|This is what the smallpox virus looks like under a microscope. Before its eradication, smallpox killed millions around the world. Now the virus exists only in labs in Russia and at the Centers for Disease Control and Prevention in Atlanta. However, some scholars fear that not all supplies are secure. Dr. Fred Murphy, Sylvia Whitfield|
The immune system is constantly changing. It matures throughout childhood, then declines as the body ages. It responds to the environment as it encounters new threats and recognizes old, familiar enemies. It can be weakened by disease, medications, or environmental toxins. As scientists learn more about how the immune system functions and changes, they can devise strategies to treat or prevent disease by manipulating the immune system. These strategies are called immune therapies.
Many diseases, such as mumps and measles, are once-in-a-lifetime events. The reason: After you have recovered from an infection, your immune system remembers. As mentioned in the Introduction, Edward Jenner developed a vaccine for smallpox using a similar disease (cowpox) and exploiting our immune system’s memory. While Jenner based his vaccine only on observation, we now know that vaccines work by taking advantage of the adaptive immune system’s memory cells. A vaccine is made from a microbe that resembles a disease-causing one to prompt the immune system to recognize it as an invader, but the microbe is weakened so that it will not cause a disease. The disabled microbe attracts the attention of phagocytes, which sound the alarm to summon lymphocytes. The resulting battle is brief—but long enough for memory B and T cells to recognize the real invader later on. That is why Jenner’s cowpox vaccine protected people against smallpox two centuries ago—and why the vaccinations you have received since childhood, for other diseases, are so important. The next time you get a ﬂu shot or some other vaccination, remember: your own internal defensive army is being activated on your behalf, and when that germ shows up, your army can eliminate it before it has a chance to cause disease.
Dead or Alive
Unlike Jenner’s, most vaccines today must be created in the laboratory. Louis Pasteur created the ﬁrst artiﬁcial vaccines by weakening the microorganisms that cause rabies and anthrax. Like Pasteur’s vaccines, modern “live” vaccines are weakened versions of disease-causing organisms. The vaccines for mumps, measles, German measles (rubella), and chicken pox are such vaccines. Inactivated (killed) vaccines are also very common. To make them, large amounts of the target organism are grown in the laboratory, then killed with heat, radiation, or chemicals. Most polio and inﬂuenza vaccines used in the United States today are inactivated vaccines. “Subunit” vaccines, such as the vaccine for whooping cough, contain only a part of the harmful organism. “Toxoid” vaccines, such as the tetanus vaccine, do not contain the organism itself, but an inactivated and attenuated version of the disease-causing toxin it produces.
Although traditional vaccines have controlled many diseases, effective vaccines against some of the biggest killers in many countries—AIDS, malaria, and tuberculosis—have not yet been discovered. New techniques in molecular biology and genetic engineering may be the key to making safe, effective, and affordable vaccines to meet these challenges.
The vaccines and natural infections described above illustrate adaptive immunity because they stimulate the body’s own immune system to adapt, or learn, to ﬁght diseases. One type of adaptive immunity occurs when the body makes antibodies, proteins that can recognize and destroy germs. This active immunity contrasts with passive immunity, which occurs when antibodies are made somewhere else (in another person, an animal, or even in the laboratory) and introduced or “passed” into the body.
We all start life with the gift of natural passive immunity. Newborn babies are protected from many diseases by the antibodies they received from their mothers through the placenta before birth. They can get even more of these passive antibodies from their mothers’ milk, especially from the antibody-rich milk (colostrum) produced immediately after birth.
Artiﬁcial passive immunization, with antibodies from humans or animals, can be used to treat or prevent diphtheria, tetanus, hepatitis, and rabies. People bitten by poisonous spiders or snakes are often treated by passive immunization.
The Monoclonal Revolution
In the 1970s a new technique for producing antibodies in the laboratory changed the world of immunology forever. Georges Köhler and César Milstein won the 1984 Nobel Prize in physiology or medicine for discovering a way to mass-produce monoclonal antibodies. In an animal’s body, antibodies are produced by many different cells and can bind to many sites on an antigen; these are called polyclonal antibodies. In contrast, monoclonal antibodies are produced in laboratory dishes by cells derived from a single antibody-producing mouse cell. A monoclonal antibody binds to a single, tiny site on an antigen and can recognize very subtle differences between cells, molecules, or germs. Because of this speciﬁcity, and because they can be produced in unlimited amounts, monoclonal antibodies have wide-ranging applications in science and medicine—from basic research to the diagnosis and treatment of diseases.
