International Team Accelerates Investigation of Immune-Related Genes

A cluster of nearly 220 genes known as the human leukocyte antigen (HLA)gene complex holds clues to many unsolved medical questions: why dotransplants sometimes fail despite close donor-recipient matches? Whatmakes certain people more susceptible to specific diseases? Why do vaccinesprotect some individuals better than others?

In search of the answers, the National Institutes of Health (NIH) is headingan initiative to catalog the HLA gene complex and explore its differencesamong populations worldwide. Nearly $20 million over five years will go tothe International Histocompatibility Working Group (IHWG), a network ofalmost 200 laboratories in more than 70 countries, to set up a centralizedHLA gene database and develop new and improved tools to decipher thisgenetic Rosetta Stone of immunology.

"The HLA gene complex comprises the most diverse and variable region in thehuman genome," explains Anthony S. Fauci, M.D., director of the NationalInstitute of Allergy and Infectious Diseases (NIAID), which is the project'slead sponsor. "Knowledge about its diversity and how these genes directimmune responses could improve our ability to predict, diagnose and treatimmune-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'sHuman Immunogenetics Program and a professor of medicine at the Universityof Washington, the project could have immediate clinical benefits, forexample, for finding better matches for bone marrow transplant recipients.

"But the potential impact of these new studies goes way beyondimmunogenetics," says Dr. Hansen. "This project will apply recent advancesin genome technology to important questions about specific diseases and helpexplain how the rich genetic differences in HLA among individuals can eitherstrengthen the immune response or open the door to autoimmune disease andinfection."

The HLA gene complex, known more generally as the major histocompatibilitycomplex (MHC), is responsible for encoding proteins that stud the surface ofthe body's cells, marking them as our own. Anything not marked as "self"can come under attack from the immune system. This includes foreign mattersuch as viruses and bacteria as well as cancerous cells and transplantedtissue. Even organs from a close blood relative can display very differentHLA markers due to the underlying distinctions within each individual's HLAgene complex; a perfect HLA-type match exists only between identical twins.

The effectiveness of a person's immune defenses for detecting and destroyingtrespasser antigens depends largely on his or her HLA gene complex.Similarly, these genes are suspected of playing a role when the immunesystem mistakenly targets the body's own cells as foreign, which is the casewith autoimmune disorders such as multiple sclerosis, rheumatoid arthritisand type 1 diabetes. The IHWG will accelerate investigations seeking todiscover the fundamental mechanics of how HLA genes direct beneficial andharmful immune responses.

"The IHWG represents more than 30 years of collaborative research among theworld's leading scientists in population-based genetics," says DanielRotrosen, M.D., director of NIAID's Division of Allergy, Immunology andTransplantation. "Its extensive international network of laboratories willcontribute significantly to NIAID's efforts to address the global healthproblems caused by infectious and immune-mediated diseases."

A primary goal of the IHWG is to create a searchable HLA database linkingmultiple interacting genes with function, ethnicity and disease. A morecentralized database will make it easier for scientists to find andcontribute new data. It also will help clinical investigators use theinformation 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 foridentifying organ donor matches for transplantation;

stimulating vaccine development by defining candidate vaccine targets indiverse populations;

clarifying the role of HLA genes in susceptibility and resistance toautoimmune diseases;

developing standardized molecular tools to explore the genetic diversityof the HLA gene complex.

Knowledge about the patterns of HLA gene combinations prevalent in differentethnic groups also could illuminate the historical relationships among theworld's subpopulations. Theoretically, someday scientists couldcustom-build vaccines based on HLA genes. Such vaccines could providebetter 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 IHWGare several other NIH sponsors, including the National Cancer Institute, theNational Institute of Diabetes and Digestive and Kidney Diseases, theNational Human Genome Research Institute, and the National Center forBiotechnology Information at the National Library of Medicine. Anothersponsor is the nonprofit Juvenile Diabetes Foundation International.

For details about IHWG research plans and workshop meetings, visithttp://www.ihwg.org.

NIAID is a component of the NIH. NIAID conducts and supports research tounderstand basic immunology and to prevent, diagnose and treat infectiousdiseases and immune-mediated disorders, including HIV disease and othersexually transmitted diseases, tuberculosis, malaria, autoimmune disorders,asthma and allergies. NIH is an agency of the U.S. Department of Health andHuman Services.

Press releases, fact sheets and other NIAID-related materials are availableon the NIAID Web site at http://www.niaid.nih.gov.