Subject: October DNCB Support Group!
From: [email-masked]
Date: Thu, 26 Sep 1996 04:02:55 -0400

Don't buy into the toxic antiviral scam!

Find out about your immune system, the importance of CD8s and how the
inexpensive topical solution DNCB can strengthen your cellular immune
response in the battle against HIV.

DNCB (dinitrochlorobenzene) is a potent topical solution that, when used
regularly, will boost the cellular immune response resulting in increased
numbers of CD8 cytotoxic T lymphocytes (CTL) and natural killer (NK) cells.
Studies of long-term nonprogressors have demonstrated that these individuals
have very stong cellular immune responses with high levels of these important
cells.

Virtually all opportunistic infections in AIDS are of an intracellular nature
and can only be controlled by a cellular immune response; therefore it is
vital to avoid AIDS therapies like AZT that compromise this protective arm of
your immune system. DNCB provides an inexpensive, non-toxic alternative that
strengthens cellular immunity in an effort to delay disease progression and
onset of opportunistic infections.

Join ACT UP San Francisco's DNCB Treatment Group for our monthly support
group meeting. 

Saturday, October 12, 1996
2:00 - 4:00 PM
Park Branch of the SF Public Library
1833 Page Street (between Cole and Shrader)
Located one block off Haight Street near Golden Gate Park. Accessible via the
7, 71, 37, 33 and N Muni lines)

For more information contact the DNCB Treatment Group of ACT UP San Francisco
at 2261 Market Street, #639 / San Francisco, CA 94114. Phone: (415) 954-8896.
Email: [email-masked].

====================

DNCB
(DRG-0080)

MODE OF ACTION: Dinitrochlorobenzene (DNCB) is a contact sensitizing agent
that enhances the function of antigen-presenting cells (APCs) via induction
of delayed-type hypersensitivity. Topical application of DNCB was previously
shown to be safe in a small number of patients with early HIV disease. One
study has followed the clinical course and examined alterations of lymphocyte
subsets in the same group of patients over a longer period of time. The
researchers concluded that prolonged use of topical DNCB is associated with
stable clinical course in most patients, despite a significant decrease in
CD4 T-cells. Lack of disease progression is associated with a stable CD8 CD38
count, and may be related to a persistent increase in natural killer cells.
This increase is probably due to DNCB-induced delayed-type hypersensitivity
that may be beneficial in HIV disease. DNCB also appears to be effective in
the treatment of cutaneous Kaposi's angiosarcoma.

National Library of Medicine

====================

Exchange of letters in the 9/96 issue of JAAD concerning DNCB and DTH.

The initial letter is from individuals involved with the military.

The abstract of the original article is included at the bottom.

--------------------

From: Journal of the American Academy of Dermatology September, 1996. Volume
35, Number 3, Part 1, pages 491-493

Improved results of delayed-type hypersensitivity skin testing in
HIV-infected patients treated with topical dinitrochlorobenzene

To the Editor.- We read with interest the article by Stricker et al. on the
use of dinitrochlorobenzene (DNCB) as immunotherapy in HIV-infected patients
(J Am Acad Dermatol 1995;33:608-11). The authors' findings appear to be
further evidence that this form of immunotherapy may be useful in HIV disease
(1).

We prepared an urushiol extract from poison ivy leaves and used it for open
patch testing of late-stage HIV-infected patients. The patients tested had
continued to report seasonal outbreaks to what they believed was poison ivy
or poison oak. All patients tested had a positive reaction, even patients
with CD4+ T-cell counts less than 200/microliter and patients with a history
of opportunistic infection.

Allergic contact hypersensitivity dermatitis (ACD) is a variant of a delayed
hypersensitivity reaction (DTH), which induces a helper T cell type I (Th1)
cytokine pattern. However, HIV disease progression has been associated with
decreases in DTHs and a cytokine switching from Th1 to a Th2 pattern. (2-4)
An explanation for continued reactivity to some contact allergens could be
that the antigen-specific effector cells in ACD may be more diverse than in
DTH. (5) Soluble hapten-protein conjugates that result in DTH are processed
through the exogenous antigen pathway and are class II-restricted; the
specific cells that mediate these reactions are CD4+ T cells. (5-7) ACD to a
challenge with a reactive hapten or prohapten is correlated with the chemical
properties of the allergen. (7) Small lipid-soluble molecules such as DNCB
and urushiol may enter the cytoplasm, and they may be presented by the
endogenous pathway through a class 1-restricted pathway; the specific cells
that mediate these reactions are primarily CD8+ T cells. (6,7)

Principal cytokines within both the Th1 and Th2 patterns serve to
down-regulate production of cytokines from the other pattern and upregulate
their own production. In addition, the Th2 cytokine, interleukin-10, may
result not only in failure to establish primary sensitivity, but may also
result in antigen-presenting cell dysfunction and the establishment of
anergy. (4,8,9)

