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How
Cytolin® Was Discovered Just over a
decade ago, three scientists who were working independently of each other discovered why
HIV does not cause disease in the other mammals it can infect. There are, of course, other
viruses that are similar to HIV and that can cause AIDS-like diseases in animals, such as
simian immunodeficiency virus (SIV) and feline immunodeficiency virus (FIV). However, the
human immunodeficiency virus (HIV) only causes disease in humans and not in the other
mammals it can infect, such as chimpanzees. In discovering why this is the case,
researchers also demonstrated why humans infected with HIV lose all of their CD4 T cells
even though only a minority of those cells become infected with HIV. This was demonstrated
by Joyce Zarling[1] at the Yerkes Primate Research Center, Leonard Adelman[2] at the
University of Southern California, and Allen D. Allen[3-4] then at Olive View-UCLA Medical
Center. The seminal paper, published in the Journal of Immunology in 1990, was by Zarling.
She and her colleagues conducted a truly elegant cross-species study. It proved to a
scientific certainty that the reason only humans develop AIDS in response to HIV infection
is that only humans respond to the infection with a proliferation of cytotoxic T
lymphocytes (CTL) that indiscriminately kill human CD4 T cells, including healthy,
uninfected CD4 T cells.
The question that Zarling and Adelman did not
answer is why this should be the case. In terms of understanding the mechanisms involved
in HIV disease, one should ask what particular mechanism the anti-self, anti-CD4 CTL use
to indiscriminately destroy human CD4 T cells. Because of the huge volume of
HIV-literature that was focused on many diverse issues, the key was to know where to look.
As a consequence, Allen was able to ascertain the cytotoxic mechanism because he had a
model to start with.
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Hepatitis, when associated with hepatitis B and C virus, has been known for years
to be a disease that is triggered by an infection and that results in the destruction of
the liver by CTL.[5-6] The destruction of the liver occurs because its surface becomes
coated with intercellular adhesion molecules (ICAM). The co-receptor to ICAM is LFA-1.
What makes a CD8 T cell a cytotoxic cell rather than a suppressor cell is the
overproduction of LFA-1.[7] When the CTL circulate through the liver, the LFA-1 binds to
the ICAM killing the hepatocytes or liver cells. Interferon-alpha is the gold standard for
treating serum hepatitis because it down regulates the ICAM molecules on the liver so that
the CTL do not harm that organ.[8] Not surprisingly, then, Bofill, et al[9] have shown
that increased numbers of CTL predict the decline of CD4 T cells in HIV patients. By
knowing the mechanism of action, Allen[10] was able to identify a class of monoclonal
antibodies that prevent the indiscriminate destruction of CD4 T cells by CTL. Cytolin® is
one such antibody.
References
1. Zarling JM, Ledbetter JA, Sias J, et al: HIV- infected humans, but not chimpanzees, have circulating cytotoxic T lymphocytes that
lyse uninfected CD4+ cells J Immunol 1990, 144: 2992-98.
2. Adelman L and Wofsy D: T-cell homeostasis:
implications in HIV infection. J Acquir Immune Defic Syndr 1993;
6:144-152.
3. Allen AD, Mathisen GE, Glover N, Au J:
Immunization against the HIV-associated anti-self, anti-CD4 cytotoxic T lymphocyte. AIDS
1993;7:1130.
4. Allen AD, Mathisen GE, Leader W, et al.
T-cell homeostatis in HIV infection: new evidence. J Acquir Immune Defic Syndr
1994;7:627-32.
5. Volpes R, Van Den Oord J, Desmet VJ:
Hepatic expression of Intercellular Adhesion Molecule-1 (ICAM-1) in Viral Hepatitis B.
Hepatology 1990;12:148-154.
6. Nouri-Aria KT, Koskinas J, Tibbs CJ, et al:
Serum intercellular adhesion molecule-1 levels in chronic hepatitis C: association with
disease activity and response to interferon a. Gut 1995; 36:599-603.
7. Morimoto C, Rudd CE, Letvin NL, Schlossman
SF:A novel epitope of the LFA-1 antigen which can distinguish killer effector and
suppressor cells in human CD8 cells. Nature 1987;330:479-82.
8. García-Monzó C, García-Buey L,
García-Sánchez A, et al: Down-regulation of intercellular adhesion molecule 1 on
hepatocytes in viral chronic hepatitis treated with interferon alfa-2b. Gastroenterology
1993;105:462-469.
9. Bofill M, Mocroft A, Lipman M, et al:
Increased numbers of primed activated CD8+ CD38+ CD45RO+ T cells predict the decline of
CD4+ T cells in HIV-infected patients. AIDS 1996;10:827-34.
10. Allen AD: U.S. Patent Nos. 5,424,066;
5,651,970; 6,534,057
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Click vial to learn the
genesis of the brand name Cytolin®. |
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