© 1994 by Donald F. Robertson.
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This article originally appeared in substantially different form in Space and Communications.
SPACE AND THE IMMUNE SYSTEM
Donald F. Robertson
Russian cosmonauts return from long missions on their Mir space station with symptoms remarkably similar to those of aging. Bones decalcify and weaken, blood production declines, and the immune system slowly decays. By and large, the mechanisms involved are not understood. But if human beings are ever to spend long periods of time in space, and expect to return to Earth, these problems must be solved.
The weakening immune system is especially worrisome. The immune system is an extremely complex network of biochemical signals and cells that coordinates and executes the body's defense against invading organisms. In the enclosed, intimate environment of a spacecraft, an infection in one astronaut could prove very hard to contain. This is especially so if the rest of the crew has problems resisting the disease.
Gerald Sonnenfeld, Director of Research Immunology at the Carolinas Medical Center, told Space & Communications, "If you are going to spend repeated, prolonged periods in space, you run two risks. One is an opportunistic infection, where something inside of you that is normally non-virulent becomes virulent because your immune system breaks down. Second is, what happens when you come back to the normal environment" with a damaged immune system and are exposed to all the diseases you have not been exposed to in your more-or- less sterile spacecraft?
Sonnenfeld is working on the immune system's response to spaceflight with NASA's Ames Research Center, and with Dr. Marvin Luttges, Director of Bioserve at the University of Colorado, and Dr. S. Keith Chapes, Director of Bioserve at Kansas State University. Bioserve is one of NASA's Centers for the Commercial Development of Space. These teams are trying to find ways "to prevent or abrogate" immunological changes caused by spaceflight.
Here on Earth, problems with the immune system have been a focus of research for over a decade, especially since the discovery of that modern plague, the Acquired Immune Deficiency Syndrome, or AIDS.
One company in the forefront of the fight against AIDS was to fly a new immunological experiment on February's Space Shuttle mission. The experiment involves live rats inoculated with a drug that, when used on Earth, is known to strongly stimulate the immune system. Chiron Corporation is a biotechnology company located just outside of San Francisco.
A Shuttle mid-deck locker was to contain twelve rats, half of them inoculated with the drug. The remaining six were a control group. No astronaut involvement was planned; the locker is sealed and the rats will be studied upon return to Earth.
Scientists want to see "whether the immune suppression caused by spaceflight can be reversed by the drug that we're treating the rats with," according to the experiment's Principal Investigator, Bob Zimmerman at Chiron.
The drug, called PEG-IL2, is an experimental modification of a commercially available product called Proleukin-IL2. Proleukin-IL2 is approved for treatment of renal cancer. "What it does biologically is stimulate the immune system very strongly," said Zimmerman.
The IL2, or Interleukin-2, in these drugs "is a natural product of the immune system, made by T-cells," said Zimmerman.
The body's many different Memory T-cells are like templates which the immune system uses to identify invading organisms. Every disease organism has unique structures on its surface called antigens. Each type of Memory T-cell carries similar structures, called receptors, that match with the invader's antigens. If a T-cell binds to an antigen, the immune system has identified that antigen. Therefore, the T-cell also has identified the antigen's parent disease organism, and the immune system can begin to organize a defense.
"T-cells which have not been exposed to a disease organism are also present" in the body, says Zimmerman, "which allows the immune system to respond to a new challenge by creating a new set of Memory T-cells. Interleukin-2 serves both as a growth factor [nutrient for the T-cells], and as an activator of all the various types of T-cells."
"The problem of AIDS," said Zimmerman, "is lack of a sub- class of T-cells," called CD4-cells. This reduction in CD4-cells allows invading organisms relatively free access to the body, eventually resulting in death through opportunistic infections. Both Proleukin-IL2 and PEG-IL2 are currently being tested on AIDS, and Zimmerman believes, "The results are encouraging at this time."
How does PEG-IL2 work? It "stimulates several lineages of cells that have IL2 receptors on them. These include `natural killer cells' or NK-cells, as well as macrophages," says Zimmerman.
Natural killer cells recognize a cell in the body that has been invaded by a virus and kills that cell. Then, the virus inside the dead cell cannot use the cell's mechanisms to multiply. Natural killer cells are normally activated by the T- cells that recognized the invading organism in the first place. But if the immune system is damaged and T-cells are in short supply, the natural killer cells must be activated artificially. Hence PEG-IL2.
The macrophages stimulated by PEG-IL2 are the body's first line of defense, and actively attack invading organisms. "And," said Zimmerman, "IL2 also causes the release of several cytokines, which are natural messengers that communicate between the different cells in the immune system. They turn on every arm of the immune system, including antibody production."
Once the natural killer cells are exposed to PEG-IL2, "they proliferate and become activated so that they can kill something as tough as tumor cells," said Zimmerman. They also "go after various types of microbial infections."
"Spaceflight essentially causes a suppression in the number and activation state of natural killer cells and T-cells," said Zimmerman. So a drug that stimulates NK-cell production and the function of T-cells may reverse spaceflight's damaging effects on the immune system.
PEG-IL2, the drug being tested on the Shuttle, is essentially the same as Proleukin-IL2, but modified to last much longer in the body. In the new drug, Proleukin-IL2 is chemically linked to polyethylene glycol; this complex molecule cannot easily get into the kidneys to be eliminated. It circulates within the body for "about ten times longer" than Proleukin-IL2 by itself.
Proleukin-IL2 must be injected several times a day. PEG-IL2 lasts for one to two weeks, avoiding the need for astronauts to re-inject the rats on board the Shuttle.
