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From MAC to HLA
Human Immunology 70 (2009) 661– 662
Contents lists available at ScienceDirect
From MAC to HLA Professor Jean Dausset, the pioneer
Jean Dausset, who received the Nobel Prize of Medicine in 1980 for his discovery of the Major Human Histocompatibility Complex (HLA), died in Palma de Majorca, Spain, on June 6, 2009 at the age of 92. Jean Dausset was born on October 19, 1916 in Toulouse (France). He studied medicine in Paris. In 1949, after a sabbatical year at Harvard Medical School (Peter Bent Brigham Hospital) with Louis K Diamond, Jean Dausset returned to the Center of Transfusion at Saint Antoine hospital (Paris) and took a keen interest in patients with an abnormally low number of leukocytes (leukopenic). From their serum, he discovered the existence of antibodies able to bind the leukocytes of another individual. This was the crucial experiment which was going to have a major impact on his whole life (1952). Soon after, Jean Dausset showed that these anti-leukocyte antibodies were generated due to the many transfusions which the patient had received. They were not auto-antibodies responsible for leukopenia as previously thought. These studies provided evidence for the existence of human leukocyte groups that Dausset related to ABO blood groups with one major difference, which is that anti-ABO blood group antibodies exist naturally, whereas antileukocyte group antibodies arise after immunization. 0198-8859/09/$32.00 - see front matter doi:10.1016/j.humimm.2009.07.010
He then designed a simple strategy which consisted of using blood from a single donor for transfusing a patient who could thus be immunized against leukocytes from this unique donor. As he expected, the patient developed antibodies which reacted with leukocytes from the donor. However, they also reacted with about 50% of the population of tested volunteers, indicating that they carry the same leukocyte group, which was called MAC, an acronym made up of the initials of the first three donors with whom the serum did not react. This discovery was published in 1958 in Acta Haematologica in which Jean Dausset already stressed the possible importance of these groups in transplantation. Two other teams had adopted the technique of leukoagglutination. One team in the Netherlands, directed by J.J van Rood, showed the existence of a clear division of the population in two allelic groups (4a and 4b); the other in California, directed by Rose Payne, demonstrated the existence of 3 antigen groups which were probably encoded by same genes (LA1, LA2, LA3). An international collaboration between different laboratories began after 1965 and is still going on these days. In these international workshops the same biological materials are tested to examine the diversity of these genes and of their antigen product.
662
/ Human Immunology 70 (2009) 661– 662
Jean Dausset was the first to realize that this discovery concerned a complex genetic system, similar to the H2 system of the mouse. To prove it, he tested 50 sera from different individuals using leukoagglutination and lymphocyto-lysis tests. The results proved the existence of at least 8 leukocyte groups postulated to belong to a single genetic system which Jean Dausset named Hu-1, according to the nomenclature suggested by George Snell for the H2 system of mice: “Hu” for human and “1” for the first system. It then had to be proven that, like the H2 system, the Hu-1 system determines the fate of allogeneic transplants. In 1964, in collaboration with Felix Rapaport, a surgeon/immunologist from the USA, Jean Dausset performed a series of skin grafts on volunteers. He showed that there was a correlation between the compatibility determined by the Hu-1 system and the survival of skin grafts. This proved that the leukocyte groups were actually tissue groups, opening the way to organ transplantation. Jean Dausset showed for the first time that the survival of grafted kidneys was correlated with the number of incompatibilities in the Hu-1 system, which was meanwhile renamed HLA (Human Leukocyte Antigen). He observed that the best graft survival was obtained when the donor was a sibling who had received from both parents the same HLA complexes. However, in practice, many patients needed and received kidneys from unrelated individuals. To find compatible donors, Jean Dausset created the first organization for the exchange of organs, France-Transplant. This was the seed for the exchanges which were going to become worldwide and which would concern other organs such as heart, liver and pancreas. By 1968, Jean Dausset believed that these tissue groups could account for certain diseases susceptibilities and this, in spite of the nearly complete failure of this design applied to the system of ABO blood groups. Using as a base the existence of a correlation between the H2 system and murine leukaemia, Jean Dausset was the first to find the equivalent in humans. Many teams in the world joined his research and many associations were created. It became possible to detect, within a family or within the general population, individuals likely to develop a certain disease if they had the corresponding allele. This led Jean Dausset to introduce, in 1972, the concept of predictive medicine. The detailed description of the HLA system discovered by Jean Dausset had tremendous consequences, be it at the philosophical level, in basic biology, or in therapy. The high polymorphism of the HLA system allowed the demonstration that each individual is
