Tissue Antigens ISSN 0001-2815

REVIEW ARTICLE

Minor histocompatibility antigens: past, present, and future Eric Spierings Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands

Key words adoptive immunotherapy; allo-immunity; graft-versus-host disease; graft-versus-leukemia effect; hematopoietic stem-cell transplantation; immunogenetics; minor H antigens; organ transplantation Correspondence Dr Eric Spierings Laboratory for Translational Immunology University Medical Center Utrecht F03.821, PO Box 85500 GA 3508 Utrecht the Netherlands Tel: +31 88 75 50978 Fax: +31 30 25 17107 e-mail: [email protected]

Abstract Minor histocompatibility (H) antigens are key molecules driving allo-immune responses in both graft-versus-host-disease (GvHD) and in graft-versus-leukemia (GvL) reactivity in human leukocyte antigen (HLA)-matched hematopoietic stem-cell transplantation (HSCT). Dissection of the dual function of minor H antigens became evident through their different modes of tissue and cell expression, i.e. hematopoietic system-restricted or broad. Broadly expressed minor H antigens can cause both GvHD and GvL effects, while hematopoietic system-restricted minor H antigens are more prone to induce GvL responses. This phenomenon renders the latter group of minor H antigens as curative tools for HSCT-based immunotherapy of hematological malignancies and disorders, in which minor H antigen-specific responses are enhanced in order to eradicate the malignant cells. This article describes the immunogenetics of minor H antigens and methods that have been developed to identify them. Moreover, it summarizes the clinical relevance of minor H antigens in transplantation, with special regards to allogeneic HSCT and solid-organ transplantation.

doi: 10.1111/tan.12445

Introduction

Minor histocompatibility (H) antigens are T-cell epitopes derived from polymorphic proteins. Minor H peptides are presented by various major histocompatibility complex (MHC) class I and class II molecules. The MHC/minor H peptide complexes can act as transplantation barriers in allogeneic human leukocyte antigen (HLA)-matched hematopoietic stem-cell transplantation (HSCT) (1–3) and in solid-organ transplantation (4). Moreover, they can induce immune responses during pregnancy (5, 6). In the clinical setting, the effect of minor H antigens became apparent in 1976. In this case, serious clinical problems occurred after an HLA-identical sibling HSCT (1, 7, 8). Subsequent in vitro experiments showed distinct cellular activities between the HLA-identical donor and the HSCT recipient (9, 10). It subsequently took almost 20 years before the first minor H epitopes were characterized molecularly (2, 11). The chemical identification was instrumental for novel research aiming at understanding the immunobiology of minor H antigenic systems and at exploring the possibilities of their clinical usefulness in HSCT and solid organ transplantation. As of today, 54 minor H antigens that are encoded by genes on autosomal chromosomes, have been identified (Table 1 and Figure 1) and their number is growing annually. This review describes the immunogenetics of minor H antigens and the various identification methodologies that are in use. Moreover, it summarizes the observed clinical effects of minor H antigen © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 347–360

mismatching in transplantation, with special regards to HSCT and solid-organ transplantation. The immunogenetics of human minor H antigens

The genetic basis for minor H immunogenic T-cell epitopes is formed by polymorphic genes. When transcribed, these polymorphic genes lead to proteins with different amino-acid sequences in recipient and donor. Once polymorphic peptides from these proteins end up in the groove of HLA molecules, minor H antigen-specific T cells may be able to recognize these differences after transplantation and evoke alloimmune reactivity. The most common form of genetic polymorphism leading to minor H antigens, is the nonsynonymous single nucleotide polymorphism (SNP). These SNPs consist of a single nucleotide difference in the genome that results in a different amino acid in the peptide. Examples thereof are the autosomally encoded minor H antigen HA-1 (12) and HA-2 (11), which were the first autosomally encoded human minor H antigens to be identified. Although most of the Y-chromosome encoded HY antigens display more than one SNP when compared with their X-gene counterpart, they essentially, consist nonsynonymous SNP-like polymorphisms (2, 3, 7, 8, 13–17). In the case of SNPs, the resulting polymorphic proteins are treated differently by the cellular processes that finally lead to antigen presentation on the cell surface or are being recognized 347

E. Spierings

Minor histocompatibility antigens

Table 1 Autosomally encoded minor H antigens by alphabetical ordera Name ACC-1Y ACC-1C ACC-2 ACC-4 ACC-5 ACC-6 C19orf48 CD19 DPH1 HA-1/A2 HA-1/B60 HA-2 HA-3 HA-8 HB-1H HB-1Y HEATR1 HER2 LB-ADIR-1 LB-APOBEC3B-1K LB-ARHGDIB-1R LB-BCAT2-1R LB-EBI3-1I LB-ECGF-1 LB-ERAP1-1R LB-GEMIN4-1V LB-LY75-1K LB-MR1-1R LB-MTHFD1-1Q LB-NISCH-1A LB-NUP133-1R LB-PDCD11-1F LB-PI4K2B-1S LB-PRCP-1D LB-PTK2B-1T LB-SON-1R LB-SSR1-1S LB-SWAP70-1Q LB-TRIP10-1EPC LB-WNK1-1I LRH-1 P2RX7 PANE1 SLC19A1 SLC1A5 SP110 T4A TRIM22 UGT2B17 UGT2B17 UGT2B17 UTA2-1 UTDP4 ZAPHIR

HLA restriction

Gene

Chromosome

HLA-A*24 HLA-A*24 HLA-B*44 HLA-A*31 HLA-A*33 HLA-B*44 HLA-B*07 HLA-DQB1*02 HLA-B*57 HLA-A*02 HLA-B*40:01 HLA-A*02 HLA-A*01 HLA-A*02 HLA-B*44 HLA-B*44 HLA-B*08 HLA-A*02 HLA-A*02 HLA-B*07 HLA-B*07 HLA-B*07 HLA-B*07 HLA-B*07 HLA-B*07 HLA-B*07 HLA-DRB1*13:01 HLA-DRB3*02:02 HLA-DRB1*03:01 HLA-A*02 HLA-B*40:01 HLA-B*07 HLA-DQB1*06 HLA-A*02 HLA-DRB3*01:01 HLA-B*40:01 HLA-A*02 HLA-B*40:01 HLA-B*40:01 HLA-A*02 HLA-B*07 HLA-A*29 HLA-A*03 HLA-DRB1*15:01 HLA-B*40:02 HLA-A*03 HLA-A*02 HLA-A*02 HLA-A*02 HLA-A*29 HLA-B*44 HLA-A*02 HLA-DPB1*04 HLA-B*07

BCL2A1 BCL2A1 BCL2A1 CTSH CTSH HMSD C19orf48 CD19 DPH1 HMHA1 HMHA1 MYO1G AKAP13 KIAA0020 HMHB1 HMHB1 HEATR1 HER-2/NEU TOR3A APOBEC3B ARHGDIB BCAT2 EBI3 TYMP ERAP1 GEMIN4 LY75 MR1 MTHFD1 NISCH NUP133 PDCD11 PI4K2B PRCP PTK2B SON SSR1 SWAP70 TRIP10 WNK1 P2X5 P2RX7 CENPM SLC19A1 SLC1A5 SP110 TRIM42 TRIM22 UGT2B17 UGT2B17 UGT2B17 KIAA1551 ZDHHC12 ZNF419

15 15 15 15 15 18 19 16 17 19 19 7 15 9 5 5 1 17 1 22 12 19 19 22 5 17 2 1 14 3 1 10 4 11 8 21 6 11 19 12 17 12 22 21 19 2 3 11 4 4 4 12 9 19