If primary sensitization can be achieved to a contact allergen, as has been
suggested by the DNCB studies, then an ongoing Th1 cytokine pattern may serve
to push the cytokine pattern in a Th1 direction, as suggested by Stricker et
al. in the article referred herein and elsewhere. (1) One concern that has
been raised with this form of immunotherapy is that any immune activation may
activate the virus through activation of infected cells. (10) However, recent
in vitro studies of T cells have shown that HIV does not appear to replicate
in Th1 cells as it does in Th2 cells, and Th1 cells are not subject to the
rapid cell death seen with Th2 cells. (11,12) Thus stimulation of a Th1
cytokine pattern may decrease replication of the virus and decrease T-cell
death. In addition, as has been shown in the DNCB studies, a Th1 cytokine
pattern may increase the cytotoxic CD8+ T cells and natural killer cells that
are probably more effective in containing the virus and have been correlated
with delayed disease progression. (1,13)

Another area in which a small reactive lipid-soluble chemical may be
potentiating a Th1 cytokine pattern is topical mechlorethamine (HN2) therapy
for mycosis fungoides (MF). (13) With disease progression there is a Th1 to
Th2 switching pattern. (14) Although the incidence of ACD in patients with MF
treated with topical HN2 varies, in most studies ACD occurs in more than 50%.
ACD to topical HN2 in patients with MF may contribute to the duration of
remission. (13) If this is true, then perhaps this increase in therapeutic
response could be attributed to the potentiation of the Th1 cytokine pattern
and the effector cells these cytokines upregulate. (15)

Although DNCB has not been shown to be a carcinogen as has HN2, it is a
mutagen. Whether or not this mutagenicity is a valid reason for limiting use
of DNCB, it has; it probably will limit the use of DNCB as an ongoing
therapeutic agent. (16,17) Urushiol does not have this limitation; however,
urushiol is not available in any standardized concentration, and there are
problems with degradation over time. A major advantage of urushiol and DNCB
in persons who are already sensitized or can be sensitized is that these
allergens have been well studied and effector T-cell populations documented.
However, there are other contact allergens that may also have some potential
as therapeutic agents, such as squaric acid dibutylester and diphencyprone,
and these have not been shown to be mutagens.

 COL Kathleen J. Smith, MC, USA (a) CAPT Dennis Vidmar MC USA (b) CAPT Henry
G. Skelton MC, USA (c) Brennie E Hackley, Jr., PhD (a) U.S. Army Medical
Research Institute for Chemical Defense Aberdeen Maryland (a) 

 Dermatology Service, National Naval Medical Center (b) Bethesda Maryland 

 Armed Forces Institute of Pathology (c) Washington, D. C.

REFERENCES

1. Stricker RB, Zhu YS, Elswood BF, et al. Pilot study of topical
dinitrochlorobenzene (DNCB) in human immunodeficiency virus infection.
Immunol Lett 1993;36:1-6.

2. Michael NL, Burke DS. Natural history of human immunodeficiency virus
infection. Dermatol Clin 1991;9:429-41.

3. Gordin FM, Hartigan PM, Khmas NG, et al. Delayed-type hypersensitivity
skin tests are an independent predictor of human immunodeficiency virus
disease progression. J Infect Dis 1994;169:893-7.

4. Clerici M, Shearer GM. A Th1 to Th2 switch is a critical step in the
etiology of HIV infection. Immunol Today 1993; 14:107-10.

5. Gocinski BL, Tigelaar RE. Roles of CD4+ and CD8+ cells in murine contact
sensitivity revealed by in vivo clonal antibody depiction. J Immunol
1990;144:4121-8.

6. Kalish RS, Johnson KL. Enrichment and function of urushiol (poison ivy)
specific T lymphocytes in lesions of allergic contact dermatitis to urushiol.
J Immunol 1990, 145:3706-13.

7. Kalish RS. Antigen processing: the gateway to the immune response. J Am
Acad Dermatol 1995;32:640-52.

8. Romagnani S, Del Prete G, Ravina MA, et al. Role of Th1/Th2 cytokines in
HIV infection. Immunol Rev 1994; 140:73-92.90.

9. Enk AH, Angeloni VL, Katz SI. Inhibition of Langerhans cell
antigen-presenting function by IL-10: a role for IL-10 in induction of
tolerance. J Immunol 1993; 1 51:2390-8.

10. Ascher MS. Sheppard HW. AIDS as immune system activation II: the panergic
imnesia hypothesis. J Acquir Immune Defic Syndr 1990;3:177-91.

11. Del Prete G, Maggi E, Pizzolo G, et al. CD30, Th2 cytokines and HIV
infection: a complex and fascinating link. Immunol Today 1995; 1 6:76-80.

12. Maggi E, Mazzetti M, Ravina A, et al. Ability of HIV to promote a Th1 to
Th0 shift and replicate preferentially in Th2 and Th0 cells. Science
1994;265:244-8.

13. Mackewicz CE, Ortega HW, Levy JA. CD8+ anti-HIV activity correlates with
the clinical state of the infected individual. J Clin Invest 1991;87:1462-6.

14. Vonderheid EC, Tan ET, Kantor AF, et al. Long-term efficacy, curative
potential. and carcinogenicity of topical mechlorethamine chemotherapy in
cutaneous T cell lymphoma. J Am Acad Dermatol 1989,20:416-28.

