A South African virologist and Nobel Prize winner, Max Theiler made major contributions to research on the viral disease known as yellow fever. During the 1930s he developed vaccines that protected millions of people from this incurable tropical affliction. For his contributions, Theiler was awarded the 1951 Nobel Prize in physiology or medicine. Using mice, he developed highly efficient methods for breeding the yellow fever virus as he pursued various strategies for vaccines. In 1934 Theiler developed a vaccine based on an “attenuated,” or weakened, form of the virus cultivated in mice.
Scratched into the skin, the virus would not cause yellow fever, but would provoke the body’s immune system to protect against any subsequent infections. Because this vaccine sometimes caused encephalitis, an inflammation of the brain, Theiler continued to refine his vaccine experiments. In 1937 he introduced another vaccine, designated 17D, based on another strain of the virus that was grown in chicken embryos. Between 1940 and 1947 the 17D vaccine was used to protect more than 28 million people in Africa and the Americas.
Today, although still a problem in remote areas, yellow fever has been vastly reduced as a health threat. 1) Immunological Tolerance Sir Macfarlane Burnet, along with Sir Peter Medaway, had been awarded the 1960 Nobel Prize in physiology or medicine for their discoveries concerning acquired immunological tolerance. Burnet explained how the body’s immune system recognizes and attacks foreign invaders, such as viruses and bacteria, but ignores the body’s own tissue. The immune system’s ability to distinguish “self” from “non-self” tissue, suggested Burnet, arose during the late stages of embryonic development.
He hypothesized that any substance present in the body before this critical period was recognized as self and tolerated, whereas any substance that presented an antigen (structures on foreign substances capable of initiating an immune response) not encountered during early development was subject to antibody assault and elimination. 2) Human Leukocyte Antigen Discovery While serving in a blood-transfusion unit of the French Free Army during World War II, Dausset observed that some patients exhibited an adverse reaction to donor’s blood even when the donor’s blood matched the type of the recipient.
In 1951 Dausset discovered that in these cases the donor’s blood had been affected by diphtheria and tetanus vaccinations that the donor had received: The vaccinations had boosted the blood’s antibodies to foreign material. He studied anemia and white blood cells (leukocytes) from 1952 to 1958. He discovered that humans have a center called the major histocompatability complex (MHC), which determines tissues and blood type affinity. When the body rejects a blood transfusion or a skin-graft it is because the MHC detects antigens that are unsuitable to the body.
Dausset determined that the MHC of humans is made up of a small area of the sixth chromosome, that he called the human leukocyte antigen (HLA). The genetic basis of the human MHC became known in 1967, when Dausset carried out skin-graft experiments involving families and unrelated individuals. Dausset worked successfully to convince transplant surgeons worldwide of the need for tissue typing. He was also the first researcher to investigate the connection between MHC and specific diseases. Connections were later found between particular HLA antigens and arthritis, juvenile diabetes, multiple sclerosis, and autoimmune diseases.
17(pp326-327) Dausset’s findings have made organ transplantation more successful than it was before tissue typing. When Zinkernagel and Doherty began their award-winning research in the early 1970s at the John Curtin School, scientists already knew that certain white blood cells—T lymphocytes, or T cells—produced by the immune system are involved in the rejection of transplanted organs. They knew that T cells kill transplanted, or foreign, tissue after recognizing certain molecules, known as major histocompatibility antigens, in the transplanted tissue, but this process was not understood.
Zinkernagel and Doherty focused their research on how the major histocompatibility antigens trigger an immune response. 18(p164) During their investigation, Zinkernagel and Doherty infected mice with the virus that causes a strain of meningitis, a disease that causes inflammation of the meninges, the membranes that cover and protect the brain and spinal cord. The infected mice developed T cells that attacked and killed cells only from the same mouse strain harboring the virus. When these same T cells were mixed with virus-infected cells from other strains of mice, the T cells were unable to recognize and kill the infected cells.
Zinkernagel and Doherty concluded that before T cells can eliminate the infected cells, they need to recognize two signals. One identifies the presence of a virus. The other signal is from “self” molecules on the major histocompatibility antigens, which indicates that the cell is part of the organism and not a foreign body. 5(p193) The work of Zinkernagel and Doherty significantly influenced the direction of research in T-cell recognition. Building on their work, other scientists determined that an infected cell ingests part of an invading virus, breaking it down into fragments.
These fragments join with the major histocompatibility antigens and move to the surface of the cell. Special receptors on the surface of T cells respond to the dual signals identified by Zinkernagel and Doherty by attaching to the infected cells and destroying them. 5(p194) 3) Use of Monoclonal Antibodies In 1975 Argentine-born British immunologist Cesar Milstein and German immunologist Georges Kohler discovered a technique to generate a quantity of white blood cells that uniformly produced only one type of antibody. These antibodies, known as monoclonal antibodies, target only one specific antigen—for example, one particular virus or toxin.
White blood cells naturally produce many different types of antibodies, each designed to mark one specific antigen. Creating monoclonal antibodies allowed scientists to tag one specific substance. Milstein and Kohler received the 1984 Nobel Prize in physiology or medicine for their work. By the mid-1990s monoclonal antibodies were commonly used in biomedical research and in diagnostic devices such as home pregnancy tests. Researchers were also working on disease treatments in which monoclonal antibodies would tag diseased cells for attack by therapeutic agents.