Peptide DYLQYVLQI DYLQCVLQI KEFEDDIINW ATLPLLCAR WATLPLLCAR MEIFIEVFSHF CIPPDSLLFPA WEGEPPCLP SVLPEVDVW VLHDDLLEA KECVLHDDLL YIGEVLVSV VTEPGTAQY RTLDKVLEV EEKRGSLHVW EEKRGSLYVW ISKERAEAL Not reported SVAPALALFPA KPQYHAEMCF LPRACWREA QPRRALLFVIL RPRARYYIQV RPHAIRRPLAL HPRQEQIALLA FPALRFVEV GITYRNKSLM YFRLGVSDPIRG SSIIADQIALKL ALAPAPAEV SEDLILCRL GPDSSKTFLCL SRSSSAELDRSR FMWDVAEDLKA VYMNDTSPL SETKQRTVL SLAVAQDLT MEQLEQLEL GEPQDLCTL RTLSPEIITV TPNQRQNVC WFHHCHPKY RVWDLPGVLK RLVCYLCFY AEATANGGLAL SLPRGTSTPK GLYTYWSAGA MAVPPCCIGV CVATMIFMI AELLNIPVLY AELLNIPVLY QLLNSVLTL RILAHFFCGW IPRDSWWVEL

dbSNP

References

rs1138357 rs1138357 rs3826007 rs2289702 rs2289702 rs9945924 rs3745526 rs2904880 rs35394823 rs1801284 rs1801284 rs61739531 rs2061821 rs2173904 rs161557 rs161557 rs2275687 rs1058808 rs2296377 rs2076109 rs4703 rs11548193 rs4740 rs112723255 rs26653 rs4968104 rs12692566 rs2236410 rs2236225 rs887515 rs1065674 rs2986014 rs313549 rs386564200 rs751019 rs13047599 rs10004 rs415895 rs1049229b rs12828016 rs3215407 rs7958311 rs5758511 rs1051266 rs3027956 rs1365776 rs9876490 rs187416296 n.a. n.a. n.a. rs2166807 rs11539209 rs2074071

24 25 24 36 36 27 94 43 46 12 53 11 19 20 22 23 95 54 96 48 48 48 48 48 48 48 30 30 30 55 35 48 37 48 30 35 48 35 35 48 29 46 26 45 44 33 56 97 44 28 28 98 49 47

dbSNP, single nucleotide polymorphism database. a For the copy number variation of UGT2B17 no dbSNP identification number has been assigned (n.a.). b The minor H antigen LB-TRIP10-1EPC contains the SNPs rs1049229, rs1049230, and rs1049232.

348

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 347–360

E. Spierings

Minor histocompatibility antigens

Identified minor H antigens 60

cummulative number

50

40

30

20

10

19 1995 1996 1997 1998 2099 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 14

0

i.e. UGT2B17 (28). Its immunogenic allele is encoded on chromosome 4. A nonimmunogenic protein is nonexisting, as its chromosomal counterpart has been deleted. Thus, after transplantation, individuals homozygous for the (partial) deletion can recognize the target cells expressing the involved protein. Deletion–insertion polymorphisms (DIPs) may also lead to minor H antigens (29). In these cases, one allele of the minor H gene has one or more extra nucleotide(s) when compared with the other allele. If the DIP comprises a full triplet of nucleotides, the resulting protein will contain an extra amino acid. Full triplet DIPs have, however, not yet been described for minor H antigens. The only DIP-based minor H antigen identified to date is LRH-1, consisting of a single nucleotide DIP leading to a shift in the open reading frame of the P2X5 gene (29). As a consequence, the immunogenic protein and the allelic counterpart is completely different on the C-terminal part following the polymorphic position. Immunologically, DIPs can be regarded in a similar fashion as the introduction of a stop codon.

year Figure 1 Cumulative number of identified minor H antigens encoded on autosomal chromosomes.

differentially by the T-cell receptor (see Ref. 18 for review). In the first step of antigen processing, a single amino-acid difference can lead to differential proteasome-mediated cleavage and subsequent destruction of the nonimmunogenic HA-3M peptide, accounting for absence thereof on the cell surface (19). Next, transport of allelic minor H peptides via transporter associated with antigen processing (TAP) into the endoplasmic reticulum can differ, as has been shown for the HA-8R and HA-8P peptides (20); the nonimmunogenic HA-8P peptide is poorly transported and subsequently not loaded into the HLA-A2 molecule. Also the stability of allelic minor H peptides may highly differ due to single amino-acid substitution; the HLA-A2/HA-1H complex has a half-life time of dissociation of 54 h at 37∘ C, whereas this is only 8 min for the HLA-A2/HA-1R complex (21). Finally, the T-cell receptor (TCR) may discriminate between the two minor H peptides, as has been described for HB-1H, HB-1Y (22, 23) and ACC-1Y, ACC-1C (24, 25). Alternatively, polymorphisms may lead to differential transcription or translation, and consequently to the absence of (parts of) a protein and thus no presence of a nonimmunogenic minor H peptide on the cell surface. For instance, SNPs can lead to the introduction of a stop codon instead of an altered amino acid (26) or to changes in intron splicing (27). With the introduction of a stop codon, the 3′ mRNA is not completely translated and a truncated protein is produced. Minor H antigen polymorphisms may also result from the absence of a complete gene, or copy-number variation (CNV). For human minor H antigens there is, as yet, only one example of CNV, © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 347–360

Minor H antigen identification Basic concepts in identification

Generally, the identification of minor H antigens starts with the isolation and expansion of antigen-specific T-cell clones from recipients after having received an HLA-identical or -matched HSCT. These T-clones can subsequently be screened for their HLA-restriction, using HLA-specific antibodies and panels of Epstein–Barr virus-transformed lymphoblastoid cell lines (EBV-LCL). The results from these panel screenings will also provide target-cell recognition patterns. T-cell clones with an identical HLA restriction and recognition patterns are assumed to recognize the same minor H antigen, whereas either a different HLA restriction or a different recognition pattern indicates different minor H antigens as target. In most studies, additional features from these T cells were characterized, including tissue-distribution analyses, phenotype analyses, and T cell-receptor spectratyping or sequencing. The T cells can subsequently be used to identify the minor H antigen they recognize. For instance, the observed tissue distribution may be correlated with expression patterns (24, 29, 30) documented experimentally or in various online databases. Identification by peptide elution

The first human minor H antigens were identified after elution of peptides from the relevant HLA molecules (2, 3, 11, 12, 19, 20, 26, 28). Peptide elution is the only method to identify the exact minor H peptide in the form as expressed on the cell surface (31). Major drawbacks of this approach are, however, the laborious and time-consuming character of the procedures and the need for dedicated equipment as high-performance liquid chromatography (HPLC) and tandem mass spectrometry 349

E. Spierings

Minor histocompatibility antigens

(MS). New technical development in the field of MS-based sequencing as electron-transfer/higher-energy collision dissociation, may well facilitate the minor H antigen identification and increase the success rate (32). Although successful for the identification of HLA class I-restricted minor H antigens, this technique has so far failed to elucidate HLA class II-restricted minor H antigens.

with testing of minor H antigen-specific T-cell clones provides a powerful alternative either by SNP typing of the analyzed target-cell panel (25), or by cellular screening of already SNP-typed target cells (43). This approach has given a significant boost to the identification of minor H antigens (44–48), leading to a total of 17 newly identified minor H antigens between 2008 and 2011 alone (Table 1).

Identification by cDNA library screening

Future prospective of minor H antigen identification

Screening of cDNA libraries has been shown to be an alternative for the identification of antigenic minor H peptides. It has successfully been applied to identify a number of autosomal minor H antigens (22, 28, 33–36). More importantly, the cDNA library screening methodology allows characterization of both HLA class I- and class II-restricted minor H antigens (30, 37). The use of specific libraries is particularly powerful for identifying H-Y epitopes, for which there are only a limited number of candidate genes (13–15, 38).

Although the identification frequency of new minor H antigens has significantly increased due to the above described technical advances (Figure 1), there are still many situations where the exact epitopes cannot be identified. Whole-genome deep sequencing may enhance the current WGAS approach in the near future and lead to a more precise identification of minor H antigens (49). Complete sequencing of human genomes is becoming more cost-effective due to new sequencing approaches as next-generation sequencing. These developments will likely further increase the success rate of minor H antigen identification via WGAS, as the complete genomic data would include all SNPs, DIPs, and CNVs. Whole-genome sequencing of existing panels or minor H antigen screening on already sequenced panels should reveal the power of this approach. Alternatively, reverse immunology approaches may help in identifying clinically relevant minor H antigens. Datasets, software, and computational power seem to be sufficient to generate candidate minor H antigens (50–52). Although three autosomally encoded minor H antigens have been identified by the reverse immunology (53–55), the major bottleneck seems to be cellular confirmation of the predicted epitopes. Combining reverse immunology with SNP typing of donor–recipient pairs (56) or by implementing the HLA-peptidome may increase the success rate of this approach.