15. Vowels BR, Lessin SR, Cassin M, et al. Th2 cytokine mRNA expression in
skin in cutaneous T cell lymphoma. J Invest Dermatol 1994;103:669-73.

16. Happle R. The potential hazards of dinitrochlorobenzene (DNCB). Arch
Dermatol 1985;121:330-2.

17. Dunagin WG. Potential hazards of dinitrochlorobenzene (DNCB) disputed.
Arch Dermatol 1986;122:11-5.

--------------------

Reply

To the Editor.- We appreciate the interest of Smith and colleagues in our
work on DNCB, (1) and we commend them for their well-informed and insightful
commentary on the immunologic benefits of contact sensitizing agents. With
the help of sophisticated biologic and molecular techniques, we are
discovering the powerful and diverse effects that DNCB, urushiol, and other
contact sensitizers exert on the cellular immune system. (2,3) As implied by
Smith et al., these effects offer a novel immunomodulatory approach to a
variety of systemic diseases, from AIDS to systemic lupus erythematosus to
Chagas' disease. (1,4,5) We can only reiterate the urgent need for controlled
clinical trials of DNCB and related compounds in these illnesses.

Smith et al. also point out the nagging concern over the reported bacterial
mutagenicity of DNCB. This issue was recently addressed in another forum. (6)
Suffice it to say that DNCB was shown to be noncarcinogenic when fed in large
quantifies to rats, mice, guinea pigs, and human beings. In contrast, the
antiretroviral medication zidovudine cannot be tested for bacterial
mutagenicity because it kills the bacteria. (7) Furthermore, the fact that
zidovudine is mutagenic in mammalian cell assays (7) certainly has not
limited its use as an "ongoing therapeutic agent" in patients with AIDS.
Thus, compared with systemic treatment with drugs such as zidovudine, topical
DNCB therapy appears to be extremely safe.

At this time, DNCB remains the most stable and best characterized contact
sensitizing agent available. (6,8)

Raphael B. Stricker, MD California Pacific Medical Center San Francisco, CA
94108
Billi Goldberg DNCB Study Group San Francisco, CA 94114
William L Epstein, MD University of California San Francisco, CA 94143

REFERENCES

1. Stricker RB, Goldberg B, Mills LB, et al. Improved results of delayed-type
hypersensitivity skin testing in HIV-infected patients tested with topical
dinitrochlorobenzene. J Am Acad Dermatol 1995;33:608-11.

2. Bour H, Peyron E, Gaucherand M, et al. Major histocompatibility complex
class I-restricted CD8+ T-cells and class II-restricted CD4+ T-cells,
respectively, mediate and regulate contact sensitivity to
dinitrofluorobenzene. Eur. J Immunol 1995;25:3006-10.

3. Kalish RS, Wood JA, LaPorte A. Processing of urushiol (poison ivy) hapten
by both endogenous and exogenous pathways for presentation to T-cells in
vitro. J Clin Invest 1994;93:2039-47.

4. Stricker RB, Goldberg B. Dinitrochlorobenzene and Chagas' disease
[letter]. Lancet 1995,345:327.

5. Stricker RB, Goldberg B, Epstein WL. Immunological changes in patient with
systemic lupus erythematosus treated with topical dinitrochlorobenzene.
Lancet 1995;345:1505-6.

6. Stricker RB, Goldberg B. Safety of topical dinitrochlorobenzene [letter].
Lancet 1995;346:1293.

7. Ayers KM. Preclinical toxicity of zidovudine. Am J Med 1988;85(suppl 2A):
186-8.

8. Epstein WL, Stricker RB. Immunomodulation by allergic contact
sensitization: the dinitrochlorobenzene story. Am J Contact Dermatitis
1995;6:117-21.

--------------------

Stricker RB, Goldberg B, Mills LB, Epstein WL. Improved results of
delayed-type hypersensitivity skin testing in HIV-infected patients treated
with topical dinitrochlorobenzene. Journal of the American Academy of
Dermatology 1995, Oct, 33:608-11.

Abstract: Background: Infection with HIV results in progressive deterioration
of cell-mediated immunity, with consequent impairment of delayed-type
hypersensitivity (DTH) skin reactivity. Topical dinitrochlorobenzene (DNCB)
is thought to increase cellular immune function in HIV infection.

Objective: Our goal was to evaluate changes in DTH skin reactivity of
HIV-infected patients who were given DNCB therapy.

Methods: DTH skin testing and lymphocyte subset analysis were performed in
five HIV-infected patients before the start of DNCB treatment and after 3
months of therapy. Topical DNCB application was carried out by the patients
according to a standardized protocol.

Results: DNCB therapy enhanced DTH skin test responses in four of five
patients. Three patients who were anergic before the start of treatment
reacted to skin test antigens while using DNCB. The skin test results did not
correlate with lymphocyte subset changes.

Conclusion: DNCB treatment improves DTH skin test responses in HIV-infected
patients, indicating a positive effect on cellular immune function.