A cluster of nearly 220 genes known as the human leukocyte antigen (HLA)
gene complex holds clues to many unsolved medical questions: why do
transplants sometimes fail despite close donor-recipient matches? What
makes certain people more susceptible to specific diseases? Why do vaccines
protect some individuals better than others?
In search of the answers, the National Institutes of Health (NIH) is heading
an initiative to catalog the HLA gene complex and explore its differences
among populations worldwide. Nearly $20 million over five years will go to
the International Histocompatibility Working Group (IHWG), a network of
almost 200 laboratories in more than 70 countries, to set up a centralized
HLA gene database and develop new and improved tools to decipher this
genetic Rosetta Stone of immunology.
"The HLA gene complex comprises the most diverse and variable region in the
human genome," explains Anthony S. Fauci, M.D., director of the National
Institute of Allergy and Infectious Diseases (NIAID), which is the project's
lead sponsor. "Knowledge about its diversity and how these genes direct
immune responses could improve our ability to predict, diagnose and treat
immune-mediated disorders and infectious diseases."
John A. Hansen, M.D., at the Fred Hutchinson Cancer Research Center (FHCRC)
in Seattle, will head the project. According to Dr. Hansen, head of FHCRC's
Human Immunogenetics Program and a professor of medicine at the University
of Washington, the project could have immediate clinical benefits, for
example, for finding better matches for bone marrow transplant recipients.
"But the potential impact of these new studies goes way beyond
immunogenetics," says Dr. Hansen. "This project will apply recent advances
in genome technology to important questions about specific diseases and help
explain how the rich genetic differences in HLA among individuals can either
strengthen the immune response or open the door to autoimmune disease and
The HLA gene complex, known more generally as the major histocompatibility
complex (MHC), is responsible for encoding proteins that stud the surface of
the body's cells, marking them as our own. Anything not marked as "self"
can come under attack from the immune system. This includes foreign matter
such as viruses and bacteria as well as cancerous cells and transplanted
tissue. Even organs from a close blood relative can display very different
HLA markers due to the underlying distinctions within each individual's HLA
gene complex; a perfect HLA-type match exists only between identical twins.
The effectiveness of a person's immune defenses for detecting and destroying
trespasser antigens depends largely on his or her HLA gene complex.
Similarly, these genes are suspected of playing a role when the immune
system mistakenly targets the body's own cells as foreign, which is the case
with autoimmune disorders such as multiple sclerosis, rheumatoid arthritis
and type 1 diabetes. The IHWG will accelerate investigations seeking to
discover the fundamental mechanics of how HLA genes direct beneficial and
harmful immune responses.
"The IHWG represents more than 30 years of collaborative research among the
world's leading scientists in population-based genetics," says Daniel
Rotrosen, M.D., director of NIAID's Division of Allergy, Immunology and
Transplantation. "Its extensive international network of laboratories will
contribute significantly to NIAID's efforts to address the global health
problems caused by infectious and immune-mediated diseases."
A primary goal of the IHWG is to create a searchable HLA database linking
multiple interacting genes with function, ethnicity and disease. A more
centralized database will make it easier for scientists to find and
contribute new data. It also will help clinical investigators use the
information as a platform for future research on immune-mediated diseases.
Other IHWG objectives include the following:
- finding more accurate DNA-based techniques to replace current methods for
identifying organ donor matches for transplantation;
- stimulating vaccine development by defining candidate vaccine targets in
- clarifying the role of HLA genes in susceptibility and resistance to
- developing standardized molecular tools to explore the genetic diversity
of the HLA gene complex.
Knowledge about the patterns of HLA gene combinations prevalent in different
ethnic groups also could illuminate the historical relationships among the
world's subpopulations. Theoretically, someday scientists could
custom-build vaccines based on HLA genes. Such vaccines could provide
better protection against diseases endemic to a group or geographic area,
such as malaria and the varying subtypes of the human immunodeficiency virus
(HIV) appearing in different parts of the world.
Participating with NIAID in funding the cooperative agreement with the IHWG
are several other NIH sponsors, including the National Cancer Institute, the
National Institute of Diabetes and Digestive and Kidney Diseases, the
National Human Genome Research Institute, and the National Center for
Biotechnology Information at the National Library of Medicine. Another
sponsor is the nonprofit Juvenile Diabetes Foundation International.
For details about IHWG research plans and workshop meetings, visit