Identification using genetic linkage

Application of genetic linkage analyses was suggested as an alternative possibility for the chemical elucidation of human minor H antigens via the identification of minor H loci (39). The method involves the use of EBV-LCL from large families consisting of three generations that can be transfected with DNA constructs to introduce the correct HLA restriction molecule. Additionally, these individuals need to be typed for genetic markers. Such cell panels are readily available; an example is the cell panel of the Centre d’Etude du Polymorphisme Humain (CEPH), in which all individuals have been typed for 3000–10,000 genetic markers (40, 41). Two initial studies using this technique localized minor H antigens on chromosomes 22 and 11, respectively, but failed to identify the exact loci, leaving the biochemical structure of the epitopes unsolved (39, 42). A retrospective study on the HA-8 antigen showed the feasibility of this approach (26). This latter study combined the genetic linkage data with HLA-binding prediction tools on nonsynonymous SNP-containing DNA sequences, resulting in identification of an epitope that matched the eluted one. Subsequently, this methodology was prospectively utilized for the first time for the molecular identification of two BCL2A1-encoded minor H epitopes, i.e. ACC-1 and ACC-2 (24). Whole-genome association scans

The above-described genetic linkage approach may lead to identification of a genetic region, but frequently fails to identify the involved gene and/or polymorphism (24, 39, 42). The genetic linkage technique is limited by its resolution and crucially depends upon the availability of large segregating families. Whole-genome association scans (WGAS) combined 350

The clinical role of minor H antigens General prerequisites

An absolute prerequisite for generation of minor H antigen T-cell responses is the absence of the immunogenic allele in the T-cell donor and the presence of the immunogenic allele in the targeted individual. Moreover, the correct HLA restriction molecule that presents the minor H peptide, should be present at least in the targeted individual and likely also in the T-cell donor (see Tables 1 and 2 for the HLA restriction molecules). Mechanistically, thymic selection of minor H antigen-specific T cells may underlie this assumption; T cells that are not able to at least recognize a self-HLA molecule are deleted. The need for the presence of the HLA restriction molecule in both donor and recipient is further motivated by the fact that minor H antigen responses are most obvious in HLA-identical HSCT settings in vivo. However, in vitro data show that the presence © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 347–360

E. Spierings

of the presenting HLA molecule in both donor and recipient is not per definition essential; HLA-A2-restricted HA-1 responses can also be induced in individuals who are HLA-A2 negative (57). The relevance of the latter concept in vivo, still remains to be demonstrated. For example, HA-3 responses are only generated against the HA-3T minor H peptide when presented in HLA-A1 (19). So in HSCT, this minor H antigen can only play a role in HLA-1 donor–recipient pairs where the recipient has at least one immunogenic HA-3T allele on its chromosome 15 and the donor is homozygous for the HA-3M allele. These requirements limit the clinical involvement of minor H antigens, as only part of the HSCT pair will meet these prerequisites. Genetic population studies have shown that the percentage of minor H antigen disparate HSCT pairs ranges between 0% and 13%, depending on the minor H antigen, donor type (matched unrelated donor or sibling donor), and ethnicity (58). Table 2 lists all autosomal minor H antigens with their disparity rates. A broad variety of molecular typing techniques is currently available to genotype recipients and donor pairs, in order to address their minor H antigen disparity for clinical and epidemiological purposes (reviewed in Ref. 59). Minor H antigen-specific T-cell responses were initially related to CD8+ cytotoxic T lymphocytes (CTL) and CD4+ T-helper cells, both associated with a detrimental role (reviewed in Ref. 60). Recently, however, it has become clear that minor H antigen disparity can also lead to the induction of regulatory T cells (Treg). Such Treg could be observed after kidney transplantation (61). Moreover, studies in healthy individuals indicate that CTL- and Treg-mediated alloimmunity against minor H antigens may coexist in healthy female and male hematopoietic stem-cell donors, due to the maternal–fetal interaction during pregnancy (62). The presence of minor H antigen-specific Tregs seems, however, to be independent of pregnancy; on the one hand such T cells can also be detected in nulliparous females and on the other hand their specificity can be directed toward minor H antigens that were absent in the fetus (63). Whether and how pregnancy status affects the graft-versus-host disease (GvHD) and potentially relapse incidences after HSCT, remains to be investigated. Hematopoietic stem-cell transplantation

Although the characterization of minor H antigens has contributed to our basic knowledge of genetic polymorphism, immunobiology, and immunogenetics, their key role is related to their clinical applicability. This clinical role has been most extensively studied in the HSCT setting. Minor H antigen mismatching has clinically been associated with an increased risk of GvHD (64–68) and an improved graft-versus-leukemia (GvL) effect (69, 70). The participation of the minor H antigens in GvHD and GvL reactions is related to their cell and tissue expression; hematopoietic system-restricted minor H antigens might be able to enhance immune responses in GvL, while © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 347–360

Minor histocompatibility antigens

broadly expressed minor H antigens are supposed to contribute to both GvHD and GvL (71). The in vivo involvement of broad minor H antigens in the GvHD arm of HSCT, was shown in great detail for HY using functional in vitro tests (71) and an in situ ex vivo skin explant assay (72). Moreover, the role of HY-specific T cells in GvHD is supported by their presence in the peripheral blood of patients with clinically manifest GvHD (73), and in GvHD-affected skin of male patients after gender-mismatched HSCT (74). As yet, data for other broadly expressed minor H antigens are limited. In general, their expression pattern has been identified by in vitro cellular recognition assays and in vitro or in silico RNA expression profiling. Ex vivo analyses on peripheral blood or on GvHD-involved tissues using HLA-minor H peptide tetramers have not been reported for autosomally expressed minor H antigens. Such studies are essential to translate the specific HY observations to a more general conclusion with respect to the role of broadly expressed minor H antigens in GvHD. Some minor H antigen mismatches, like A2/HY and HA-8, seem to contribute to the GvHD risk only in HLA-identical sibling transplantation, while others as A1/HY and HA-3 are also effective in matched unrelated donor HSCT (67). Speculatively, these differential effects may be the result of differences in immunogenicity. In general, the immunogenicity of a peptide is correlated to both its dissociation rate from and its affinity for the MHC molecule (75–78). Likewise, we previously reported a crucial difference in half-life between the HA-1H and HA-1R alleles in complex with HLA-A2 (21). Thus, hypothetically, the immunogenicity of minor H antigens in the HLA-matched vs the HLA-identical transplantation setting may depend on the stability of the involved HLA/minor H peptide complexes and highly stable/immunogenic minor H antigens may exert a clinically detectable effect even in partially HLA-mismatched settings. In silico stability analysis of the HA-8, A2/HY, HA-3, and A1/HY peptides using HLA peptide binding prediction software BIMAS [http://www-bimas.cit.nih.gov/molbio/hla_bind/ (79)] revealed no clear-cut differences in the estimated half-times of dissociation (Table 3). Interestingly, when comparing the nonimmunogenic counterparts of these minor H antigens, the two HLA-A2-restricted minor H antigens displayed a 45- to 80-fold shortening in the estimated half-time of dissociation, leading to predicted half-time values lower than 45 s. Contrary, the HLA-A1-restricted nonimmunogenic peptides reveal a marginal decrease when compared with the immunogenic alleles, resulting in estimated half-time values of 450 min for the HA-3M peptide and 25 min for the A1/HX peptide. Identification of the mechanisms underlying the immunogenic hierarchy of minor H antigens, including the role of such relative stability differences, is important, as it may in the future lead to a minor H antigen-mismatch scoring system for the risk assessment of GvHD in each individual recipient–donor combination. 351

E. Spierings

Minor histocompatibility antigens

The role of HA-1 in GvHD after HSCT is controversial. The effect of mismatching for the hematopoietic system-restricted minor H-antigen HA-1 on GvHD has been studied by several investigators reporting different outcomes. Whereas some studies observed an association between HA-1 mismatching and the development of GvHD, others did not (69, 80–82). Biologically, no correlation is expected, as the HA-1 antigen

should not be present on GvHD target tissues such as gut, skin, and liver. The reported association of HA-1 with GvHD may be explained by the putative presence of recipient’s residual dermal antigen-presenting cells (APCs) after HSCT (72, 83). These APCs reside in recipient’s skin for various time spans (72). Moreover, they are capable to stimulate HA-1-specific T cells an in ex vivo in situ skin model (83). This concept

Table 2 Genotype frequencies of minor H antigens and their known HLA restriction elementsa Matched unrelated HSCT HLA restriction