At ﬁrst, monoclonal antibodies were less useful for treating disease because the human immune system sees antibodies made by mouse cells as foreign and rapidly eliminates them from the body. With the help of genetic engineering, researchers continue to investigate ways to “humanize” monoclonal antibodies to make them more effective against human diseases. Hundreds of monoclonal antibodies are now being tested in clinical trials.
|Mothers pass antibodies to their babies through the placenta before birth and through their milk after birth. These antibodies help bolster the babies’ immune systems at a time when they are more vulnerable to infection. Peggy Greb|
|César Milstein © The Nobel Foundation|
|Georges Köhler © The Nobel Foundation|
Monthly injections of humanized monoclonal antibodies against respiratory syncytial virus (RSV) during the RSV season can protect premature babies and young children with chronic lung disease from serious respiratory infection. Monoclonal antibody therapy also shows promise against West Nile virus and some antibiotic-resistant bacteria.
The usefulness of monoclonal antibodies is not limited to infectious diseases. Many are under investigation or approved for use against allergic and autoimmune diseases (including rheumatoid arthritis, inﬂammatory bowel disease, asthma, and diabetes) and to prevent organ transplant rejection. These antibodies can suppress the immune system by blocking important molecules on the cell surface that recognize attack signals.
Monoclonal antibodies can also ﬁght cancer. They can block receptors that the cancer cell needs to survive or—when bound to drugs, toxins, or radioactive particles—deliver cancer-killing weapons precisely to their targets.
A fascinating new mechanism of monoclonal antibodies is that they can coat tumor cells so that the immune system’s dendritic cells then detect the tumor and present numerous other tumor antigens to the lymphocytes, thus triggering adaptive immunity.
Stem Cell Transplants
Stem cell transplants are a kind of immune therapy that transfers cells instead of antibodies. Blood-forming stem cells are immature cells that will become red and white blood cells and platelets. The bone marrow (the spongy material in the center of some bones) contains blood-forming stem cells. Blood-forming stem cells can also be isolated from the circulating blood and from the umbilical cords of newborn babies (after the cord is cut, cells are harvested from the discarded portion of the cord).
These are not the controversial embryonic stem cells, cells from human embryos or fetal tissue that can develop into other types of cells and tissues. For the most part, immunologists have not been drawn into the debate surrounding embryonic stem cells because the discovery of blood stem cells in bone marrow revealed the secret of rebuilding the immune system via bone marrow transplants.
Regardless of how the controversy over embryonic stem cells plays out, transplants of the stem cells found in bone marrow (also called bone marrow transplants) are a viable, noncontentious treatment for some immune deﬁciency diseases and certain cancers. Cells can be obtained from a living donor, or the patient’s own stem cells can be removed and later introduced back into the patient. In the case of tumors, the patient’s tumor cells are ﬁrst destroyed with drugs and/or radiation, but this also destroys the body’s immune system, leaving the patient with a weakened immune defense. The beauty of stem cells is that they regenerate the full immune system. After the stem cells are injected into the patient’s blood, they migrate to the bone marrow, where they mature into blood cells, including all the different cells of the immune system. This is an intricate process involving, among other things, the action of cytokines. Cytokines are a large family of proteins, each of which regulates distinct steps in the life of stem cells and their immune descendents. Only very small amounts of cytokines are required to regulate stem cells and other immune cells.
Benjamin Reese / Custom Medical Stock Photo
The patient and stem cell donor must be a good genetic match for the transplant to succeed. If the match is poor, transplanted cells may recognize the patient’s body as foreign and attack it. This is called graft-versus-host disease. In some cases, transplanted immune cells may attack the skin, causing rashes, or the intestine, causing severe inﬂammation. In other cases, the patient’s body may attack and reject the donor cells. Successful matches, however, make possible a promising treatment for a variety of immune problems.
On the Horizon
Many other kinds of immune therapy are under investigation. Some of these techniques involve removing cells from the patient’s body and treating them in the laboratory to make them more aggressive disease ﬁghters. Other techniques use cytokines or other substances to stimulate the immune system. Some new immune therapies are described in “Research Advances: Recent and Prospective”.
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