Phenotype Frequencies of Autosomal Minor Histocompatibility Antigens Display Significant Differences among Populations

Abstract

Minor histocompatibility (H) antigens are allogeneic target molecules having significant roles in alloimmune responses after human leukocyte antigen–matched solid organ and stem cell transplantation (SCT). Minor H antigens are instrumental in the processes of transplant rejection, graft-versus-host disease, and in the curative graft-versus-tumor effect of SCT. The latter characteristic enabled the current application of selected minor H antigens in clinical immunotherapeutic SCT protocols. No information exists on the global phenotypic distribution of the currently identified minor H antigens. Therefore, an estimation of their overall impact in human leukocyte antigen–matched solid organ and SCT in the major ethnic populations is still lacking. For the first time, a worldwide phenotype frequency analysis of ten autosomal minor H antigens was executed by 31 laboratories and comprised 2,685 randomly selected individuals from six major ethnic populations. Significant differences in minor H antigen frequencies were observed between the ethnic populations, some of which appeared to be geographically correlated. Peptides from cellular proteins evoking alloimmune responses in human leukocyte antigen–identical transplantation are called minor histocompatibility (H) antigens. Upon hematopoietic stem cell transplantation (HSCT) for hematological malignancies or for solid tumors, responses to minor H antigens may have detrimental effects, e.g., graft-versus-host-disease and graft rejection, but can also significantly contribute to the eradication of the tumor cells. We designated the latter antigens as “tumor” minor H antigens. Current clinical trials aim at using these tumor minor H antigens to boost the graft-versus-tumor response. So far, it is unclear how frequently the HSCT recipient and donor differ in their minor H antigens and thus how many cancer patients are eligible for minor H antigen-based treatment. Therefore, worldwide 31 laboratories joined forces to determine the genotype and phenotype frequencies of ten autosomally encoded minor H antigens in six ethnic populations. The frequencies vary depending upon ethnic background and geographic location of the population, implying that the potential applicability of the tumor minor H antigens differs from one population to another. Depending on the population, the current theoretical percentages of clinical application of the eight tumor minor H antigens in HLA-matched combinations is estimated at 12% to 34%.