Minor H antigen

HLA-A*01 HLA-A*02 HLA-A*02 HLA-A*02 HLA-A*02 HLA-A*02 HLA-A*02 HLA-A*02 HLA-A*02 HLA-A*02 HLA-A*02 HLA-A*02 HLA-A*02 HLA-A*02 HLA-A*03 HLA-A*03 HLA-A*24 HLA-A*24 HLA-A*29 HLA-A*29 HLA-A*31 HLA-A*33 HLA-B*07 HLA-B*07 HLA-B*07 HLA-B*07 HLA-B*07 HLA-B*07 HLA-B*07 HLA-B*07 HLA-B*07 HLA-B*07 HLA-B*07 HLA-B*08 HLA-B*40:01 HLA-B*40:01 HLA-B*40:01 HLA-B*40:01 HLA-B*40:01 HLA-B*40:02 HLA-B*44 HLA-B*44 HLA-B*44 HLA-B*44 HLA-B*44 HLA-B*57

HA-3 HA-1/A2 HA-2 HA-8 HER2 LB-ADIR-1 LB-NISCH-1A LB-PRCP-1Db LB-SSR1-1S LB-WNK1-1I T4A TRIM22c UGT2B17d UTA2-1 PANE1 SP110 ACC-1Y ACC-1C P2RX7 UGT2B17d ACC-4 ACC-5 C19orf48 LB-APOBEC3B-1K LB-ARHGDIB-1R LB-BCAT2-1R LB-EBI3-1I LB-ECGF-1 LB-ERAP1-1R LB-GEMIN4-1V LB-PDCD11-1F LRH-1b ZAPHIR HEATR1 HA-1/B60 LB-NUP133-1R LB-SON-1R LB-SWAP70-1Q LB-TRIP10-1EPCc SLC1A5 ACC-2 ACC-6 HB-1H HB-1Y UGT2B17d DPH1

352

Identical related HSCT

Genetic disparity (%)

Immunological disparity (%)

Genetic disparity (%)

Immunological disparity (%)

5.8 25.0 3.8 17.8 24.9 23.4 19.9 17.8 24.9 22.6 19.9 1.9 3.4 24.0 4.2 14.6 24.8 3.5 23.6 3.4 7.3 7.3 10.9 22.9 21.7 2.5 25.0 8.4 25.0 24.6 23.7 24.8 24.9 24.9 25.0 23.0 24.2 24.0 1.0 24.4 24.8 23.1 3.4 21.7 3.4 14.4

1.8 13.0 2.0 9.3 12.9 12.2 10.3 9.2 13.0 11.8 10.3 1.0 1.8 12.5 1.1 3.9 4.2 0.6 1.7 0.2 0.3 0.2 2.9 6.0 5.7 0.7 6.6 2.2 6.6 6.5 6.2 6.5 6.6 6.0 3.1 2.9 3.0 3.0 0.1 0.5 6.7 6.2 0.9 5.9 0.9 1.1

2.2 10.1 1.1 6.7 11.7 10.6 8.9 8.5 11.1 9.3 7.8 1.0 1.0 11.0 1.3 5.4 11.9 1.2 11.4 1.0 3.6 3.6 3.8 10.0 8.5 0.6 10.8 4.2 11.1 10.7 9.5 10.9 11.4 11.1 10.1 11.1 10.8 10.5 0.2 12.2 11.9 9.8 0.9 10.1 1.0 7.0

0.7 5.3 0.6 3.5 6.1 5.5 4.7 4.4 5.8 4.8 4.1 0.5 0.5 5.7 0.4 1.4 2.0 0.2 0.8 0.1 0.2 0.1 1.0 2.6 2.2 0.2 2.8 1.1 2.9 2.8 2.5 2.9 3.0 2.7 1.3 1.4 1.4 1.3 0.0 0.2 3.2 2.6 0.3 2.7 0.3 0.5

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 347–360

E. Spierings

Minor histocompatibility antigens

Table 2 Continued Matched unrelated HSCT

Identical related HSCT

HLA restriction

Minor H antigen

Genetic disparity (%)

Immunological disparity (%)

Genetic disparity (%)

Immunological disparity (%)

HLA-DPB1*04 HLA-DQB1*02 HLA-DQB1*06 HLA-DRB1*03:01 HLA-DRB1*13:01 HLA-DRB1*15:01 HLA-DRB3*01:01 HLA-DRB3*02:02

UTDP4-1e CD19 LB-PI4K2B-1Sc LB-MTHFD1-1Q LB-LY75-1K SLC19A1 LB-PTK2B-1Tf LB-MR1-1Rf

9.5 24.9 9.4 22.6 23.6 20.4 20.3 20.3

6.2 10.4 4.1 5.6 2.7 0.3 5.4 7.4

4.6 11.9 3.2 9.4 10.6 8.8 8.0 9.7

3.0 5.0 1.4 2.3 1.2 0.1 2.2 3.5

dbSNP, single nucleotide polymorphism database; HLA, human leukocyte antigen; HSCT, hematopoietic stem-cell transplantation. a Minor H antigen genotype frequencies were obtained from the dbSNP database at http://www.ncbi.nlm.nih.gov/projects/SNP/ (accessed 8 August 2014), selecting the largest European HapMap population. If HapMap data were absent, the largest reported Caucasian population was used. Disparity rates for HLA-matched unrelated donors and HLA-identical related donors were calculated as described before (58), in which the genetic disparity rate is the chance that a specific combination consists of a recipient that is positive for the immunogenic minor H allele, either homozygous or heterozygous, and of a donor that is homozygous negative. The immunological disparity includes the frequency of the HLA restriction molecule into the calculations. b Allele frequency data for LRH-1 (29) and LB-PRCP-1D (48) were obtained from their respective identification publications. Their genotype data were estimated. c For LB-PI4K2B-1S, LB-TRIP10-1EPC, and TRIM22, genotype data were estimated using the allele frequencies in dbSNP. d UGT2B17 frequency data obtained from Spierings et al. as described (58). In all estimations, a Hardy–Weinberg equilibrium was assumed. e HLA frequency data were obtained from Maiers et al. (99), Caucasian population. HLA-DPB1 frequency data were obtained from http://allelefrequencies.net (accessed 8 August 2014) selecting Caucasian populations and using the average of United States percentages (100). f HLA-DRB3 allele frequencies were obtained from Gragert et al. (100) using the Caucasian population data. All HLA phenotype frequencies were estimated using the formula [1 − ((1 − p)2 )] x 100%, in which p is the allele frequency of the relevant HLA allele. Data have been ordered by their HLA restriction molecule. Table 3 Stability analyses of the minor H antigens HA-3, HA-8, A1/HY, and A2/HY. Higher BIMAS scores indicate a more stable HLA-peptide complex BIMAS

Minor H peptide VTEPGTAQY IVDCLTEMY RTLDKVLEV FIDSYICQV

Minor H antigen

HLA-restriction

HA-3 A1/HY HA-8 A2/HY

HLA-A*01 HLA-A*01 HLA-A*02 HLA-A*02

may also explain the correlation between mismatching for the hematopoietic system-restricted ACC-1 and the incidence of GvHD (83), although the ACC-1 minor H antigen has not yet been studied in that perspective, yet. The role for hematopoietic system-restricted minor H antigen-specific CTL during GvL is supported by the observation that the appearance HA-1-specific cytotoxic T cells in the peripheral blood or bone marrow of patients can coincide with the therapeutic effect of donor lymphocyte infusion (DLI) (84, 85). In parallel, CTL specific for the hematopoietic system-restricted minor H antigens HA-1, HA-2, and LRH-1 coincide with remission of hematological malignancies after donor lymphocyte infusion (86). Retrospective clinical studies on the GvL effect of hematopoietic-system restricted minor H-antigen mismatches in HSCT are, however, ambiguous. Some studies showed no correlation between HA-1 mismatching and relapse (29, 85), while others indicated an association between HA-1 mismatching and lower leukemia relapse rates in © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 347–360

score Immunogenic peptide 2250.000 25.000 33.705 40.472

BIMAS score Nonimmunogenic peptide

450.000 25.000 0.742 0.463

HLA-A2-positive chronic myeloid leukemia (CML) recipients who received a myeloablative HSCT from an HLA-identical related donor (69, 70). The ambiguous reports may reflect the dependency of the minor H antigen-related GvL effect on the presence of GvHD. Such dependency was revealed in a study on relapse in recipients of HA-1 mismatched HSCT grafts; HA-1 mismatching only affected the relapse incidence in patients suffering from GvHD (87). We confirmed these observations in a multicenter analysis of the role of eight hematopoietic-system restricted minor H antigens on outcome of HSCT (67), which hinted to GvHD as a crucial pre-requisite for an efficient minor H antigen-related GvL response. Further elucidation of such dependencies could increase the efficacy of minor H antigen-based immunotherapy in HSCT. Various prospective clinical studies involving minor H antigens and their specific T-cell responses have been performed and are currently ongoing. In order to provide a full overview of these clinical trials, the clinical trial databases at 353

