HIV
disease have been proposed in the past. One explanation was based on the knowledge that
the Langerhans cells of the epidermis and dendritic cells throughout the body are infected
with HIV and that the infected cells have an impaired antigen-presenting capacity 21-23. Exposure to DNCB was thought to correct
the dysregulation that develops between the infected antigen-presenting cells and T-cells,
leading to control of HIV replication in various organ systems 8.
Another explanation was that repeated exposure to DNCB amplifies the CD8 + cytotoxic
T-lymphocyte (CTL) and natural killer (NK) cell subsets that enhance cell-mediated
immunity (CMI). Enhanced CMI promotes the type of cell function and cytokine production
that are necessary for survival for a person infected with HIV 8, 24-27. It was
speculated that upregulation of the CMI response by DNCB could reverse the pathological
"Thl/Th2 switch" described in HIV patients 26,
with consequent mobilization of CTLs and NK cells that are lethal for HIV.
Very recently, a more detailed understanding of how DNCB works appears to have emerged.
The understanding follows from studies of the signalling molecules known as cytokines and
chemokines that are produced by the immune system in response to HIV infection 28,29. These studies show how the known effects of DNCB
result in the initiation of a cascade attack to limit the effects of HIV disease,
involving the following processes:
- DNCB, when applied weekly to the skin (close to a major lymph node
site), activates antigen presenting cells, such as Langerhans cells, dendritic cells, and
macrophages, through the delayed-type hypersensitivity (DTH) reaction, with the result
that cell-mediated immunity (CMI) is increased.
- CMI, the Th1-predominant immune response, activates CTLs and NK cells
by the following mechanism:
- CMI activation results in secretion of the Th1 cytokines tumor
necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma). These transmitters
activate HIV-infected macrophages to produce a chemokine known as RANTES. RANTES is also
produced by infected and/or activated T-cells and endothelial cells.
- RANTES and two other chemokines, macrophage inflammatory protein
(MIP)-1-alpha, and macrophage inflammatory protein (MIP)-1-beta, attract more CTLs and NK
cells.
- CTLs and NK cells go to the site of chemokine production and
recognize activated HIV-infected cells (macrophages, T-cells).
- Once at those sites, CTLs and NK cells do several things:
- As is well established, they kill cells infected with HIV and other
intracellular organisms including mycobacteria (which cause tuberculosis), viruses such as
cytomegalovirus (CMV) and herpes simplex virus (HSV), protozoa such as toxoplasma and
cryptosporidium, and fungi such as cryptococcus and histoplasma.
- They prevent healthy cells from becoming infected by blocking the
macrophage tropic (M-tropic) receptor CCR5, through which viruses such as HIV would
otherwise enter and infect those cells.
- They produce more chemokines from their own catalytic granules, which
enlarge the pool of natural chemokines, thus attracting more CTLs and NK cells.
- Thus the cascade continues as long as DNCB is used regularly,
maintaining an ongoing cell-mediated immunity.
- Because DNCB is a treatment that arrests the development of HIV
disease (a containment treatment, not a cure), treatments must continue for the balance of
a patient's life.
- Particular note should be taken of the properties of RANTES. It is
the most powerful natural blocker of M-tropic HIV infection during the asymptomatic stage
of HIV disease, typically lasting years.
- Furthermore, the killing of HIV infected cells prevents the immune
system from allowing HIV to switch from the M-tropic stage to the T-lymphocyte tropic
(T-tropic) stage that typically results in "full blown" AIDS and death.
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