PI Perspective #18

April 1996     View PDF     En español

Report from the Immune Restoration Think Tank

The fifth meeting of Project Inform’s Immune Restoration Think Tank: The Dobson Project took place in Houston, Texas in November of 1995. The Think Tank is a component piece of Project Inform’s advocacy efforts, Project Immune Restoration, and represents the only activist initiative in the country focusing research attention on issues of advanced HIV-disease and the restoration of the immune system. As a result of this effort, several new technologies have moved into the clinic and many more are on the clinical cusp. Numerous collaborative efforts have been forged, many of which are international in scope, to apply new information in the clinical environment. Highlights from the Houston meeting include discussion of the following fields:

• xenograft (cross-species) transplantation
• thymus transplantation
• CD4+ cell expansion
• novel approaches to interfere with the disease process.

Xenograft Transplantation
The recent baboon-to-human bone marrow transplant which received so much media attention had been discussed and worked on for nearly two years in the Immune Restoration Think Tank prior to the clinical experiment. Several collaborators on the project are regular Think Tank participants (see article on Baboon-to-Human Bone Marrow Transplant). Cross-species transfer of immune cells and tissue was discussed at the Think Tank meeting in spring of 1993, as researchers sought ways to protect immune cells from further destruction by HIV. Because there are few, if any, proven ways to protect immune cells from viral infection, attention focused on the possibility of transferring cells from animal species which cannot be productively infected by HIV, such as baboons and pigs. While the baboon-to-human bone marrow transplant has already moved into human studies, other cross-species transplant approaches are increasingly catching the attention of the AIDS research community.

All cells of the immune system originate in the bone marrow. Where a cell matures will determine its function, however. Certain immune cells, such as B-cells, mature in the bone marrow. Other cells, such as T-cells (including CD4+ and CD8+ T-cells), mature in an organ called the thymus. Some researchers believe the thymus is an early target of HIV and is destroyed or impaired by viral infection. Some propose that if there is no place for bone marrow cells to mature (e.g., thymus), it may be unlikely that new T-cells will develop as a result of cross-species bone marrow transplantation. Therefore, researchers at Massachusetts General Hospital are pursuing animal studies to determine if cross-species transplantation of both bone marrow cells and thymus tissue is feasible. Unlike the San Francisco General Hospital protocol, these researchers are using bone marrow and tissue from pigs rather than baboons. Research suggests that pig cells and tissues are also resistant to HIV-infection. Because there appear to be far fewer diseases of pig origin that cause disease in humans, it may be much safer to use pigs in cross-species transplant experiments. While there was great interest among Think Tank participants in seeing this research proceed quickly, pig-to-human transplantation is not yet near the clinic and further animal experimentation is necessary to move this field along.

Thymus Transplantation
As noted, the thymus is an important organ for T-cell development. Bone marrow cells maturing in the thymus become new T-cells. The role of the thymus in HIV disease progression has been hotly discussed since the first Immune Restoration Think Tank meeting. Difficulties in assessing the state of the thymus have been a barrier in moving this field along. Dr. Michael McCune recently initiated a study looking at non-surgical ways to evaluate the thymus in people with HIV and AIDS. Preliminary findings suggest that in early-stage HIV disease, the size of the thymus is similar to that of people who are not HIV-infected. This is good news, suggesting that perhaps in early-stage disease the immune ‘environment’ may be more intact than previously believed. However, the functionality of the thymus may not necessarily correlate with its size and there may still be thymic dysfunction which does not show up in this procedure. In more advanced disease, the thymus appears to be smaller. This suggests that the thymus may be damaged by infection with HIV, or by other factors associated with advanced disease, such as increases in immune factors which are known to damage the thymus. It is also possible that the reduced size simply reflects some aspect of the wasting process or other metabolic disorders associated with advanced disease. Dr. McCune has now begun a parallel study to evaluate the condition of bone marrow of people living with HIV/AIDS. Both of these research projects, which were initiated by discussions in the Think Tank, are critically important in understanding the potential of several immune restoration techniques in HIV disease. For more information on these studies, call Pam Carroll of the Gladstone Institute of Virology at 415-695-3815.

In addition to research into the state of the thymus, Think Tank participants encouraged efforts in human thymus transplantation. Two studies developed by Think Tank participants have already begun to enroll. The first is a small study conducted in collaboration with the University of Vermont, which will enroll six people with low CD4+ cell counts. The second protocol is being conducted at Prince of Wales Hospital in Sydney, Australia. Thymic tissue is obtained from children undergoing heart surgery (where half of a child’s thymus is routinely discarded to open up access to the heart). The tissue is surgically implanted between the stomach muscles (where the stomach muscles join in the center of the belly). The primary objective of the study is first to determine if the thymus will ‘engraft’ or take hold in a person with HIV. Additional tests will determine if the transplant results in a change in the kind of immune cells circulating in the blood, or in viral replication. Studies initiated as a result of the Think Tank represent first steps, which may take some time to perfect. It is necessary to see if the simplest approach, human thymus transplantation, works. If it does not, it may be necessary to find a way to protect the thymus against HIV-infection. This might be accomplished by gene therapy, or cross-species approaches outlined earlier in this article.