E. Spierings

Minor histocompatibility antigens

Table 4 Overview of registered clinical trials studying minor H antigens in an observational fashion Outcome measures in relation to minor H antigens

Identifier/sponsor

Study title

NCT00957736; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA

Chronic graft-versus-host disease in patients who have undergone donor stem cell transplant

NCT00306332; Radboud University Nijmegen Medical Centre, the Netherlands NCT01020539; Columbia University, New York, NY, USA

T-cell and B-cell depletion in allogeneic peripheral blood stem cell transplantation

Allogeneic stem cell transplantation followed by targeted immune therapy in average risk leukemia (AML/MDS/JMML)

NCT02117297; New York Medical College, New York, NY, USA

HSCT plus immune therapy in average risk AML/MDS

NCT00104858; Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Fludarabine phosphate, radiation therapy, and rituximab in treating patients who are undergoing donor stem cell transplant followed by rituximab for high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma

Primary: Investigation of SNP profiles of a select group of candidate non-HLA genes, including minor H antigens, in classic cGvHD vs nonclassic GvHD. Secondary: Clinical relevance of minor H antigen-specific CTL responses for the GvL effect. Secondary: Expression of minor histocompatibility antigens on AML tissue, genotyping of donor and recipient, and monitor the development of minor H antigen-specific CTL. Secondary: Expression of minor histocompatibility antigens on AML tissue, genotyping of donor and recipient, and monitor the development of minor H antigen specific CTL. Secondary: Isolation of minor H antigen-specific CTL.

Status Terminated

Terminated

Active, not recruiting

Recruiting

Recruiting

CTL, cytotoxic T lymphocyte; GvHD, graft-versus-host-disease; cGVHD, chronic graft-versus-host-disease; GvL, graft-versus-leukemia; HLA, human leukocyte antigen; SNP, single nucleotide polymorphism; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; JMML, Juvenile myelomonocytic leukemia.

http://clinicaltrials.gov, http://clinicaltrialsregister.eu, http:// www.controlled-trials.com, and http://www.cancer.gov/search/ results (all accessed on 23 June 2014) were searched for the keywords ‘minor histocompatibility antigen’ (or) ‘mhag’ (or) ‘miha’ (or) ‘SCT’ (and) ‘minor’. The results were manually screened for their relevance. Completed studies were queried in PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) and via Google (http://www.google.com; both accessed 4 August 2014) using the trial identifiers. The results of the trial database searches could be classified into two groups: (i) trials in which minor H antigens were in an observational fashion (Table 4) and (ii) trials in which minor H antigens were included in the intervention strategy and part of the primary outcome analyses (Table 5). Five clinical trials have been documented that investigate minor H antigens in an observational fashion (Table 5). Two of these trials have been terminated. With respect to these two trials, no publications or public reports analyzing HSCT outcome in relation to minor H antigens could be found. Three of the trials are still active and basically focus on monitoring the development of minor H antigen-specific CTL after HSCT. Such trials are essential to further investigate the role of minor 354

H antigens in transplant outcome, as they may provide data on the occurrence of minor H antigen-specific T cells after HSCT in a qualitative and quantitative way. Moreover, these studies may provide a better insight in the temporospatial features of these T cells. A total of seven trials were reported to include minor H antigens in the intervention strategy (Table 5). So far, only one study (NCT00107354) performed adaptive immunotherapy using minor H antigen-specific T cells. This study lead to the identification a novel B27/HY minor H antigen (7) and of the autosomally encoded minor H antigens DPH10 and P2RX7 (46). Moreover, analysis of the seven included patients provided some insight into the cytotoxicity of the protocol; pulmonary toxicity was observed in three patients, with one severe case, and five patients achieved complete but transient remissions after therapy. Five studies use a vaccination strategy to boost the minor H antigen-specific response in the recipient after HSCT. Three of them administer minor H peptide(s) in their protocol, while two apply dendritic cells (DC) as a carrier for the minor H antigen. No public reports on these trials have been published so far. The last study investigates the interesting option to induce minor H antigen-specific T cells in © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 347–360

E. Spierings

Minor histocompatibility antigens

Table 5 Overview of registered clinical trials including minor H antigen in the intervention strategy Outcome measures Phase in relation to minor H antigens

Identifier/sponsor

Study title

NCT02117297; University of Chicago, Chicago, WI, USA

Minor histocompatibility vaccination after allogeneic stem cell transplantation for advanced hematologic malignancies

1

NCT00107354; Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Cellular adoptive immunotherapy in treating patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes that relapsed after donor stem cell transplant Vaccination with human minor H antigen (HA-1) peptide in patients showing minimal residual disease or mixed chimerism after allogeneic stem cell transplantation and donor lymphocyte infusion A phase I/II study of vaccination against minor histocompatibility antigens HA-1 or HA-2 after allogeneic stem cell transplantation for advanced hematological malignancies A phase I/II ‘minor histocompatibility antigen’ (mHag)-based dendritic cell vaccination trial after allogeneic stem cell transplantation to improve the safety and efficacy of donor lymphocyte infusions

1

ISRCTN80896844; Leiden University Medical Centre, the Netherlands

ISRCTN11974092; Hannover Medical School, Germany

EudraCT 2012-002435-28; University Medical Center Utrecht, the Netherlands

EudraCT 2012-002879-34; Radboud University Nijmegen Medical Centre, the Netherlands

ISRCTN23537803; University of Birmingham, UK

Vaccination with minor histocompatibility antigen-loaded donor DC vaccines to boost graft-versus-tumor immunity after partially T cell-depleted stem cell transplantation A phase I clinical trial of the vaccination of healthy human volunteers against the minor histocompatibility antigen (mHAg) HA-1 using a DNA and MVA ‘prime/boost’ regimen

Status

Primary: Effect of HA-1/HA-2-peptide vaccination on HA1/HA-2-specific T cell immunity. Secondary: Toxicity. Primary: Toxicity of adoptively transferred minor H antigen-specific CTL. Secondary: Persistence and migration of minor H antigen-specific CTL, anti-leukemic activity. Primary: Toxicity; appearance of HA-1 specific CD8+ lymphocytes. Secondary: Bone marrow chimerism; disease activity.

Terminated

1/2

Primary: Toxicity of immunization. Secondary: Prevention of relapse of leukemia.

Completed

1/2

Primary: Safety and efficacy, the occurrence of GvHD and the induction of a positive response to the combined DLI and DC treatment. Secondary: The effect of minor H antigen vaccination on the immune status of the patient. Primary: Safety, toxicity, development of GvHD and the appearance of minor H antigen-specific CD8+ T cells. Secondary: Minimal residual disease and mixed chimerism. Primary: Safety and toxicity. Secondary: Timing and magnitude of peak HA-1 specific cytotoxic T-lymphocyte responses

1/2

1/2

1

Completed

Completed

Ongoing

Ongoing

Ongoing

CTL, cytotoxic T lymphocyte; GvHD, graft-versus-host-disease; MVA, Modified Vaccinia Ankara.

unprimed healthy individuals (ISRCTN23537803). This vaccination approach may in the future lead to induction of minor H antigen-specific T cells in the HSCT donor. Cotransplantation of these cells with the HSC graft may enhance the GvL effect. Alternatively, after transplantation, the relevant CTL may be isolated from the donor and added to donor lymphocyte infusion protocols or in adoptive transfer protocols after further expansion. The results of all these studies are of great importance as they will further elucidate the feasibility and effectiveness of minor H antigen-based immunotherapy. Organ and tissue transplantation