unique. There are so many possible combinations between alleles of the HLA system that practically each formula is unique. In terms of basic immunology, the HLA system made it possible to understand one of the essential mechanisms of immunity—the recognition of self and non-self thanks to the presentation of foreign peptides by HLA molecules. On the therapeutic level, the most obvious consequence was its immediate application to tissue transplantation. Finally, the discovery of the HLA system paved the way for the association of many afflictions to particular HLA alleles. Jean Dausset believed that predictive medicine would become important not only to the diseases associated with the HLA system, but also with other genes of the entire genome. This drove him, in 1984, to create the C.E.P.H.—Centre of Study of Human Polymorphism—with the aim of detecting genes that predispose individuals to diseases including those outside the HLA system. For that purpose, it was first necessary to establish physical and genetic maps of the human genome. Jean Dausset made samples from patients used to study the genetics of the HLA system available to the wider scientific community. Ray White, who had described DNA markers using the R.F.L.P. technique, joined the project, adding to it a large sample cohort from Utah. A hundred laboratories in the world collaborated in this project. It was the first biological material shared internationally as a reference point and is still in use today. This enabled the C.E.P.H. to generate the first markers of the human genome, which thereafter allowed cloning and identification of the disease-associated genes, a major advance in medical genetics. In 1991, Jean Dausset was interested in a new development of the HLA system. With Edgardo D. Carosella, he studied the HLA-G molecule which, contrary to other HLA molecules, is involved in tolerance. This seems to be involved in maternal tolerance to the fetus, which is incompatible because half of the genes are inherited from the father. Professor Dausset was a member of the Academy of Sciences, a foreign member of the American Academy of Sciences, an honorary member of the American Academy of Arts and Sciences and a founding member of the Organization of the Human Genome. He received many prestigious prizes such as the Landsteiner Award and those of the Koch and Wolf Foundations. He was an advisor to many research institutions. Edgardo D. Carosella, M.D. Research Director at the French Agency of Atomic Energy Head of the Hemato-Immunology Department
Contents lists available at ScienceDirect
From MAC to HLA Professor Jean Dausset, the pioneer
Jean Dausset, who received the Nobel Prize of Medicine in 1980 for his discovery of the Major Human Histocompatibility Complex (HLA), died in Palma de Majorca, Spain, on June 6, 2009 at the age of 92. Jean Dausset was born on October 19, 1916 in Toulouse (France). He studied medicine in Paris. In 1949, after a sabbatical year at Harvard Medical School (Peter Bent Brigham Hospital) with Louis K Diamond, Jean Dausset returned to the Center of Transfusion at Saint Antoine hospital (Paris) and took a keen interest in patients with an abnormally low number of leukocytes (leukopenic). From their serum, he discovered the existence of antibodies able to bind the leukocytes of another individual. This was the crucial experiment which was going to have a major impact on his whole life (1952). Soon after, Jean Dausset showed that these anti-leukocyte antibodies were generated due to the many transfusions which the patient had received. They were not auto-antibodies responsible for leukopenia as previously thought. These studies provided evidence for the existence of human leukocyte groups that Dausset related to ABO blood groups with one major difference, which is that anti-ABO blood group antibodies exist naturally, whereas antileukocyte group antibodies arise after immunization. 0198-8859/09/$32.00 - see front matter doi:10.1016/j.humimm.2009.07.010
He then designed a simple strategy which consisted of using blood from a single donor for transfusing a patient who could thus be immunized against leukocytes from this unique donor. As he expected, the patient developed antibodies which reacted with leukocytes from the donor. However, they also reacted with about 50% of the population of tested volunteers, indicating that they carry the same leukocyte group, which was called MAC, an acronym made up of the initials of the first three donors with whom the serum did not react. This discovery was published in 1958 in Acta Haematologica in which Jean Dausset already stressed the possible importance of these groups in transplantation. Two other teams had adopted the technique of leukoagglutination. One team in the Netherlands, directed by J.J van Rood, showed the existence of a clear division of the population in two allelic groups (4a and 4b); the other in California, directed by Rose Payne, demonstrated the existence of 3 antigen groups which were probably encoded by same genes (LA1, LA2, LA3). An international collaboration between different laboratories began after 1965 and is still going on these days. In these international workshops the same biological materials are tested to examine the diversity of these genes and of their antigen product.
