Stem Cells, Vol. 19, No. 6, 556-562,
November 2001
© 2001 AlphaMed Press
CD Antigens 2001: Aims and Results of HLDA Workshops
David Masona,
Pascale Andréb,
Armand Bensussanc,
Chris Buckleyd,
Curt Civine,
Edward Clarkf,
Masja de Haasg,
Sanna Goyerth,
Martin Hadami,
Derek Hartj,
Václav Ho
ej
ík,
Stefan Meuerl,
James Morrisseym,
Reinhard Schwartz-Albiezn,
Stephen Shawo,
David Simmonsp,
Mariagrazia Uguccioniq,
Ellen van der Schootg,
Eric Vivierb,
Heddy Zolar
a The Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, United Kingdom;
b Centre d'Immunologie, Parc Scientifique de Luminy, Cedex, France;
c Faculte de Medicine de Creteil, Cedex, France;
d Division of Immunity and Infection, MRC Center for Immune Regulation, Department of Rheumatology, University of Birmingham, Edgbaston, Birmingham, United Kingdom;
e Johns Hopkins Comprehensive Cancer Center, Baltimore, Maryland, USA;
f Department of Microbiology, University of Washington, Seattle, Washington, USA;
g CLB, Department of Experimental Immunohematology, Amsterdam, The Netherlands;
h Laboratory of Molecular Hematology/Division of Molecular Medicine, North Shore University Hospital, Manhasset, New York, USA;
i Kinderklinik, Medizinische Hochschule Hannover, Hannover, Germany;
j Mater Medical Research Institute, Aubigny Place, Mater Hospital, Queensland, Australia;
k Institute of Molecular Genetics AS CR, Prague, Czechoslovakia;
l Institut für Immunologie der Univ. Heidelberg, Heidelberg, Germany,
m Professor of Biochemistry, University of Illinois College of Medicine, Urbana, Illinois, USA;
n German Cancer Research Center, Heidelberg, Germany;
o National Institute of Health, Bethesda, Maryland, USA;
p Director of Biology Celltech R&D Ltd., Cambridge, United Kingdom;
q Institute for Research in Biomedicine, Bellinzona, Switzerland;
r University of Adelaide, Department of Pediatrics, Women's and Children's Hospital, South Australia, Australia
David Y. Mason, Ph.D., The Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, United Kingdom. Telephone: 44-1865-220356; Fax: 44-1865-763272; e-mail: david.mason{at}ndcls.ox.ac.uk
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THE TRADITION OF HLDA WORKSHOPS
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The process of categorizing the antigenic molecules and epitopes associated with human white cells, via the collaborative study of monoclonal antibodies, dates back to the early 1980s, when the first HLDA (Human Leucocyte Differentiation Antigen) Workshop was held in Paris. This initial meeting listed only 15 agreed-upon molecular entities, but it created an internationally agreed basis for the nomenclature of leucocyte molecules (the CD scheme), and also provided a forum for reporting studies on their function and practical relevance. A further six HLDA meetings have been held since the first Paris meeting. The most recent of these (HLDA7) took place last year in Harrogate, UK, and the proceedings of the meeting will be published later this year (Leucocyte Typing VII, Oxford University Press).
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THE AIMS AND APPROACHES OF THE 7TH HLDA WORKSHOP
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The Limitations of "Blind" Antibody Screening
It was apparent at the previous meeting, HLDA6, held in Kobe, Japan in 1996, that the technique of detecting molecular entities by screening coded panels of monoclonal antibodies against human cells was becoming obsolete. Antibodies to the most immunogenic molecules had already been produced, and fewer laboratories than in the early days were prepared to devote resources to raising new antibodies, since the probability of finding novel reagents becomes ever less likely. As a consequence many antibodies in HLDA6 were reagents (submitted by laboratories that were not equipped to characterize them) that proved to be of known specificity.