Knowledge on the role of minor H antigen mismatches in solid organ graft survival is limited and far from conclusive. Two © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 347–360

studies on autosomal HLA class I-restricted minor H antigens, one in a large cohort of cadaveric kidney transplants matched for HLA-A, -B, and -DR (88) and another in a small cohort of HLA-identical living related transplants (89), respectively, showed no effect of minor H antigen mismatching. Studies on correlations between HY mismatching and graft survival, however, support the hypothesis that HY mismatching affects the clinical outcome of kidney transplantation (90). This discrepancy may be explained by the fact that antibodies, rather than CTL responses, are key players in graft rejection. Indeed, female recipients of male kidneys more frequently show HY antibody development after transplantation than other gender combinations (91). Moreover, the same study showed a strong correlation with acute rejection and with plasma cell infiltrates in biopsied kidneys (91). Interestingly, RPS4Y1 appeared to 355

E. Spierings

Minor histocompatibility antigens

be the most frequently recognized antigen, an HY antigen against which CD4 positive, HLA class II-restricted have been identified before (15). Such helper T cells are likely essential in generating minor H antigen-specific IgG antibody responses. Thus, when addressing the role of minor H antigens in organ transplantation, a focus on antibodies and HLA class II-restricted T-helper epitopes might be preferred to the analysis of HLA class I-restricted CTL epitopes. Both the HA-3 and HY minor histocompatibility antigens are expressed on a broad variety of cell types and tissues, including corneal tissue, which provides a rationale for their potential role in organ transplantation (19, 71). We previously investigated the role of minor H antigen mismatching on the outcome of cornea transplants (92) and observed that mismatching for the minor histocompatibility antigen A1/HY significantly promotes cornea rejection. For A1/HA-3, no significant effects were detectable. This latter finding may be related to the small sample size of the study cohort; the allele frequency of the HA-3-restricting HLA-A1 is only 10% and the HA-3 antigen has a low disparity rate of only approximately 15% (58). These factors resulted in eight HA-3 mismatched cases in the entire cornea transplant cohort. Consequently, the effects of HA-3 on tissue transplant outcome can only be studied in large study cohorts, an objective we are currently pursuing prospectively in a cohort of approximately 1500 cornea transplantations (D. Boehringer, ClinicalTrials.gov Identifier: NCT00810472). Conclusion

The identification of minor H antigens has gained an enormous momentum lately, leading to the identification of a total of 54 autosomally encoded antigens. When combining the minor H antigen frequencies and the HLA frequencies, one or more immunological disparity will be present in at least 80% of all HSCT, solid organ transplantations, or pregnancies. Thus, clinical studies on minor H antigens no longer seem to be hampered by lack of relevant cases. New genome-based techniques for minor H antigen identification provide means to rapidly expand this percentage, in order to cover almost all transplants in the future. So far, there is no uniform nomenclature for minor H antigens, making the communication error prone. The rapidly growing number of identified minor H antigens supports the construction of such a nomenclature system and a central database, in order to prevent Babylonian speech confusion. A repository containing all basic characteristics will be made available soon via the IMGT/HLA Database (93). Knowledge on minor H antigens in solid organ transplantation is limited and studies report controversial results. Elucidation of their role in solid organ transplantation, either related to harmful effector mechanisms or to protective immune regulation, is a major challenge. Particularly a better understanding of the role of minor H antigen-specific T cells in immune 356

regulation may open interesting therapeutic options to improve solid organ outcome. Minor H antigen mismatching certainly has an effect on HSCT outcome. While fully matching for all broadly expressed minor H antigens is practically not feasible, immunotherapeutic intervention using hematopoietic system-specific minor H antigens to induce GvL, is a promising strategy (67, 87). Nevertheless, the documented clinical trials show that activity in this direction is limited to a few centers, which may be caused by various reasons: (i) The logistics for such trials are rather complex and costly. In adaptive strategies, large numbers of T cells need to be generated in advance, in order to apply them as soon as clinically needed. A similar problem occurs with vaccination strategies using dendritic cells. (ii) The applicability of a single minor H antigen is limited due to the need for the correct minor H antigen disparity between donor and recipient and the correct HLA restriction molecule. At its best, approximately 12%–13% of the total HSCT population can be treated with one single antigen [(58) and Table 2]. This obstacle may be overcome by including a panel of minor H antigens, as is ongoing in trial EudraCT 2012-002435-28 (Table 5). Implementation of five minor H antigens in this trial leads to an inclusion rate of approximately 30%. (iii) The therapeutic effect of minor H antigen-based therapy may well be dependent upon other clinical parameters. For instance, hematopoietic system-specific minor H antigen mismatching leads to a particularly effective GvL effect in recipients with, but not without GvHD (67, 87). Extended investigations on such aspects are required to define the optimal conditions for minor H antigen immunotherapy. The ongoing intervention studies are likely to lead to a better insight herein. Conflict of interest

E.S. is mentioned as inventor on a patent titled “Method for prediction of an immune response against mismatched human leukocyte antigens”; number: WO 2014072467 A1. References 1. Goulmy E, Termijtelen A, Bradley BA, van Rood JJ. Alloimmunity to human H-Y. Lancet 1976: 2: 1206. 2. Wang W, Meadows LR, den Haan JM et al. Human H-Y: a male-specific histocompatibility antigen derived from the SMCY protein. Science 1995: 269: 1588–90. 3. Pierce RA, Field ED, den Haan JM et al. Cutting edge: the HLA-A*0101-restricted HY minor histocompatibility antigen originates from DFFRY and contains a cysteinylated cysteine residue as identified by a novel mass spectrometric technique. J Immunol 1999: 163: 6360–4. 4. Goulmy E, Bradley BA, Lansbergen Q, van Rood JJ. The importance of H-Y incompatibility in human organ transplantation. Transplantation 1978: 25: 315–9. 5. Verdijk RM, Kloosterman A, Pool J et al. Pregnancy induces minor histocompatibility antigen-specific cytotoxic T cells: implications for stem cell transplantation and immunotherapy. Blood 2004: 103: 1961–4.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 347–360

E. Spierings

6. Mommaas B, Stegehuis-Kamp JA, Van Halteren AG et al. Cord blood comprises antigen-experienced T cells specific for maternal minor histocompatibility antigen HA-1. Blood 2004: 105: 1823–7. 7. Rosinski KV, Fujii N, Mito JK et al. DDX3Y encodes a class I MHC-restricted H-Y antigen that is expressed in leukemic stem cells. Blood 2008: 111: 4817–26. 8. Warren EH, Gavin MA, Simpson E et al. The human UTY gene encodes a novel HLA-B8-restricted H-Y antigen. J Immunol 2000: 164: 2807–14. 9. Goulmy E, Gratama JW, Blokland E, Zwaan FE, van Rood JJ. A minor transplantation antigen detected by MHC-restricted cytotoxic T lymphocytes during graft-versus-host disease. Nature 1983: 302: 159–61. 10. van Els CA, D’Amaro J, Pool J et al. Immunogenetics of human minor histocompatibility antigens: their polymorphism and immunodominance. Immunogenetics 1992: 35: 161–5. 11. den Haan JM, Sherman NE, Blokland E et al. Identification of a graft versus host disease-associated human minor histocompatibility antigen. Science 1995: 268: 1476–80. 12. den Haan JM, Meadows LM, Wang W et al. The minor histocompatibility antigen HA-1: a diallelic gene with a single amino acid polymorphism. Science 1998: 279: 1054–7. 13. Vogt MH, de Paus RA, Voogt PJ, Willemze R, Falkenburg JH. DFFRY codes for a new human male-specific minor transplantation antigen involved in bone marrow graft rejection. Blood 2000: 95: 1100–5. 14. Vogt MH, Goulmy E, Kloosterboer FM et al. UTY gene codes for an HLA-B60-restricted human male-specific minor histocompatibility antigen involved in stem cell graft rejection: characterization of the critical polymorphic amino acid residues for T- cell recognition. Blood 2000: 96: 3126–32. 15. Spierings E, Vermeulen C, Vogt MH et al. Identification of HLA class II-restricted H-Y-specific T-helper epitope evoking CD4+ T-helper cells in H-Y-mismatched transplantation. Lancet 2003: 362: 610–5. 16. Zorn E, Miklos DB, Floyd BH et al. Minor histocompatibility antigen DBY elicits a coordinated B and T cell response after allogeneic stem cell transplantation. J Exp Med 2004: 199: 1133–42. 17. Ivanov R, Aarts T, Hol S et al. Identification of a 40S ribosomal protein S4-derived H-Y epitope able to elicit a lymphoblast-specific cytotoxic T lymphocyte response. Clin Cancer Res 2005: 11: 1694–703. 18. Spierings E, Goulmy E. Minor H antigens in medicine and biology. In: Mehra N, ed. HLA System in Medicine and Biology. New Delhi: Jaypee Brothers Medical Publishers Ltd., 2009, 544–54. 19. Spierings E, Brickner AG, Caldwell JA et al. The minor histocompatibility antigen HA-3 arises from differential proteasome-mediated cleavage of the lymphoid blast crisis (Lbc) oncoprotein. Blood 2003: 102: 621–9. 20. Brickner AG, Warren EH, Caldwell JA et al. The immunogenicity of a new human minor histocompatibility antigen results from differential antigen processing. J Exp Med 2001: 193: 195–206. 21. Spierings E, Gras S, Reiser JB et al. Steric hindrance and fast dissociation explain the lack of immunogenicity of the minor

