Immune Restoration -- Conference Outlines Future Directions

The Immune Restoration Think Tank, sponsored by San Francisco-based Project Inform, brings together an invited group of leading researchers from around the world for a
three-day informal meeting to plan future research directions on immune restoration in late-stage AIDS, and to develop new collaborative projects. The fourth such meeting took place in
Oakland, California, on February 24-26. Participants in the latest meeting included William Paul, M.D., Director of the U.S. Office of AIDS Research; Robert Gallo, M.D., National Cancer Institute; Clifford Lane, M.D. [see IL-2 article above], and Steven Schnittman, M.D., National Institute of Allergy and Infectious Diseases; Thomas Merigan, M.D., Stanford University; Robert Schooley, M.D., University of Colorado; John Dwyer, M.D., Prince of Wales Hospital, Australia; John Mills, M.D., MacFarlane Barnet Center for Medical Research, Australia; Michael McCune, M.D., Systemics; David Katz, M.D., Lidak Pharmaceuticals; Arthur Amman, M.D., Ariel Project; and about two dozen other researchers.

The major reason for this project is the uncertainty about whether the immune system could recover, without assistance, from advanced AIDS, even if the virus could be completely stopped. No one knows the answer at this time. In tests of the new protease inhibitors, which are very good at stopping HIV at least temporarily in many patients, there are some cases of large CD4 (T-helper) count increases even in patients who started with very low counts, well under 50; however, the average response is not this good. Also, we do not know how well the new cells will work; CD4 cells are not all the same, but there are millions of different clones, each able to recognize particular antigens (foreign proteins from bacteria, viruses, etc.). Some of these clones might be missing when the CD4 cells return following antiviral treatment; if so, immune-restoration therapy may be necessary.

The February 24-26 Meeting

The Immune Restoration Think Tank meetings are by invitation only and are closed to the press, so that scientists can discuss preliminary work without fear of partial or misleading coverage. After the meeting, a press conference and a physicians' presentation provided an overview of what was discussed.

The major (but not only) focus of the February 24-26 Think Tank is immune restoration by transplantation of "progenitor" cells -- cells which can grow and differentiate to replace those which are missing. Some of this initial work will be with people who have an HIV-negative identical twin. But there is also research in transplanting cells from relatives or other donors, after tests for compatibility. It may also be possible to transplant animal cells which cannot be infected by HIV -- or, by various approaches to gene therapy, make some of the person's own cells immune or resistant to HIV infection, then give them back to the patient.

As a backup, in case these approaches fail, it may also be possible to harvest cells from persons in early-stage HIV infection, and freeze them for use later when they are needed by the same person. The cells might also be grown outside the body (to produce more of them) before they are returned to the patient.

In addition, there is renewed interest in transplantation of part of a thymus gland. This may be necessary to "educate" the new T-cells as they mature in the body. Thymic transplantation may be needed because the thymus gland normally deteriorates with age. Also, the thymus might be damaged by HIV, although this is not known for sure.

What Is Being Done Now?

* Cryopreservation. In Australia, a project for cryopreservation (freezing) of cells from persons with early HIV infection is already underway; over 60 patients have had cells preserved, seven have had cells returned. One patient is believed to have had immune competence restored.

* Thymic transplantation. Dr. Dwyer, now in Australia, plans to begin a new thymic transplantation project within months. In an earlier project, in 1984 at Yale, he already transplanted portions of a thymus gland into 20 patients with HIV. The benefit was temporary -- probably because there was no drug then to control the virus, and also because the technology necessary to preserve the gland was not available. Today, with the benefit of what has been learned in the last 11 years, the treatment may work better.

* Cells from relatives. Immune-cell transplantation from relatives has been used recently in a small number of patients, with encouraging results in some cases.

* Twin studies. In one recent case, cell transplantation between identical twins produced very good immune restoration. There is considerable interest in revisiting twin studies.

* Stem cells. Stem cells are special cells which can divide into many kinds of immune cells, repopulating the immune system. A protocol to harvest stem cells from persons with HIV was designed in the previous Immune Restoration Think Tank, and is now about to begin.

* Cells from animals. Successful engraftment of immune cells between species has been done in animal tests. And human immune cells have been successfully transplanted into baboons. But transplanting immune cells from animals to humans has not yet been attempted.

* Specific immunity. Another area of interest is immune therapies to enhance specific immunity to a particular infection. Certain opportunistic infections and tuberculosis may be targeted first; later, such approaches may be used to restore or improve immunity to HIV itself.

* HIV-specific immunity. By learning what components of the immune system are working against HIV, "we might learn to manipulate these, and have a major ally."

* Endocrine system. Another therapeutic approach looks at the endocrine system -- which has unfortunately been largely ignored in AIDS research so far. It is known that various endocrine abnormalities occur in AIDS -- abnormalities which often can be routinely corrected in medical practice. It is possible that correcting some of them could make a big difference in the course of HIV disease -- but due to lack of research, not much is known so far.

* Growth hormone. It might be possible to use human growth hormone for correcting various endocrine disorders -- not only for treating wasting syndrome, which is now becoming an accepted use for this prescription drug.

* Gene therapy. Gene therapy to make stem cells resistant to HIV infection (so that they will repopulate the immune system with HIV-resistant cells) are still in the laboratory research stage, not yet ready for testing in patients. The ultimate goal of this research is to deliver a new gene with a single injection -- using a harmless virus as a "vector" to infect cells inside the body and insert the gene into the DNA of those cells. This would avoid the trouble and expense of processing cells outside the body, and could produce an AIDS/HIV treatment suitable for use around the world.

* Scientific collaboration. An underlying theme is the rapidly growing interest in doing basic biological research in the context of clinical investigation. This requires a close working relationship between laboratory researchers, and those who do clinical trials.

For more information about the Immune Restoration Think Tank, call Project Inform, 800/822-7422.