HLA: The Compatibility Genes for Transplantation
The ability of the immune system to distinguish “self” from “non-self” is critical for fighting infection and controlling the potential cancerous cells, all the while avoiding attacking one’s own tissues. Human leukocyte antigen (HLA) molecules are cell surface receptors that present peptide antigens to T-cells to mediate the adaptive immune response. Through the antigen presentation pathway, HLA allows the immune system to assay both self and non-self proteins inside the cells and in the environment around the cells. Because pathogens mutate so that their proteins are poorly presented by HLA to avoid an immune response, HLA genes in human populations have been subject to balancing selection, which maintains many versions of HLA genes, or alleles, in the population. There are over 13,000 known alleles of HLA Class I genes (HLA-A,B,C) and 4,500 alleles of HLA Class II genes(HLA-DRB1, DQA1, DQB1, DPA1, DPB1). The number of possible combinations for these HLA variants is so high that many of us have a HLA genotype that is unique.
Improving Matching Algorithms for Transplantation with HLA Genetics
Before arriving at Tulane, Dr. Gragert worked for 12 years in the Bioinformatics Research department at National Marrow Donor Program / Be The Match, the US registry that facilitates unrelated stem cell transplants. Over 30 million people around the world have volunteered to join a registry and have their HLA genes typed to potentially donate stem cells. In bone marrow stem cell transplantation, closer HLA matching between donor and recipient reduces the risk of graft-versus-host disease, where the recipient’s new immune system recognizes the new body it is in as foreign. Dr. Gragert analyzes HLA frequencies in global populations and uses this information to inform algorithms that identify the best match in large registries. The Gragert Lab is now working to adapt the large HLA datasets and informatics tools developed originally for stem cell matching for new applications in solid organ transplantation. In kidney transplantation, closer HLA matching reduces the likelihood of developing antibodies that lead to organ rejection. Currently, kidneys are matched at a broad HLA antigen level, rather than the more specific allele level defined by HLA molecular typing assays. Dr. Gragert has developed bioinformatics tools for streamlining the process of getting molecular typing into the kidney allocation system. At Tulane, we are now able to become the bridge for collaboration between the US stem cell registry Be The Match and the United Network for Organ Sharing, which manages the national organ allocation system. By working together we can improve outcomes for all transplant recipients.
The lab is currently funded by two NIAID grants – “HLA Immunogenetics and Kidney Allograft Outcomes” (NIAID R01AI173095) and “MHC and KIR Sequencing and Association Analyses in the iGeneTRAiN Studies” (NIAID U01AI152960).
HLA Variation Influences Cancer Development and Immunotherapy Treatment
Cancerous cells are able to survive in the human body by evading the immune system. Among different cancer subtypes, there are different types of genetic mutations. Some HLA alleles are better at helping the immune system detect these mutations, shaping the evolution of tumors. The targets of immune cells are often HLA molecules that present antigens derived from mutated cancer-associated proteins. The Gragert Lab uses large stem cell registry datasets from Be The Match to identify which HLA alleles influence the risk of developing blood diseases treated by bone marrow transplantation, such as leukemias and lymphomas. HLA genes also influence the risk of developing autoimmune diseases, such as severe aplastic anemia, which is a catastrophic loss of the bone marrow stem cells. A new category of treatment called cancer immunotherapy has been developed that unleashes the immune system to attack cancerous cells. New research indicates that HLA variants are also associated with response to immunotherapy. Understanding how the immune system uses HLA to fight cancer will ultimately help optimize immunotherapy regimens.