Predictions for the Study of Immunity
One of the greatest victories in immunology came in 1979 with the complete eradication of smallpox. Yet the road to this achievement began 200 years ago with Edward Jenner’s discovery of a smallpox vaccine, using nonvirulent cowpox material.
For centuries, scientists and physicians have recognized the body's amazing capacity to resist disease, but understanding of the mechanisms of immunity has come only in the last 30 years as scientists finally gained the tools necessary to describe the complex systems of immunity.
In spite of our discoveries, humanity is still faced with many challenges. Many antibiotic-resistant pathogens - the so-called “super bugs” - have grown resistant to the tried and true antibiotics such as penicillin, and to new drugs almost as quickly as they are developed. Old diseases such as TB appear to be on the rise again, and new dangers seem to be creeping out of the jungle. Can science keep up?
Klaus Elgert, an immunologist at Virginia Tech, is optimistic that science will overcome the threat of resistance to antibiotics.
“Antibiotics are stop-gaps,” he explains. “Disease organisms evolve rapidly and we don't. But our immune system is designed to meet this evolution. We design antibiotics to stall the disease - to attack it until our system is geared up to eradicate it.
“But some organisms are evolving too quickly,” Elgert says. “We're turning the clock back on fighting infections,” he says. “In some cases, we're having to remove infected tissue.” In other cases, such as with HIV, scientists are finding suites of new drugs that work in combination.
“The super bugs are driving researchers to look at the disease organism and to devise a way to kill it beyond antibiotics.” He's confident that will happen. “We've identified the genetic information in disease organisms that confers antibiotic resistance and we're learning how the organisms defeat the antibiotics and how they pump drugs out. The bugs get more sophisticated, but so does our response. The immune system is pretty capable.”
What we've learned from AIDS
The most intensive lessons have been learned from AIDS.
“AIDS has brought home what viruses can do, how deadly they are, and has shown us that we need better control of viral infections,” says Elgert.
Viruses take over the genetic machinery of cells. “HIV insert their own genetic code next to the code for other important factors for certain immune cells, such as interleukin 2. Thus, when our immune response turns on the production of these factors, it also turns on the virus. Through AIDS research, we have learned how some immune cells are turned on and how genes turn cells on and off.
“Some people survive, we've found, because a molecule on the surface of their cells is missing so the virus can't get in. It's the same reason we don't get canine distemper. Our cells don't have a receptor for that disease virus.” This realization should lead to genetically engineered treatments and vaccines.
Sometimes heavy funding of one area can be shortsighted; but “We've learned a lot about viruses from the study of AIDS,” says Elgert. “What we've learned will not only benefit other patients' illnesses; it has exposed molecular and cellular regulation mechanisms that otherwise would have gone undiscovered for some time - opening new doors for many areas of basic research.
“We've learned a tremendous amount about how viruses control cells, the molecular biology of cells, and even how cancer cells work.”
Cancer and the Immune System
Elgert's respect for the immune system is a result of his research on how cancer interacts with the immune system, particularly with macrophages (Mfs). Mfs are cells in the immune system that digest intruders, or antigens, then display the digested components to other immune cells to elicit their help. Cancer cells sabotage the ability of Mfs to communicate with other cells of the immune system. Elgert and his colleagues, including his graduate students, have discovered that cancer cells can manipulate gene expression in Mfs through chemical signals so that Mfs do not suppress tumor growth (in fact, tumors can even cause Mfs to promote tumor growth). They are doing research to determine how to return the Mf to its normal activity, to enhance the immune system's ability to fight cancer, and to find other chemicals to kill cancer cells.
Elgert explains that cancer is the “uncontrolled growth of tumor cells and the loss of immune surveillance and of the ability to destroy aberrant cells. The cause of this loss of control is varied and differs among different types of tumors.”
The long-term objective of research in his lab is to understand the cellular and molecular events involved in tumor-induced immune suppression by Mfs. “We have documented that tumor growth is associated with a decrease in immune function caused by a reduction of positive regulatory factors and an increase in negative regulatory factors,” he reports.
1) The tumor itself releases negative factors when some cancer cells mimic immune-system cells; and
2) The immune cells are altered, especially Mfs, so that they join the cancer cells in turning down the immune system.
Mfs help regulate infections and tumors by producing interleukin (IL)-12, a vital communication molecule between Mfs and other immune cells. What if Mfs don't produce enough IL-12? Elgert's research has demonstrated that Mfs in animals with tumors make less IL-12.
In addition, the researchers have discovered that the impact is not limited to the tumor; the immune system throughout the body is compromised.
Combating Loss of Immunity
To combat the loss of immune function, Virginia Tech's immunologists are investigating two possible therapeutic agents that stimulate the immune response: paclitaxel (taxol) and IL-12. It has long been recognized that taxol disables cancer cells - particularly in the cancers that affect women's reproductive systems. The discovery that taxol also stimulates Mfs to produce IL-12 is relatively new.
The researchers are examining how taxol boosts Mf function, determining how tumor growth alters IL-12 regulation, and examining the effectiveness of taxol and IL-12 in compensating for the documented loss of immune system function using a novel combined gene therapy and chemotherapy approach. “Eventually it may be possible to treat diseases such as cancer by selectively stimulating under-active parts of the immune system and by reducing the tumor's ability to suppress immune responses,” says Elgert.
He proposes that soon scientists will even be able to engineer cells to produce IL-12, then inoculate the site of the tumor with the cells, which will undergo a limited number of cell replications and then die. The IL-12 produced by the engineered cell will augment immune activity local to the tumor.
Within 10 years, it is very likely that the human genome will be mapped and there will be a catalog of normal genes. “The next step will be to learn how to introduce normal genes to replace or inactivate abnormal genes, to provide genes when they are missing, or to turn-on inactive genes. For example, can the ability to produce IL-12 be turned on if cancer has turned it off?” asks Elgert.
Once we map the genome, we may be able to engineer genes to prevent disease, he suggests. This level of sophistication is already seen with DNA vaccines that cause cells to express molecules that the immune system can recognize and attack. “We can introduce a carrier virus to display a harmless piece of a dangerous virus so the immune system learns to recognize it. We can take out a cancer cell, insert a gene to make it more recognizable to our immune system, reinsert the cancer cell, then let our immune system take over,” he explains. “But there is a certain risk - like using an attenuated rather than killed virus vaccine.”
“What causes the immune cell to do what it does, whether good or bad? Maybe by the year 2050, we'll have answered this question and be sitting with the gods,” says Elgert. “It will be intriguing to find out if our predictions coincide with what happens. No matter the results, the trip will be exciting.”