Major vs minor histocompatibility antigens

In this issue of Blood, Martin et al found that the number of minor histocompatibility antigen mismatches doubles in unrelated vs sibling HLA-matched transplants, but has less impact on graft-versus-host disease (GVHD) than mismatching at HLA-DP.¹ 

Minor histocompatibility antigens are small peptides that are found on the cell surface in association with class I or class II major histocompatibility complex (MHC) molecules. Minor histocompatibility antigens correspond to polymorphic structures and are therefore instrumental in the molecular definition of self to the immune system. Single amino acid differences are detectable by T cells that can become immunoreactive and cause GVHD in the context of HLA-matched allogeneic stem cell transplantation.²  Although >100 minor histocompatibility antigens have been identified and sequenced, few data are available on the global role of minor histocompatibility antigen disparities on the development of GVHD. In particular, is the total number of minor histocompatibility antigen mismatches important in the prediction of GVHD? Alternatively, is a constrained number of minor histocompatibility antigens responsible for most of the GVHD observed? Does the dogma of MHC-mismatching predominance over minor histocompatibility antigen mismatching in terms of immunoreactivity still hold as we learn more about minor histocompatibility antigens?

Martin et al have used a genomic approach to answer these questions. Genome sequencing of donor and recipient allowed identification of coding single nucleotide polymorphisms (SNPs), likely to correspond to minor histocompatibility antigens, and HLA-typing confirmation. Although coding SNPs theoretically correspond to minor histocompatibility antigens, a number of non-SNP events can generate minor histocompatibility antigens.³  In addition, one has to realize that transcriptional, translational, and posttranslational modifications can substantially alter the nature of peptides expressed on MHC molecules.⁴  Hence, the composition of the minor histocompatibility antigen repertoire cannot be predicted based solely on genomic data.⁵  To date, the best approach to minor histocompatibility antigen identification relies on proteomic analysis using mass spectrometry.^6-8  However, the complexity of proteomic studies and high peptide numbers have hampered the development of a complete map of minor histocompatibility antigens. At the present time, high-throughput mass spectrometry and incumbent in-depth bioinformatic processing are still under development. This is necessary in order to enable accurate evaluation and modeling of antigenic differences in the high numbers (thousands) of patients undergoing stem cell transplantation that must be compared in order to assess their impact on GVHD while taking confounding clinical parameters into consideration. Nevertheless, SNPs, as measured in the present article, provide a reasonable estimation of minor histocompatibility antigens that is commensurate with the objectives of the study.

Based on population genetics, matched unrelated donors are expected to harbor greater differences in minor histocompatibility antigen repertoire than sibling transplants. Here the authors found that the use of unrelated donors implies a twofold increase in magnitude of genome-wide minor histocompatibility antigen disparity. How important is a doubling in the number of minor histocompatibility antigen discrepancies on GVHD occurrence? No significant difference in acute or chronic GVHD occurrence could be found with this increase. In contrast, mismatching at the single HLA-DP locus generated a clear increase in GVHD. These results immediately suggest that mismatching at a single HLA locus is more important than mismatching at half of all minor histocompatibility antigen loci. Consistent with this, the total number of unshared minor histocompatibility antigens (presented by HLA class I and II allotypes) between 2 MHC-identical subjects is inferior to 100,⁹  whereas each HLA allotype can present around 5000 different peptides. Hence, mismatching for a single HLA allele could lead to the presentation of thousands of nonself MHC-peptide complexes, an order of magnitude over the total number of unshared minor histocompatibility antigens. These findings therefore emphasize the crucial need for stringent HLA matching, particularly in the setting of unrelated transplants.

In the context of HLA-identical sibling donor transplantation, Martin et al found that an increase in minor histocompatibility antigen disparity increased severe (grade III-IV) and stage 2-4 gut GVHD. However, SNP mismatching did not correlate with chronic GVHD. Nevertheless, the ∼60% of grade II-IV acute GVHD and ∼40% chronic GVHD observed in sibling HLA-matched pairs should be attributable to minor histocompatibility antigen mismatching. This suggests that anti-minor histocompatibility antigen immune response can become saturated. It also underlines the role of a select subset of peptides with greater immunogenicity: immunodominant minor histocompatibility antigens. The recent observation that MHC class I–associated peptides are not randomly distributed across the genome, but rather originate from a restricted fraction of the exome, suggests some form of hierarchy in minor histocompatibility antigen development.¹⁰  It will be useful to determine whether the increased number of SNPs identified in unrelated donors reflect genomic polymorphisms that are less likely to be expressed by MHC molecules or are less immunogenic.

The insights gained on minor histocompatibility antigens and their clinical impact are also highly encouraging for the development of therapeutic approaches. Indeed, the current publication suggests that minor histocompatibility antigens represent particularly appealing targets in order to eliminate leukemia and other cancer cells without causing GVHD.^1,2  In addition, recent technological developments in proteogenomics have allowed the identification of minor histocompatibility antigens that are preferentially expressed on hematopoietic cancer cells over epithelial cells, and can be used for T-cell immunization.⁸  The multiple strategies that have become available to study minor histocompatibility antigen biology, investigate their role in GVHD and graft-versus-leukemia activity, and intervene clinically have overcome the obstacles to minor histocompatibility antigen usage in the fight against cancer. It is about time that minors are not minor anymore.