Selection of Antibodies
With these considerations in mind, HLDA7 adopted a different approach: instead of screening poorly characterized antibodies, reagents were selected (and actively solicited) for which at least some molecular data were already available. A substantial number of monoclonal antibodies reactive with leucocyte-associated molecules exist that do not meet the traditional criteria for establishing a new CD specificity (i.e., the existence of at least two independent antibodies of the same specificity). This rule dates from the first HLDA Workshop two decades ago. Since that time biochemical and molecular biological techniques for characterizing the targets of new antibodies have come to be widely used. Consequently, it is now considered appropriate to establish a CD designation for a molecule if its gene has been cloned and at least one specific monoclonal antibody has been studied in the Workshop.
New Workshop Sections
Four new Sections were introduced in HLDA7 to add to the traditional list from past meetings: namely Dendritic Cells, Stem/Progenitor Cells, Erythroid Cells, and Carbohydrate Structures. Although it has been recognized for many years that monoclonal antibodies reactive with human leucocytes can be specific for carbohydrate epitopes (e.g. the carbohydrate CD category CD15 was identified at the first Workshop), they had not received specific attention in any Workshop. The inclusion of erythroid molecules, although it may seem out of place in a "Leucocyte Workshop," was justified by the number of molecules shared between white and red cells (e.g., cytokine receptors) that hint at unexplored functions of red cells.
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THE YIELD OF NEW CD SPECIFICITIES IN HLDA7
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This more active approach to the identification of new CD specificities represented a break with tradition, but the results justified the new approach, since a total of well over 80 new entities were added to the list of CD specificities. This compares favorably with previous Workshops (an average of fewer than 30 CD specificities per Workshop), and it also largely avoided the laborious screening in multiple laboratories of antibodies that prove to be directed against known CD molecules.
Tables 1 and 2
list the new specificities established at HLDA7. Full details will be found in Leucocyte Typing VII, and molecular, functional, and other data can be found for many of these new specificities on the PROW (Protein Reviews on the Web) website (http://www.ncbi.nlm.nih.gov/prow).
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THE EIGHTH WORKSHOP
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Plans are well advanced for HLDA8, to be organized in Adelaide in 2004 under the aegis of Prof. H. Zola (see: www.hlda8.org). It is sometimes assumed that the catalog of surface molecules associated with human hemopoietic cells is now essentially complete, but there is abundant evidence in the literature for novel surface molecules that would merit study at the next Workshop, and that could provide the basis for new CD designations. Table 3 comprises a list of potential new molecules reported following the production of monoclonal antibodies, and also a more extensive list of surface molecules identified via gene cloning. In most instances, no antibodies are available against the putative new leucocyte/endothelial markers in this latter group. Specific and well-characterized reagents, whether monoclonal or polyclonal, are needed not only for detecting these new "virtual" molecules but also for defining functional domains, for characterizing 3-D protein structure, and for analyzing protein-protein interactions. It may be added that cloning of gene sequences often reveals multiple members of new or existing molecular families (e.g., the Toll-like receptors) and may identify surface receptors that bind more than one ligand or vice versa, (e.g., the TALL-1 and APRIL ligands for TACI and BCMA). Furthermore, a number of leucocyte-associated markers have been cloned from mice and other species, and almost all will have human homologues. HLDA8 will provide a forum for a range of antibody-based studies based on this accumulating corpus of genomic and proteomic data.
As in HLDA7 in which four new sections were added, it may be possible to include neuronal cells in HLDA8. Many neuronal cells express cell surface proteins found on leucocytes and vice versa (e.g., CD56, CD100, CD168, CD171). Furthermore, the guidance cues used by neuronal cells share similarities to those involved in leucocyte extravasation, so the expression of these molecules in common may reflect shared biological processes. It may also be noted that other molecules such as the mucins, thought to be primarily associated with epithelial cells, are now being described on leucocytes.
Finally, it remains to be established how HLDA8 and subsequent Workshops should deal with lineage- or stage-restricted leucocyte molecules that are localized within the cell cytoplasm (or nucleus). Given the importance of many of these molecules in signaling pathways initiated via known surface CD molecules, their identification and study is an inevitable extension of the work of the first seven HLDA Workshops. Whether a new "intracellular CD" categorization scheme is devised for such molecules, they are of importance for many laboratories interested in human hematopoietic cells, and their study will be among the aims of the next Workshop.
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Received June 25, 2001;
accepted for publication July 30, 2001.
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The Tradition of HLDA...
The Aims and Approaches...