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 347–360

Minor histocompatibility antigens

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

histocompatibility HA-1Arg null allele. J Immunol 2009: 182: 4809–16. Dolstra H, Fredrix H, Maas F et al. A human minor histocompatibility antigen specific for B cell acute lymphoblastic leukemia. J Exp Med 1999: 189: 301–8. Dolstra H, de Rijke B, Fredrix H et al. Bi-directional allelic recognition of the human minor histocompatibility antigen HB-1 by cytotoxic T lymphocytes. Eur J Immunol 2002: 32: 2748–58. Akatsuka Y, Nishida T, Kondo E et al. Identification of a polymorphic gene, BCL2A1, encoding two novel hematopoietic lineage-specific minor histocompatibility antigens. J Exp Med 2003: 197: 1489–500. Kawase T, Nannya Y, Torikai H et al. Identification of human minor histocompatibility antigens based on genetic association with highly parallel genotyping of pooled DNA. Blood 2008: 111: 3286–94. Brickner AG, Evans AM, Mito JK et al. The PANE1 gene encodes a novel human minor histocompatibility antigen that is selectively expressed in B-lymphoid cells and B-CLL. Blood 2006: 107: 3779–86. Kawase T, Akatsuka Y, Torikai H et al. Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen. Blood 2007: 110: 1055–63. Murata M, Warren EH, Riddell SR. A human minor histocompatibility antigen resulting from differential expression due to a gene deletion. J Exp Med 2003: 197: 1279–89. de Rijke B, van Horssens-Zoetbrood A, Beekman JM et al. A frame-shift polymorphism in P2X5 elicits an allogeneic cytotoxic T lymphocyte response associated with remission of chronic myeloid leukemia. J Clin Invest 2005: 115: 3506–16. Stumpf AN, van der Meijden ED, van Bergen CA, Willemze R, Falkenburg JH, Griffioen M. Identification of 4 new HLA-DR-restricted minor histocompatibility antigens as hematopoietic targets in antitumor immunity. Blood 2009: 114: 3684–92. Rotzschke O, Falk K, Wallny HJ, Faath S, Rammensee HG. Characterization of naturally occurring minor histocompatibility peptides including H-4 and H-Y. Science 1990: 249: 283–7. Mommen GP, Frese CK, Meiring HD et al. Expanding the detectable HLA peptide repertoire using electron-transfer/higher-energy collision dissociation (EThcD). Proc Natl Acad Sci U S A 2014: 111: 4507–12. Warren EH, Gavin MA, Xuereb SM et al. A single nucleotide polymorphism in the SP110 nuclear phosphoprotein gene creates a minor histocompatibility antigen whose expression is regulated by interferon-gamma. Blood 2002: 100: 73A. van de Corput L, Chaux P, van der Meijden ED, De Plaen E, Falkenburg FJH, van der Bruggen P. A novel approach to identify antigens recognized by CD4 T cells using complement-opsonized bacteria expressing a cDNA library. Leukemia 2005: 19: 279–85. Griffioen M, Honders MW, van der Meijden ED et al. Identification of 4 novel HLA-B*40:01 restricted minor histocompatibility antigens and their potential as targets for graft-versus-leukemia reactivity. Haematologica 2012: 97: 1196–204. Torikai H, Akatsuka Y, Miyazaki M et al. The human cathepsin H gene encodes two novel minor histocompatibility antigen

357

Minor histocompatibility antigens

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

358

epitopes restricted by HLA-A*3101 and -A*3303. Br J Haematol 2006: 134: 406–10. Griffioen M, van der Meijden ED, Slager EH et al. Identification of phosphatidylinositol 4-kinase type II beta as HLA class II-restricted target in graft versus leukemia reactivity. Proc Natl Acad Sci U S A 2008: 105: 3837–42. Vogt MH, van den Muijsenberg J, Goulmy E et al. The DBY gene codes for an HLA-DQ5 restricted human male specific minor histocompatibility antigen involved in GvHD. Blood 2002: 99: 3027–32. Gubarev MI, Jenkin JC, Leppert MF et al. Localization to chromosome 22 of a gene encoding a human minor histocompatibility antigen. J Immunol 1996: 157: 5448–54. Dausset J, Cann H, Cohen D, Lathrop M, Lalouel JM, White R. Centre d’etude du polymorphisme humain (CEPH): collaborative genetic mapping of the human genome. Genomics 1990: 6: 575–7. Murray JC, Buetow KH, Weber JL et al. A comprehensive human linkage map with centimorgan density. Cooperative Human Linkage Center (CHLC). Science 1994: 265: 2049–54. Gubarev MI, Jenkin JC, Otterrud BE, Leppert MF, Schallheim JM, Beatty PG. Localization to chromosome 11 of a gene encoding a human minor histocompatibility antigen. Exp Hematol 1998: 26: 976–81. Spaapen RM, Lokhorst HM, van den Oudenalder K et al. Toward targeting B cell cancers with CD4+ CTLs: identification of a CD19-encoded minor histocompatibility antigen using a novel genome-wide analysis. J Exp Med 2008: 205: 2863–72. Kamei M, Nannya Y, Torikai H et al. HapMap scanning of novel human minor histocompatibility antigens. Blood 2009: 113: 5041–8. Spaapen RM, de Kort RA, van den Oudenalder K et al. Rapid identification of clinical relevant minor histocompatibility antigens via genome-wide zygosity-genotype correlation analysis. Clin Cancer Res 2009: 15: 7137–43. Warren EH, Fujii N, Akatsuka Y et al. Therapy of relapsed leukemia after allogeneic hematopoietic cell transplantation with T cells specific for minor histocompatibility antigens. Blood 2010: 115: 3869–78. Broen K, Levenga H, Vos J et al. A polymorphism in the splice donor site of ZNF419 results in the novel renal cell carcinoma-associated minor histocompatibility antigen ZAPHIR. PLoS One 2011: 6: e21699. van Bergen CA, Rutten CE, van der Meijden ED et al. High-throughput characterization of 10 new minor histocompatibility antigens by whole genome association scanning. Cancer Res 2010: 70: 9073–83. Oostvogels R, Minnema MC, van Elk M et al. Identification of minor histocompatibility antigens based on the 1000 Genomes Project. Haematologica 2014. http://www.ncbi.nlm.nih.gov/ pubmed/25150256. DeLuca DS, Eiz-Vesper B, Ladas N, Khattab BA, Blasczyk R. High-throughput minor histocompatibility antigen prediction. Bioinformatics 2009: 25: 2411–7. Schuler MM, Donnes P, Nastke MD, Kohlbacher O, Rammensee HG, Stevanovic S. SNEP: SNP-derived epitope prediction program for minor H antigens. Immunogenetics 2005: 57: 816–20.

