IL-12: Potential Treatmentt Restores Immune Response in Laboratory Test

IL-12, a newly-discovered substance which is naturally
present in the body in small amounts, has been found to
restore certain immune responses which are diminished or lost
in HIV infection.(1) This result, recently published by
researchers at the U.S. National Cancer Institute, was found
in cells of HIV-positive donors. IL-12 was administered to
these cells in a laboratory test. IL-12 has not yet been
tested in humans, but clinical trials are expected in 1994.
[Note: Do not confuse IL-12 with IL-2, another immune
modulator which is also being tested as a potential AIDS
treatment.]

Two of the researchers on this study, Mario Clerici, M.D.,
and Gene M. Shearer, Ph.D., proposed a theory earlier this
year of a "TH1-to-TH2 switch" -- a change in immune function
which occurs in HIV infection, and may cause the disease to
progress faster.(2) According to this theory -- which is
accepted by many but not all researchers -- in early HIV
infection, the body first defends itself effectively against
the virus by one kind of response (called the TH1 response;
'TH' stands for T-helper); this response consists mainly of
cellular immunity, i.e. certain cells which destroy infected
cells. But then, while the patient is still asymptomatic, the
immune system switches to a TH2 response, which mainly
produces antibodies, which appear to be less effective than
cellular immunity in controlling HIV infection. Each kind of
response tends to suppress the other; so when the switch to a
TH2 response occurs, the protective TH1 response is largely
lost. IL-12 may reverse this switch and restore cellular
immunity against HIV and other pathogens.

Two teams, Genetics Institute, Inc., Cambridge,
Massachusetts, working with the Wistar Institute,
Philadelphia, Pennsylvania, and Hoffmann-La Roche, Inc.,
Nutley, New Jersey, each independently discovered IL-12.
Genetics Institute and Wistar initially named their discovery
Natural Killer-cell Stimulatory Factor (NKSF). Roche named
its discovery Cytotoxic Lymphocyte Maturation Factor (CLMF).
Genetics Institute and Roche have agreed to cross-license
each other so that each company may proceed independently in
the further development of IL-12.

A December 10 news release from the National Cancer Institute
explained the new IL-12 study. It is the best description for
non-scientists, so we reproduce it in full:

"National Cancer Institute (NCI) scientists have succeeded in
restoring normal immune responses to cultured cells from HIV-
infected donors. The scientists used a natural blood
substance, interleukin-12 (IL-12), which will be tested in
asymptomatic HIV-positive individuals within the next several
months. HIV is the virus responsible for AIDS.

"T lymphocytes from many HIV-infected people do not show
normal immune reactions when they are exposed to antigens
such as influenza virus. By adding the immune regulator IL-12
to cultures of these cells, the NCI scientists and their
colleagues were able to augment the cells' immune reactions.

"'In the test tube, this is the most powerful immune response
modulator we have seen,' said Gene M. Shearer, Ph.D., of the
National Cancer Institute's Experimental Immunology Branch.

"IL-12 was identified in 1991 by scientists at the Wistar
Institute, Philadelphia, and Hoffmann-La Roche, Inc., Nutley,
New Jersey. It is an interleukin -- one of a class of
proteins produced by lymphocytes that transmit signals to
regulate growth of immune cells.

"Mario Clerici, M.D., Shearer, and their colleagues at NCI
and the National Institute of Allergy and Infectious Diseases
(NIAID), Bethesda, Maryland, along with researchers at
Lackland Air Force Base, San Antonio, Texas, and Genetics
Institute Inc., Cambridge, Massachusetts, performed the
current study, which appears in the December 10 issue of
Science.

"The investigators tested white blood cells from HIV-negative
and HIV-positive individuals by exposing cultures of the
cells to several antigens, including influenza virus and
synthetic versions of HIV envelope peptides. Cells from HIV-
negative donors reacted to antigens with T-cell
proliferation, interleukin-2 (IL-2) production, and
interferon-gamma (IFN-gamma) production. (These cells did not
react to the HIV envelope peptides, however, because of the
donors' lack of previous exposure to HIV.)

"Cells from HIV-positive individuals did not respond fully to
any of the test antigens unless IL-12 was added. In the
presence of IL-12, the cultures reacted normally to challenge
with the antigens, showing T-cell proliferation, IL-2
production, and IFN-gamma production. The immune responses of
cells from HIV-negative donors were normal whether or not IL-
12 was added.

"Shearer and Clerici have previously shown that, in HIV-
infected individuals, a switch from one pattern, type 1, of
interleukin production to a different pattern, type 2, is
associated with disease progression. The type 1 pattern
principally enhances cellular immunity, while type 2 is
linked with antibody production. Because Shearer and Clerici
believe that cellular immunity is more effective than
antibodies in combating HIV infection, they have been
interested in finding ways to promote the type 1 pattern. The
results of the current study suggest that IL-12 may have this
effect.

"NIAID scientists recently tested IL-12 in mice with a
disease similar to AIDS and found that it had a positive
effect on the animals' immune function (Ricardo Gazzinelli,
Ph.D., and others, unpublished results). Preliminary (phase
I) studies of IL-12 in HIV-infected people are being planned
by the manufacturer, Genetics Institute, Inc., and should
begin in the first half of 1994."

References

1. Clerici M, Lucey DR, Berzofsky JA, and others. Restoration
of HIV-specific cell-mediated immune responses by
interleukin-12 in vitro. SCIENCE. December 10, 1993; volume
262, pages 1720-1724.

2. Clerici M and Shearer GM. A TH1-->TH2 switch is a critical
step in the etiology of HIV infection. IMMUNOLOGY TODAY.
March 1993; volume 14, number 3, pages 107-111.