Human Clinical Trials Under Way for Promising Therapy Developed At UA to Boost Immune System; Peptide May Thwart Onset of AIDS

George Humphrey
Nov. 30, 2000

Human clinical trials are under way on an innovative peptide-based therapy developed at the University of Arizona College of Medicine that researchers hope will allow people infected with HIV to maintain good health without ever developing the symptoms associated with AIDS.

The therapy also may be useful in maintaining the health of older individuals, who often have poorly functioning immune systems, as well as for individuals with autoimmune disorders. The "Phase I" human clinical trials, which will involve 18 patients, are taking place in San Francisco.

In repeated studies, the UA-developed "T-cell receptor peptide therapy" prevented development of abnormal immune responses in mice infected with an AIDS-like retrovirus, maintaining normal immune responses seen in healthy mice. (A peptide is a fragment of protein consisting of two or more amino acids.)

The therapy was developed by John Marchalonis, Ph.D., chairman of the UA department of microbiology and immunology, and Ronald Watson, Ph.D., professor at the UA College of Public Health. Allergene, a privately held San Mateo, Calif.,-based biotechnology company, acquired the rights to the technology and is in charge of the human clinical trials. (In addition, a patent has been approved for the technology.) The UA Office of the Vice President for Research provided seed funding to initiate the research, which has been published in the Journal of Immunology, among other publications.

"Basically, we have developed a very promising therapy -- and we believe it's a gentle, well-tolerated therapy," Marchalonis points out. "We're not claiming this is a vaccine against AIDS. Instead, this is a way to maintain a normal T-cell immune system in someone who is HIV-positive."

Watson adds, "Most AIDS drugs are aimed at killing the virus. This is a novel approach: Using this unique peptide that Dr. Marchalonis developed we were able to keep the immune system in balance. In our studies, this therapy maintained 80-90 percent of the immune function in mice with AIDS -- with no side effects. The treated mice then were able to fight off an infection, cryptosporidium, common to AIDS patients and others with severely damaged immune systems. These animal studies provide a shining light for what we might be able to do for humans."

Once in the body, HIV slowly reproduces and is attracted to certain T-helper cells that play critical roles in the function of the immune system. Their number and activity determine how well the immune system is functioning. When total T-cell numbers drop below a certain level, or the T-helper cells are excessively activated leading to immunosuppression, many people with HIV no longer can fight off opportunistic infections and certain cancers.

Marchalonis found that HIV (and the mouse retrovirus) "hyper-stimulate" two of the 24 subsets of T-helper cells, as the immune system attempts to fight the retrovirus infection. Injection of the peptide slowed this activity for one subset without damaging the remaining groups needed for resistance to other pathogens.

"This peptide therapy apparently prevented these particular T-helper cells from becoming hyper-stimulated, even though the mice still were infected with the retrovirus. Thus, their immune system remained in balance, yielding nearly normal disease resistance," he says.

The road that led to this discovery began when Marchalonis and his team found that healthy people and healthy mice have natural antibodies against a particular piece of their own T-cell receptors. "They're autoantibodies -- they're against your own proteins and you have them without being ill. This particular autoimmune marker is amplified in autoimmune diseases, but is also present in low levels in healthy people as part of the body's regulation of the immune system."

(The autoantibody studies were supported by the National Cancer Institute and the Arizona Disease Control Research Commission.) After the UA researchers found elevated levels of these autoantibodies in other conditions that affect the immune system, such as aging and pregnancy, they examined serum from AIDS patients. "We found they had elevated levels of these autoantibodies as well," Marchalonis says, adding that the elevated antibodies were the body's attempt to "turn off" the T-cells that were being chronically stimulated by the retroviral HIV infection.

AIDS, in humans and mice, causes a "shift" in the immune system. It suppresses a "T-helper 1 response" that destroys infectious agents by stimulating a "T-helper 2 response" that promotes high levels of antibodies. "Because these antibodies usually aren't protective against viruses or pathogens, we saw the need to balance the activity of T-helper 1 and 2 cells. Therefore, we attempted to suppress hyper-activated T-helper 2 cells with our peptide."

Watson continues, "We gave the peptide to mice and found that it prevented this pattern from developing. The T-cells maintained the profile of a healthy mouse, with strong T-helper 1 function and without excessive T-helper 2 cell stimulation, even though the mouse was infected with the retrovirus." The researchers also injected the mice with a control peptide, which was about the same size but had a different sequence.

"The mice showed no response to the control peptide. Neither the test peptide nor the control induced antibodies, but the test peptide had a profound effect on the function of the mouse T cells," Marchalonis says.

The UA researchers believe the therapy has great promise for humans. "The peptides are basically the same in people and mice; they're recognized in both systems. This is because we basically have the same genes. And the 'T-helper 1 to T-helper 2 shift' -- the disease process -- is the same in HIV-infected people and retrovirus-infected mice; he explains. "This peptide therapy should provide a gentle way of restoring the T-cell immunity to protect against subsequent infections. If you could lower the virus burden, using the new combination drug therapies to combat HIV, and then bring back your immune system with this peptide therapy, I think a patient should lead a virtually normal life."




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