CD4+ Cell Expansion
There are primarily two ways of thinking about where new T-cells are coming from when there is an increase in T-cells. One way, of course, is through the thymus pathway, or other tissues which may support new T-cell development from bone marrow cells. The other is when already existing cells start dividing and reproducing themselves (i.e., cell “expansion” or cloning). Since the first Think Tank, Project Inform has been instrumental in moving several cell therapy techniques into human testing, concentrating mostly on CD8+ cell expansion. For the last several years, Think Tank participants have also been discussing and trying to overcome the barriers of CD4+ cell expansion. The rationale behind CD4+ cell expansion is simple: if you have very low CD4+ cell numbers, is it possible to take some of these CD4+ cells, grow them outside the body, and reinfuse them? Bruce Walker, a Think Tank participant, began developing techniques to accomplish this as early as 1993. Since then, he has shown that it is possible to grow large quantities of CD4+ cells, even from people with very low CD4+ counts. By adding triple-drug combination antiviral therapies to the cells outside the body, and then stimulating their growth, he has been able to eliminate virus from the cells. Not wanting to re-infuse the cells, fearful that they would simply become new targets for HIV-infection and result in increases in viral replication, Dr. Walker has continued to work on this technology in the laboratory setting. Ultimately, he would like to use gene therapy on these cells, and somehow render them resistant to HIV-infection.

At the Houston meeting, Dr. Walker shared data on techniques to grow the cells, rendering them somewhat resistant to HIV-infection, even without genetic manipulation. Moreover, Dr. Walker has established a technique to make these cells HIV-specific in their activity, possibly resulting in an antiviral effect. Think Tank participants strongly encouraged Dr. Walker to move this technology into clinical trials and to begin re-infusing the cells back into people with HIV. As a result, this protocol is now being developed and we are hopeful that it will start enrolling patients later this year.

Exploring New Mechanisms
Dr. David Pauza of the University of Wisconsin presented data on a novel approach to interfering with HIV disease using pertussis toxin. In laboratory animals, Dr. Pauza administered the agent known to cause Whooping Cough to monkeys suffering from advanced SIV (Simian Immunodeficiency Virus) infection (a retrovirus similar to HIV which infects and kills monkeys). After a single tiny dose of the toxin, these monkeys showed signs of improved health and many maintained or increased CD4+ cell number and reduced viral load. These preliminary data are encouraging and sparked lively debate at the Houston Think Tank meeting. It is not understood how or why the toxin caused this effect. It was first believed that the toxin caused the lymph nodes to evacuate all the infected cells out into the bloodstream, but further analysis suggests that it works the other way: it may be blocking the entry of T-cells into the lymph nodes. Either way, the effect is the same since it stops the process by which great quantities of T-cells collect in the lymph nodes and become infected by the HIV-infected dendritic cells which are waiting there. Similar to making two feuding children stay in different rooms so they cannot harm one another, keeping the virus and cells separated may allow the immune system some time to ‘heal’. This mechanism, while not wholly understood, clearly warrants further exploration. There is general agreement that the lymph nodes eventually break down from the constant onslaught of virus being reproduced inside. Perhaps this slows or stalls that process while also protecting T-cells by keeping them in the peripheral blood and out of the lymph nodes.

While this ‘theory’ is quite interesting, it is not clear if using pertussis toxin in people living with HIV/AIDS is the best way to test the theory. At the wrong dosage, pertussis toxin may have severe, and possibly deadly, drug interactions with other commonly used therapies and can certainly cause disease by itself. In the animal experiments, disease did not occur because very tiny doses of the toxin were all that was needed to trigger the desired effect. But it is quite unclear what the proper dose would be in humans, and whether it might differ in people with advanced immune deficiencies. Research is proceeding to study the feasibility of testing this approach in humans. Enthusiasm for testing should be tempered with the reality that studies in monkeys may not be relevant to humans. Getting overly excited about animal data, or skipping important steps to determine the safe human use of an approach, could be more harmful than helpful.

Through the Think Tank process, Project Inform continues to bring together top researchers from around the world, working inside and outside the field of AIDS, to discuss new directions for immune restoration research. In the few short years since the first meeting of the Immune Restoration Think Tank, the project has received international acclaim for moving this field of research forward leaps and bounds. In addition to being featured at many national and international AIDS conferences as a model for community interaction with HIV research, the project has helped push the frontiers of science and foster research efforts into novel approaches targeting advanced HIV disease. For more information on the Immune Restoration Think Tank, call the Project Inform Hotline at 1-800-822-7422.

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