From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: Interesting TP-5 Clinical Trial
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6728
Organization: unspecified
Date: Thu, 7 Jan 93 00:51:18 PST

        CLINICAL TRIAL RESULTS CAN BE VERY CONTRADICTORY

The Silvestris et al. article is very interesting for a number of 
reasons. At the end of 12 months, the average absolute number of T4 
cells per cubic millimeter was approximately 280 greater in the TP-5 
group as compared to placebo, but the T8 cells dropped about 200 in the 
TP-5 group. Along with these results, antibodies IgG, IgA, and IgM 
secreted (nanograms/ml) increased by 200 or greater in the TP-5 group as 
compared to placebo at the end of 12 months. 

How exactly should such results be evaluated? Using the past and present 
focus on T4 cells, the results are good. But, if the importance of T8 
cells are considered, the results are negative. The increases in 
antibodies are excellent if one believes that they are important in 
controlling HIV and other pathogens. On the other hand, these increases 
can be viewed negatively from the perspective that such antibody 
activation (TH2) suppresses the cell mediated immune response (Th1) of 
cytotoxic T lymphocytes by production of IL-4 and IL-10 cytokines.

Suppression of the CMI could cause a decrease in destruction of infected 
T4 lymphocytes resulting in increased T4 peripheral blood counts. What 
is also interesting about thymopentin is that it cause release of 
ACTH-like immunoreactivity (ACTH-LIR) by human lymphocytes. This is 
shown in the article by Buzzetti et al. Adrenocorticotropic hormones and 
steroids of the adrenal cortex are known to be immunosuppressive.

When the T8 cells are entered into the equation, efficacy of a treatment 
takes on a new perspective. By using the past and present focus on T4 
cells, TP-5 looks very promising. But if you use the T8 focus along with 
what is known about Th1/Th2 and steroids, TP-5 is not promising at all. 
Conversely, DNCB has shown to increase CTLs and NKs but has little 
effect on increasing T4 counts. But we know that DNCB works from 
histories on long-term users of DNCB that will be submitted as an 
abstract to the Berlin AIDS Conference. 

At the very least, results of clinical trials should report, in detail, 
lymphocyte counts and subsets.
======================================================================= 
Silvestris F; Gernone A; Frassanito MA; Dammacco F. Immunologic effects 
of long-term thymopentin treatment in patients with HIV-induced 
lymphadenopathy syndrome. Journal of Laboratory and Clinical Medicine, 
1989 Feb, 113(2):139-44. 

Abstract: The immunologic effects of a year-long therapeutic trial with 
the synthetic thymic hormone thymopentin were investigated in 29 
patients with human immunodeficiency virus--induced lymphadenopathy 
syndrome. Peripheral T4 and T8 lymphocyte subsets and in vitro 
immunoglobulin synthesis with pokeweed mitogen (PWM) were monitored 
before treatment, every 4 months during treatment, and after treatment. 
Significant increases in circulating T4 cells and a reduction of PWM-
induced immunoglobulin suppression were noted in the 21 patients who 
completed the trial. Furthermore, addition of thymopentin to the in 
vitro cultures improved the PWM response of T and B cells. After 
thymopentin treatment, a slight variability of clinical symptoms, 
including weight loss, diarrhea, night sweats, or a combination of 
these, was also noted in several subjects. 

Page 142:
There was a general, though variable, increase in the number of T4 
cells, with a corresponding reduction of the T8 subset in the patients 
with LAS [lymphadenopathy syndrome] who received treatment.
======================================================================= 
Buzzetti R; Valente L; Barletta C; Scavo D; Pozzilli P. Thymopentin 
induces release of ACTH-like immunoreactivity by human lymphocytes.   
Journal of Clinical and Laboratory Immunology, 1989 Aug, 29(4):157-9. 

Abstract: Peripheral mononuclear (PMN) cells are known to produce ACTH-
like immunoreactivity (ACTH-LIR) in vitro. Based on these findings the 
aim of this study was to find out whether thymopentin (the active 
pentapeptide of the native hormone thymopoietin) may stimulate ACTH-LIR 
production and release by cultured normal human lymphocytes. Thymopentin 
at concentration of 1 microgram/ml was capable of inducing ACTH-LIR 
release by normal human PMN cells (median 22 pg/ml) whereas ACTH-LIR 
inside cells was lower (median 11 pg/10(7) cells). The chromatographic 
characterization of the eluted material identified the presence of ACTH 
immunoreactive peptides with the elution characteristics of the 
precursors 31 K proopiomelanocortin, 22 K ACTH and 4.5 K ACTH, together 
with higher molecular weight material (greater than 43 K). These data 
demonstrate that thymopentin induces ACTH-LIR release by human 
lymphocytes, thus adding a novel factor to those already reported 
(corticotrophin releasing factor, lipopolysaccharide, viruses) capable 
of such function.

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