PEG-IL2 may help other parts of the body withstand the stress and microgravity of spaceflight. Conceivably, immunosuppression may play a role in bone decalcification, in which case Interleukin-2 may help to limit the weakening of an astronaut's bones.
Interleukin-2 "is a very powerful drug that is absolutely critical to the function of the immune system," said Zimmerman. "It can turn on a whole variety of different parts of the immune system. And that is why we think, with a broad response like that, it is going to be very valuable to overcome stress-related immunosuppression."
Immunosuppression in space may be caused by simple stress. Zimmerman said, "There is actually a syndrome in cattle that we have looked at as a possible therapeutic target called shipping fever. When they lock cattle up in cattle cars and drive them across country to feedlots, obviously that is very stressful on the animals. They have a lot of problems with disease outbreak." Likewise, when people get over-stressed they often get colds or the flu. This is caused by a stress-related suppression of the immune system. Experiments on the ground have shown that stress by itself causes a suppression of the immune system very similar to that found in orbit, and that PEG-IL2 appears to help.
It is hard to imagine anything more stressful than spaceflight. The stress comes from exposure to microgravity and from confinement in a small capsule.
Asked if this experiment could separate microgravity-related stress from confinement-caused stress, Zimmerman said, "The rats are probably in better shape in terms of [living] space than the humans. There are very clear regulations about how much physical space they have to have, so they are provided with the same amount of space that rats on Earth get." Any immunosuppression observed in the un-drugged control group of rats is likely to be microgravity-induced.
Once the rats are returned to Earth, the scientists will study the rats' blood chemistry and "every imaginable thing that you could dream up" to determine the status of the immune systems of those rats that were on the drug, and those that were not, according to Zimmerman.
Initial examinations will be done at the landing site as soon as the rats can be removed from the Shuttle mid-deck. Samples will be sent to laboratories around the country. Chiron is on the theoretical end of things, said Zimmerman: "We are doing a very limited part of the assays here."
Zimmerman would like to test other immune-stimulating drugs on future Shuttle missions. Asked if he saw this as the beginning of an on-going series of experiments, Zimmerman said, "That would be ideal. I don't know if we'll be allowed to do that, but it's something we would like to look at."
The Clinton Administration has initiated planning for a number of cooperative Shuttle missions to Russia's space station, Mir. Space & Communications pointed out that NASA is looking for a large number of small, relatively simple, long-term experiments. Zimmerman agreed that long-term experiments beyond the Shuttle's one- to two-week capability would be valuable. But, he said, cosmonauts "would have to learn to re-inject the rats, because the duration of the effect of the drug is only about a week or two."
With the International Space Station, NASA is planning longer space missions, which could result in greater damage to the immune system. Asked if he saw NASA as a potential market for the drug, Zimmerman said, "Sure. Not as a `market,' but as some people who could benefit from its use. I think that in terms of `markets' you look at tens of thousands, or hundreds of thousands, of people, not the twelve people that are up there in space." Zimmerman said his group had not yet discussed going beyond rats, to trying the drug in space on astronauts.
This experiment is not being done solely for the benefit of NASA's astronauts. Chiron's experiments with PEG-IL2 are very much applied research, said Zimmerman. The Shuttle experiment "provides us with another way of looking at immunosuppression, so we can say [to the Food and Drug Administration], we've looked at three or four models of immunosuppression, we believe IL2 has shown a positive effect in these models, and we would like to use it in humans. Our goal, obviously, is to take it into humans."
This could lead to some very valuable drugs. In addition to helping people with AIDS, "Old age is a stage of immunosuppression," said Zimmerman. "It is very clear that elderly people produce less IL2. In a pie-in-the-sky situation, we would like to believe that we could actually boost the immune systems of elderly people with this drug," or do the same for "stressed out people." However, "That is pretty far away. I think this drug might have the opportunity to do that, but it might be five or ten years from now because these are very big, long-term studies."
If the drug is available now, why so long until it can be applied to anything but cancer? "Imagine how many elderly patients you would have to [give the drug to], and for what duration of time you would have to look at them, to say that the frequency of influenza is up or down over the course of one winter or two winters," said Zimmerman. This kind of testing is very expensive. Will the Shuttle experiment short-cut any of that? "Yes, in the sense that any additional piece of information that you have makes you smarter about your clinical trials, about what patients you go into" with the drug, and how you administer the drug.
In contrast to Chiron, Gerald Sonnenfeld's primary interest is applying the drug to reduce astronaut immunosuppression. The Chiron experiment "is a logical follow-on to the state-of-the- art," said Sonnenfeld.
A drug can be tested on a trial-and-error basis, without understanding the mechanisms that are causing the immunosuppression. It is very difficult to separate microgravity, stress, radiation, and other environmental factors in space. According to Sonnenfeld, it makes sense to test a drug, that in Earth-bound applications is known to support the immune system, even before knowing what causes the immune system's failure in space.
The Vice President for Research at Cetus Corporation, which was bought by Chiron about two years ago, originally proposed the experiment to NASA before leaving at the time of the merger. NASA's Ames Research Center brought in Sonnenfeld, who acted as intermediary between the corporate scientists at Chiron, and NASA Ames and the Shuttle program.
Chiron is donating the drug, while Bioserve Space Technologies in Boulder, Colorado, is providing technical expertise with Space Shuttle requirements and procedures. NASA Ames is managing NASA's end of the project, but is not providing direct funding to the corporations and universities sponsoring the experiment.