A Brief History of the International
Histocompatibility Workshops

Background

The field of human immunogenetics, a branch of genetics research focused on genes involved in the immune response, has been the subject of intense study for the last 35 years. This is especially true for that part of immunogenetics dealing with the major histocompatibility complex (MHC), a series of closely linked and highly polymorphic genes found in humans on chromosome number 6. The MHC genes and the cell surface protein molecules encoded by the MHC play a critical role in T cell recognition and function as antigens during transplantation. Since the description of the first human leukocyte antigen group termed MAC in 1958, there has been rapid growth in the interest and knowledge about the genetic structure and biologic function of the MHC which in man is known as the Human Leukocyte Antigen (HLA) system. The dramatic advance in knowledge has been due largely to the early appreciation of the scope of work necessary to elucidate the HLA system requiring broad collaboration beyond what is possible within individual laboratories. This led to the organization of an international group of investigators willing to share reagents and unpublished data. The first HLA antigens were defined by individual groups using their own reagents, antisera and cell panels, identified locally. An exchange of reagents was necessary to compare antisera to standardize the definition of antigens and to establish a common nomenclature. The most pragmatic and effective way to promote this collaboration was through the organization of workshops designed to bring investigators together and to create the opportunity to exchange reagents for mutual study. The first HLA workshop involved scientists from several countries and proved to be a seminal event, an impetus for more extensive collaborations in the following years. In addition to providing a mechanism for exchanging reagents, the International HLA Workshops have also been on the forefront of promoting new technology and disseminating both reagents and technical skills worldwide. This has been an invaluable resource for stimulating immunogenetics research and facilitating rapid translation of new technology and knowledge to patient care.

The International Histocompatibility
Workshops: A Retrospective

First Histocompatibility Workshop: 1964

The First Histocompatibility Testing Workshop was organized by Dr. Bernard Amos and held in his laboratory at Duke University in Durham, North Carolina in June of 1964. Participants included 23 pioneering investigators actively engaged in the study of the recently discovered human "leukocyte antigens." The workshop was convened for the purpose of comparing the different in vitro assay systems used at the time to define antigens which were described as Hu-1 (Dausset and Ivanyi), LA (Payne and Bodmer), and Four (van Rood). Among the assay methods studied in the "wet workshop" format at Duke were serology (including agglutination, cytotoxicity, leukocyte and platelet complement fixation, and mixed hemabsorption), the mixed lymphocyte culture reaction, the normal lymphocyte transfer test, and skin grafting. For the serology "component", very few sera were available for testing, and participants in the wet workshop were only able to study six sera consisting of one ml each! It was at this workshop that Paul Terasaki introduced the microcytotoxicity test for serologic typing, and described the first positive leukocyte antibody crossmatch test associated with hyperacute renal graft rejection. The results of the first workshop were modest from the technical and reproducibility standpoints but the potential power of this collaborative work was very apparent and everyone agreed that an important step had been taken in establishing a spirit of international cooperation. Thus began the commitment to sharing reagents, standardizing methods and accepting a common nomenclature.

Reference: Histocompatibility Testing: Report of a Conference and Workshop. Washington DC: National Academy of Sciences - National Research Council, 1965.

In addition, an informative and insightful first-hand account of the first workshop by its organizer and chief proponent can be found in: Amos DB. HLA - A Mouser's Recollections. In: History of HLA: Ten Recollections. Terasaki PI (ed.), Los Angeles: UCLA Tissue Typing Laboratory, 1990: 61-97.

The Second Histocompatibility Workshop: 1965

The Second Histocompatibility Testing Workshop, organized by J.J. van Rood, was held in Leiden, Netherlands in August of 1965 and brought together 71 participants with an interest in further extending knowledge of human leukocyte antigen systems. This workshop set the format for future workshops: the study of a well-characterized cell panel (provided by van Rood) by different laboratories using their own sera and their own techniques. The 1965 workshop also saw the introduction of the computer to permit rapid analysis of the complex results obtained from many serologic reactions. By analyzing both family and population data, it was shown that most of the antigens recognized in the workshop belonged to a single genetic system, for which there was still no standardized nomenclature. The workshop included a study of skin grafting experiments, and it was demonstrated by this method that the antigens being studied behaved as transplantation antigens.

