February 24, 2002
By Judy Siegel-Itzkovich
Judy Siegel-Itzkovich meets Prof. Rolf Zinkernagel, a pioneering explorer of the human immune system
Think of the body's immune system as the border patrol, police sappers and commandos all rolled up into one defensive and offensive force. The spleen and lymph nodes are the main bases, sending out T-cells to patrol the body's pathways for foreign invaders and to kill any they find.
But how does the immune system differentiate between dangerous enemies such as viruses, bacteria or even cancer cells, and harmless visitors like donated blood of the same type, or even the body's own "friendly" cells?
Why are there only three main blood types, A, B (or combinations of the two) and O, but hundreds of thousands of varieties of histocompatibility types that make matching donated organs so difficult?
These questions have been explored by University of Zurich Prof. Rolf Zinkernagel, co-recipient of the Nobel Prize in Physiology or Medicine in 1996, who earlier this month was awarded the 2002 Rabbi Shai Shacknai Memorial Prize in Immunology and Cancer Research from the Lautenberg Center for General and Tumor Immunology at the Hebrew University-Hadassah Medical School.
Zinkernagel, 58, did his pathfinding work in immunology in Australia when he was barely 30, along with Dr. Peter Doherty of Queensland. The two scientists, who shared the $1.2 million Nobel, worked between 1973 and 1975 at the John Curtin School of Medical Research in Canberra.
They found out how the "flagpoles" on the surface of cells, which give humans their distinctive tissue type, alert the immune system to foreign invaders. Their findings paved the way for the current understanding of how immune systems recognize microbial invaders and the body's own cells.
The two scientists used mice to study how the immune system, particularly T-lymphocytes, recognize virus-infected cells and distinguish them from healthy cells. They discovered "killer lymphocytes," which in a test tube attacked and killed cells infected by a virus.
But they also discovered that the "killer T-cells" worked only against a specific virus in a specific mouse and could not be transferred to a genetically different animal to kill the virus.
Such discoveries have had a significant impact on the study of diseases such as rheumatoid arthritis, multiple sclerosis and diabetes, and the new knowledge provides a basis for the "construction" of improved and specific vaccines against diseases.
Former New Jersey senator Frank Lautenberg established the annual Shacknai prize in memory of his rabbi. The Israeli-born Shaknai, spiritual leader of the Wayne, New Jersey, Jewish community, died of cancer at the age of 38.
The prize sponsors three lectures by the esteemed recipient to Israeli immunology and oncology researchers.
Married and the father of three, Zinkernagel was born in Basel and originally intended to be an architect. In an interview with The Jerusalem Post, the distinguished scientist spoke about his decision to study medicine. He earned his medical degree from the University of Basel in 1970, and thought he might become a surgeon.
But he became so interested in how diseases developed that he decided to invest his energies in immunology. Now director of his university's Institute of Experimental Immunology, he has had an illustrious career, with many honors, including the prestigious Lasker Prize, Paul Ehrlich Prize and Gairdner Award, as well as publications and editorial board memberships in many research journals and honorary doctorates.
Without intending to, Zinkernagel and Doherty discovered the phenomenon of major histocompatability complex (MHC) restriction, which demonstrated for the first time a physiological function for histocompatibility proteins. This discovery and the theories that Zinkernagel proposed to interpret it fueled research in immunology that has led to significant developments, says Prof. Eitan Yefenof, director of the Lautenberg Center.
Among them are the discovery of the T-cell receptor, functional disparity between different classes of MHCs, superantigens, antigen processing and antigen presentation.
Yefenof notes that because the team's discoveries were made when they were young, many colleagues dismissed them as nonsense.
Immunologists had been certain that a series of genes coded for proteins were responsible for rejection of donated organs. In the 1950s, MHCs were discovered in mice as the cause for rejection of transplanted organs.
In the Sixties, techniques were developed to identify the proteins and create maximum compatability between the donor organs and the recipient, but the rejection mechanism was not understood.
THERE ARE six major human MHCs - three donated by one's father and three by one's mother. But there are very many unique combinations of them in each individual, and the chance for an exact match is one in 600,000.
No donated organ exactly matches the MHC combination of the recipient (unless they are identical twins or in some cases non-identical siblings). Thus, if there is no perfect match, immunosuppressive drugs must be taken by an organ recipient for the rest of his life to prevent the immune system from rejecting the organ.
However, one can get a better match and increase the chance for its successful acceptance by the body by looking for an organ from a member of one's specific ethnic or racial group.
The "job" of MHCs is to present a foreign protein to the immune system; each is built with a "groove" of a certain size that accepts the peptide of the antigen. If a "self" peptide can fit into the groove, it won't be recognized by the immune system.
If all humans had the same protein, such a lack of specificity would mean a single germ could kill everyone. The large variety of MHCs prevents this from happening, says Yefenof. A pathogen would kill some, but most would survive.
But since transplanting an organ from one person to another is not a "natural" thing in the eyes of evolution, the protective MHC poses major difficulties in finding an organ compatible with the donor's own histocompatibility makeup.
SO ZINKERNAGEL and Doherty came along and, through their work on mice, found that the immune system doesn't recognize the foreign protein as something from outside the body, but as "self."
In the Eighties, it became clear that MHCs have a three-dimensional structure that "catch" the antigen peptide and present it to the immune system. Zinkernagel's unconventional, anti-dogmatic, stimulating approach and his findings have led to a large number of researchers going into the field of molecular biology and immunology, Yefenof adds.
Zinkernagel, who came to Israel to receive his prize despite initial fears about security in the area, said he was very glad he came; his lectures aroused a great deal of interest among Israeli researchers.
Among the subjects he spoke about was immunological "memory" - how the immune system recalls meeting up with a virus or antigen years or even decades before.
"This is not 'memory' such as that in the brain, in which new 'wiring' of nerve connections change the brain with each new experience," Zinkernagel said. "This 'memory' requires the presence of a tiny amount of protein lingering in the body that keeps the immune system 'alert.' "
A low level of infection - such as ongoing exposure to the polio virus from the environment - is needed to stimulate an ongoing immune response. This requires either frequent vaccine boosters or delivering new sources of relevant peptides to the body's lymph nodes or spleen, perhaps someday even with a skin patch.
Zinkernagel and his team in Zurich are now looking at the immune response to pathogens that, like HIV, linger and cause delayed damage to the body.
"Many infections of viral or bacterial origin, particularly those of low pathogenicity, actually show up only after five, 10, 15 or 20 years. So I'm mostly interested in these balances between an infectious agent and the immune response that may eventually lead up to disease at a rather slow rate."
Zinkernagel noted that heart disease or autoimmune diseases such as type I diabetes, rheumatic arthritis or multiple sclerosis are believed to be triggered at least in part by an infection. Two decades ago, he said, nobody associated these things with infectious disease.
Zinkernagel said getting a Nobel Prize for work he conducted as a young man does not pressure him to make other pioneering discoveries. Asked why it took the Nobel Prize committee so long to make him and Doherty laureates - a quarter of a century passed between their discovery and their award - Zinkernagel shrugs.
"Immunology seems to be a subject of the physiology or medicine Nobel every seven years or so. There is a cycle. In 1981, a Nobel was awarded for work on a major transplantation antigen, so it was a good base for giving a Nobel for work we did."
He is in regular contact with Israeli immunologists, and he follows their work. He is well aware of the Israeli scientists' complaints about the lack of state research money.
"We have the same problem in Switzerland. Science budgets haven't increased in 10 years. Your country, like mine, lacks natural resources and has to depend on knowhow to succeed. It's the brains that count.
"I urge Israel to boost its science
budgets and promote research."
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