662
/ Human Immunology 70 (2009) 661– 662
Jean Dausset was the first to realize that this discovery concerned a complex genetic system, similar to the H2 system of the mouse. To prove it, he tested 50 sera from different individuals using leukoagglutination and lymphocyto-lysis tests. The results proved the existence of at least 8 leukocyte groups postulated to belong to a single genetic system which Jean Dausset named Hu-1, according to the nomenclature suggested by George Snell for the H2 system of mice: “Hu” for human and “1” for the first system. It then had to be proven that, like the H2 system, the Hu-1 system determines the fate of allogeneic transplants. In 1964, in collaboration with Felix Rapaport, a surgeon/immunologist from the USA, Jean Dausset performed a series of skin grafts on volunteers. He showed that there was a correlation between the compatibility determined by the Hu-1 system and the survival of skin grafts. This proved that the leukocyte groups were actually tissue groups, opening the way to organ transplantation. Jean Dausset showed for the first time that the survival of grafted kidneys was correlated with the number of incompatibilities in the Hu-1 system, which was meanwhile renamed HLA (Human Leukocyte Antigen). He observed that the best graft survival was obtained when the donor was a sibling who had received from both parents the same HLA complexes. However, in practice, many patients needed and received kidneys from unrelated individuals. To find compatible donors, Jean Dausset created the first organization for the exchange of organs, France-Transplant. This was the seed for the exchanges which were going to become worldwide and which would concern other organs such as heart, liver and pancreas. By 1968, Jean Dausset believed that these tissue groups could account for certain diseases susceptibilities and this, in spite of the nearly complete failure of this design applied to the system of ABO blood groups. Using as a base the existence of a correlation between the H2 system and murine leukaemia, Jean Dausset was the first to find the equivalent in humans. Many teams in the world joined his research and many associations were created. It became possible to detect, within a family or within the general population, individuals likely to develop a certain disease if they had the corresponding allele. This led Jean Dausset to introduce, in 1972, the concept of predictive medicine. The detailed description of the HLA system discovered by Jean Dausset had tremendous consequences, be it at the philosophical level, in basic biology, or in therapy. The high polymorphism of the HLA system allowed the demonstration that each individual is
unique. There are so many possible combinations between alleles of the HLA system that practically each formula is unique. In terms of basic immunology, the HLA system made it possible to understand one of the essential mechanisms of immunity—the recognition of self and non-self thanks to the presentation of foreign peptides by HLA molecules. On the therapeutic level, the most obvious consequence was its immediate application to tissue transplantation. Finally, the discovery of the HLA system paved the way for the association of many afflictions to particular HLA alleles. Jean Dausset believed that predictive medicine would become important not only to the diseases associated with the HLA system, but also with other genes of the entire genome. This drove him, in 1984, to create the C.E.P.H.—Centre of Study of Human Polymorphism—with the aim of detecting genes that predispose individuals to diseases including those outside the HLA system. For that purpose, it was first necessary to establish physical and genetic maps of the human genome. Jean Dausset made samples from patients used to study the genetics of the HLA system available to the wider scientific community. Ray White, who had described DNA markers using the R.F.L.P. technique, joined the project, adding to it a large sample cohort from Utah. A hundred laboratories in the world collaborated in this project. It was the first biological material shared internationally as a reference point and is still in use today. This enabled the C.E.P.H. to generate the first markers of the human genome, which thereafter allowed cloning and identification of the disease-associated genes, a major advance in medical genetics. In 1991, Jean Dausset was interested in a new development of the HLA system. With Edgardo D. Carosella, he studied the HLA-G molecule which, contrary to other HLA molecules, is involved in tolerance. This seems to be involved in maternal tolerance to the fetus, which is incompatible because half of the genes are inherited from the father. Professor Dausset was a member of the Academy of Sciences, a foreign member of the American Academy of Sciences, an honorary member of the American Academy of Arts and Sciences and a founding member of the Organization of the Human Genome. He received many prestigious prizes such as the Landsteiner Award and those of the Koch and Wolf Foundations. He was an advisor to many research institutions. Edgardo D. Carosella, M.D. Research Director at the French Agency of Atomic Energy Head of the Hemato-Immunology Department