Reference: Histocompatibility Testing 1965. Copenhagen: Munksgaard, 1965.

The Third Histocompatibility Workshop: 1967

The Third Histocompatibility Testing Workshop was organized by R. Ceppellini and was held in Torino, Italy in June of 1967 and included 110 participants. A workshop cell panel derived from eleven families and 21 unrelated donors was studied by 16 teams using 476 antisera. Thirteen different specificities were identified in independent fashion by the teams. The results of this combined effort, clearly and elegantly summarized by Ceppellini in a landmark chapter published in the Workshop Proceedings, demonstrated unequivocally that the antigens under study belonged to a single genetic system, with two subloci. Following the workshop (September, 1967), it was decided to name this system HL-A to designate it as the major system of leukocyte antigens in man.

Reference: Curtoni ES, Mattiuz PL, Tosi RM, eds. Histocompatibility Testing 1967. Copenhagen: Munksgaard, 1967.

The Fourth Histocompatibility Workshop: 1970

The Fourth Histocompatibility Workshop, organized by Paul Terasaki, was held in Los Angeles in January of 1970 and brought together fifteen different laboratories testing 116 highly selected antisera. This was the first workshop in which antisera were exchanged by mail and in which each participating laboratory used a standard microlymphocytotoxicity assay. The results of the workshop established the existence of 11 official HL-A specificities (HL-A1, 2, 3, 5, 7, 8, 9, 10, 11, 12 and 13), and at least eight other specificities that were given given provisional designations (e.g., W27). Thorsby, Sandberg and Kissmeyer-Nielsen provided evidence of a third (HLA-C) locus, and Boyum's method using ficoll hypaque for mononuclear cell separation was first used in a workshop format.

Reference: Terasaki PI, ed. Histocompatibility Testing 1970. Copenhagen: Munksgaard, 1970.

The Fifth Histocompatibility Workshop: 1972

The Fifth Histocompatibility Workshop, organized by Jean Dausset and held in Evian, France in May of 1972, had as its major objective a world-wide population study of the HLA system. Forty-nine ethnic and racial groups were studied by 75 different laboratories using 118 selected antisera. Results from this workshop provided an important cornerstone of HLA frequency data for many of the world's populations; much of this data is still referenced today. Ten new HLA designations, each given provisional nomenclature, were defined in the workshop: W16, W21, W23, W24, W25, W26, W29, W30, W31 and W32.

Reference: Dausset J, Colombani J, eds. Histocompatibility Testing 1972. Copenhagen: Munksgaard, 1973.

The Sixth Histocompatibility Workshop: 1975

The Sixth Histocompatibility Workshop, organized by F. Kissmeyer-Nielsen and held in Arhus, Denmark in June-July of 1975, had as its main objectives an investigation of the determinants and genetics of the MLR (subsequently termed the HLA-D locus) and the better identification and characterization of specificities belonging to the three previously-defined HL-A loci (subsequently termed HLA-A, B and C). This workshop was the first to include the use of D region homozygous typing cells (HTC) to study determinants of the HLA-D locus. A total of 62 HTC and 178 selected antisera were exchanged between participating laboratories. On the basis of workshop results, the WHO nomenclature committee named the first six HLA-D determinants. The first five HLA-C antigens were also named. At the Workshop Conference, numerous reports were made of HLA antigens that were expressed on B cells but not on T cells. These antigens were termed "Ia-like" or "D region associated B cell antigens", and their description paved the way for the future description and characterization of the HLA-DR locus and the DR series of leukocyte antigens. A total of 15 new HLA specificities were given WHO designations following the workshop, including the first antigens defined at the HLA-C locus (Cw1-Cw5).

Reference: Histocompatibility Testing 1975. Kissmeyer-Nielsen F, ed. Copenhagen: Munksgaard, 1975.

More history.

A Brief History of the International Histocompatibility Workshops