From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: Simplifed How DNCB Works
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6420
Organization: unspecified
Date: Fri, 6 Nov 92 08:27:11 PST

                             HOW DNCB WORKS
                            by Billi Goldberg

DNCB is applied weekly on the skin at various sites which initiates 
contact sensitivity.  The Langerhans cells in the skin at the 
application site pick up the DNCB antigen, migrate from the skin, change 
into veiled dendritic cells, continue their migration to the nearest 
lymph node, change into interdigitating dendritic cells. Once in the 
lymph nodes, they present the DNCB antigen to T4 helper cells, thus 
initiating a Th1 response or cell mediated immune response or Type IV 
Delayed Type Hypersensitivity response (they can all be considered 
the same thing). The T4 helper cells then proliferate forming T4 cells 
which then circulate and activate effector cells (primarily 
macrophages) to rid the sysem of the DNCB antigen. At the same time 
T4 memory cells are produced adding to the T4 memory pool for the 
DNCB antigen (hapten). Each time DNCB is applied, these memory 
cells are activated thus initiating a systemic Th1 response to DNCB. 
The longer DNCB is used, the response becomes faster, more potent, 
and more effective because there are more circulating DNCB T4 
memory cells.

The result of this specific systemic Th1 response to DNCB is the non-
specific activation of macrophages. Many of these macrophages are 
infected with HIV and other intracellular pathogens that cause AIDS 
but are unable to present these pathogen antigens due to infection. 
The microbial pathogens of AIDS are of the obligate intracellular type. 
The activation of these macrophages result in phagocytosis of the 
pathogens which are then presented by macrophages to T4 and T8 memory 
cells specific for the presented pathogen. The activated T cells 
initiate specific systemic responses to destroy the presented pathogens. 
This results in more activated macrophages, more pathogens presented, 
more T memory cells activated, more infected cells destroyed, ad 
infinitum.  Since pathogens can be presented on both self and non-self 
parts of the antigen presenting cells (Class I and Class II MHC), 
cytotoxic T lymphocytes, natural killer cells, neutrophils, and killer 
macrophages are also activated to accomplish the destruction.  There is 
also an excellent probability that dendritic cells (the most potent 
antigen presenting cells in the immune system) are also activated in the 
lymphoid tissues to present more self and non-self antigens thus 
activating even more T memory cells and increasing the Th1 response 
against the pathogens involved in AIDS.

It is extremely important to remember that the antibody or Th2 or 
humoral responses is not directly involved in fighting the infections of 
AIDS. The denial of this fact is the primary reason that there has been 
no progress in realistic treatments for AIDS. In point of fact, there is 
research to show that activating the antibody or Th2 response may 
suppress the Th1 response. This would allow the intracellular 
pathogens to be uncontrolled since their control depends on the Th1 or 
cell-mediated immune response. There is also research to show that 
immune complexes (HIV + antibody) can be internalized through the 
antibody receptor (Fc) of monocytes and macrophages thus spreading 
and increasing HIV infection of these cells.

Delayed Type Hypersensitivity is an extremely effective and potent 
immune modulator that forces priming and activation of macrophages 
that are non-responsive due to infection.  DNCB, then, acts like an 
adjuvant or biological response modifier. These phenomena have been 
researched in-depth and are considered a factual part of scientific 
knowledge. On page 1292 of the recent edition of The Merck Manual is 
the following: "Skin malignancies have regressed after induction of 
delayed hypersensitivity to dinitrochlorobenzene (DNCB) and subsequent 
direct application of DNCB to the tumor."

Below are the scientific explanations of what happens. This process has 
been an integral part of the scientific literature for many years. 
Meltzer and Nacy have explained it brilliantly.  DNCB is not new; it has 
been used for decades.  But, since the cost of DNCB is minimal and there 
is no profit to be made, it has been ignored.

The following is from Chapter 28 titled "Delayed-Type Hypersensitivity 
and the Induction of Activated, Cytotoxic Macrophages" by Monte S. 
Meltzer and Carol A. Nacy in Fundamental Immunology (1989), second 
edition, published by Raven Press.

Page 775:
  "Contact sensitivity is a variant form of DTH in which certain 
reactive chemicals (usually small molecular weight compounds or metal 
ions that can diffuse into the epidermis) covalently bind to skin 
proteins and create neoantigens. Such neoantigens prime or sensitize the 
exposed animal to a second cutaneous application of the reactive 
chemical (contactant). A portion of the neoantigen is host derived. 
Thus an animal exposed to trinitrochlorobenzene (TNCB or picryl 
chloride) solution epicutaneously responds to a repeated cutaneous 
exposure with a vigorous DTH response. Intradermal injection of TNCB 
covalently bound to an irrelevant protein such as albumin fails to 
elicit this response. Neoantigens induced in the epidermis are taken up 
by Langerhans cells. These highly efficient, antigen-presenting 
dendritic cells migrate into the dermis, enter lymphatics, and travel to 
the cortical region of the draining lymph node where they present the 
antigen to CD4+ T cells. Application of normally sensitizing chemicals 
to skin devoid of Langerhans cells (skin treated with corticosteroids, 
UVB light, or cellophane adhesive tape) does not induce contact 
sensitivity and may produce specific immunologic tolerance to the 
contactant."

Pages 766-767:
  "Coincident with the development of DTH during infection is a 
widespread activation of free and fixed mononuclear phagocytes 
throughout the body. Tissue macrophages develop profound alterations in 
morphology, cell proliferation, phagocytosis, and the capacity to 
destroy intracellular and extracellular microorganisms. Each of these 
changes is dependent on interactions with sensitized lymphocytes. These 
systemic changes in the antimicrobial activity of immunologically 
activated macrophages may explain observations made as early as 1936 
that animals responding to reinfection with one microorganism (bacterium 
A) [DNCB] acquire the ability to resist nonspecifically infection with 
antigenically unrelated pathogens (bacterium B, C, or D). Unlike the 
long-lived, antigen specific, DTH response, this nonspecific element of 
acquired resistance is short lived and can only be reexpressed by 
further exposure to the original microbe (bacterium A) [DNCB].

  "Thus the DTH response to foreign antigens induces a series of 
immune reactions whose ultimate purpose is the short-term accumulation 
of nonspecifically cytotoxic, macrophage effector cells. Mononuclear 
phagocytes rapidly and preferentially accumulate at sites of infection. 
These inflammatory cells co-locate with antigen-reactive, sensitized T 
cells and undergo dramatic changes in their functional state. The 
activated macrophages that result are pleuripotent cytotoxic effector 
cells which destroy viruses, bacteria, fungi, single and multicellular 
parasites, allografts, and tumor cells. This complex network of 
cell-mediated reactions is controlled by an even more complex 
interaction of various cytokines, those released by the T cell, the 
macrophage, and even the target cell. DTH reactions are not self- 
destructive overreactions to foreign antigens, but rather tightly 
controlled body defenses against tissue allografts, infection , and 
neoplastic change."

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