E. Spierings

52. Halling-Brown M, Quartey-Papafio R, Travers PJ, Moss DS. SiPep: a system for the prediction of tissue-specific minor histocompatibility antigens. Int J Immunogenet 2006: 33: 289–95. 53. Mommaas B, Kamp J, Drijfhout JW et al. Identification of a novel HLA-B60-restricted T cell epitope of the minor histocompatibility antigen HA-1 locus. J Immunol 2002: 169: 3131–6. 54. Wenandy L, Kollgaard T, Letsch A et al. The 1170 A-P single-nucleotide polymorphism (SNP) in the Her-2/neu protein (HER2) as a minor histocompatibility antigen (mHag). Leukemia 2009: 23: 1926–9. 55. Hombrink P, Hassan C, Kester MG et al. Discovery of T cell epitopes implementing HLA-peptidomics into a reverse immunology approach. J Immunol 2013: 190: 3869–77. 56. Armistead PM, Liang S, Li H et al. Common minor histocompatibility antigen discovery based upon patient clinical outcomes and genomic data. PLoS One 2011: 6: e23217. 57. Mutis T, Blokland E, Kester M, Schrama E, Goulmy E. Generation of minor histocompatibility antigen HA-1-specific cytotoxic T cells restricted by nonself HLA molecules: a potential strategy to treat relapsed leukemia after HLA-mismatched stem cell transplantation. Blood 2002: 100: 547–52. 58. Spierings E, Hendriks M, Absi L et al. Phenotype frequencies of autosomal minor histocompatibility antigens display significant differences among populations. PLoS Genet 2007: 3: e103. 59. Spierings E. Molecular typing methods for minor histocompatibility antigens. Methods Mol Biol 2014: 1109: 115–38. 60. Goulmy E. Human minor histocompatibility antigens. Curr Opin Immunol 1996: 8: 75–81. 61. Cai J, Lee J, Jankowska-Gan E et al. Minor H antigen HA-1-specific regulator and effector CD8+ T cells, and HA-1 microchimerism, in allograft tolerance. J Exp Med 2004: 199: 1017–23. 62. Van Halteren AG, Jankowska-Gan E, Joosten A et al. Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members. Blood 2009: 114: 2263–72. 63. Dierselhuis MP, Jankowska-Gan E, Blokland E et al. HY immune tolerance is common in women without male offspring. PLoS One 2014: 9: e91274. 64. Akatsuka Y, Warren EH, Gooley TA et al. Disparity for a newly identified minor histocompatibility antigen, HA-8, correlates with acute graft-versus-host disease after haematopoietic stem cell transplantation from an HLA-identical sibling. Br J Haematol 2003: 123: 671–5. 65. McCarroll SA, Bradner JE, Turpeinen H et al. Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease. Nat Genet 2009: 41: 1341–4. 66. Hobo W, Broen K, van der Velden WJ et al. Association of disparities in known minor histocompatibility antigens with relapse-free survival and graft-versus-host disease after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2013: 19: 274–82. 67. Spierings E, Kim YH, Hendriks M et al. Multicenter analyses demonstrate significant clinical effects of minor histocompatibility antigens on GvHD and GvL after

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 347–360

E. Spierings

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

HLA-matched related and unrelated hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013: 19: 1244–53. Jervis S, Collins P, Tate D et al. Increased severity of acute graft versus host disease as a result of differential expression following a homozygous gene deletion. Int J Immunogenet 2013: 40: 116–9. Gallardo D, Arostegui JI, Balas A et al. Disparity for the minor histocompatibility antigen HA-1 is associated with an increased risk of acute graft-versus-host disease (GvHD) but it does not affect chronic GvHD incidence, disease-free survival or overall survival after allogeneic human leucocyte antigen-identical sibling donor transplantation. Br J Haematol 2001: 114: 931–6. Katagiri T, Shiobara S, Nakao S et al. Mismatch of minor histocompatibility antigen contributes to a graft-versus-leukemia effect rather than to acute GVHD, resulting in long-term survival after HLA-identical stem cell transplantation in Japan. Bone Marrow Transplant 2006: 38: 681–6. de Bueger MM, Bakker A, van Rood JJ, Van der Woude F, Goulmy E. Tissue distribution of human minor histocompatibility antigens. Ubiquitous versus restricted tissue distribution indicates heterogeneity among human cytotoxic T lymphocyte-defined non-MHC antigens. J Immunol 1992: 149: 1788–94. Dickinson AM, Wang XN, Sviland L et al. In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens. Nat Med 2002: 8: 410–4. Mutis T, Gillespie G, Schrama E, Falkenburg JH, Moss P, Goulmy E. Tetrameric HLA class I-minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease. Nat Med 1999: 5: 839–42. Kim YH, Faaij CM, Van Halteren AG et al. In situ detection of HY-specific T cells in acute graft-versus-host disease-affected male skin after sex-mismatched stem cell transplantation. Biol Blood Marrow Transplant 2012: 18: 381–7. Chen Y, Sidney J, Southwood S et al. Naturally processed peptides longer than nine amino acid residues bind to the class I MHC molecule HLA-A2.1 with high affinity and in different conformations. J Immunol 1994: 152: 2874–81. Ressing ME, Sette A, Brandt RM et al. Human CTL epitopes encoded by human papillomavirus type 16 E6 and E7 identified through in vivo and in vitro immunogenicity studies of HLA-A*0201-binding peptides. J Immunol 1995: 154: 5934–43. Sette A, Vitiello A, Reherman B et al. The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. J Immunol 1994: 153: 5586–92. van der Burg SH, Visseren MJ, Brandt RM, Kast WM, Melief CJ. Immunogenicity of peptides bound to MHC class I molecules depends on the MHC-peptide complex stability. J Immunol 1996: 156: 3308–14. Parker KC, Bednarek MA, Coligan JE. Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol 1994: 152: 163–75.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 347–360

Minor histocompatibility antigens

80. Goulmy E, Schipper R, Pool J et al. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med 1996: 334: 281–5. 81. Tseng LH, Lin MT, Hansen JA et al. Correlation between disparity for the minor histocompatibility antigen HA-1 and the development of acute graft-versus-host disease after allogeneic marrow transplantation. Blood 1999: 94: 2911–4. 82. Spellman S, Warden MB, Haagenson M et al. Effects of mismatching for minor histocompatibility antigens on clinical outcomes in HLA-matched, unrelated hematopoietic stem cell transplants. Biol Blood Marrow Transplant 2009: 15: 856–63. 83. Kim YH, Vyth-Dreese FA, Schrama E et al. Exogenous addition of minor H antigen HA-1+ dendritic cells to skin tissues ex vivo causes infiltration and activation of HA-1 specific cytotoxic T cells. Biol Blood Marrow Transplant 2011: 17: 69–77. 84. Kircher B, Stevanovic S, Urbanek M et al. Induction of HA-1-specific cytotoxic T-cell clones parallels the therapeutic effect of donor lymphocyte infusion. Br J Haematol 2002: 117: 935–9. 85. Marijt WA, Heemskerk MH, Kloosterboer FM et al. Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci U S A 2003: 100: 2742–7. 86. van der Harst D, Goulmy E, Falkenburg J et al. Recognition of minor histocompatibility antigens on lymphocytic and myeloid leukemic cells by cytotoxic T-cell clones. Blood 1994: 83: 1060–6. 87. Mutis T, Brand R, Gallardo D, van Biezen A, Niederwieser D, Goulmy E. Graft-versus-host driven graft-versus-leukemia effect of minor histocompatibility antigen HA-1 in chronic myeloid leukemia patients. Leukemia 2010: 24: 1388–92. 88. Heinold A, Opelz G, Scherer S et al. Role of minor histocompatibility antigens in renal transplantation. Am J Transplant 2008: 8: 95–102. 89. Dierselhuis MP, Spierings E, Drabbels J et al. Minor H antigen matches and mismatches are equally distributed among recipients with or without complications after HLA identical sibling renal transplantation. Tissue Antigens 2013: 82: 312–6. 90. Gratwohl A, Dohler B, Stern M, Opelz G. H-Y as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study. Lancet 2008: 372: 49–53. 91. Tan JC, Wadia PP, Coram M et al. H-Y antibody development associates with acute rejection in female patients with male kidney transplants. Transplantation 2008: 86: 75–81. 92. Bohringer D, Spierings E, Enczmann J et al. Matching of the minor histocompatibility antigen HLA-A1/H-Y may improve prognosis in corneal transplantation. Transplantation 2006: 82: 1037–41. 93. Robinson J, Halliwell JA, McWilliam H, Lopez R, Parham P, Marsh SG. The IMGT/HLA database. Nucleic Acids Res 2013: 41: D1222–7. 94. Tykodi SS, Fujii N, Vigneron N et al. C19orf48 encodes a minor histocompatibility antigen recognized by CD8+ cytotoxic T cells from renal cell carcinoma patients. Clin Cancer Res 2008: 14: 5260–9. 95. Bleakley M, Otterud BE, Richardt JL et al. Leukemia-associated minor histocompatibility antigen

359

Minor histocompatibility antigens

discovery using T-cell clones isolated by in vitro stimulation of naive CD8+ T cells. Blood 2010: 115: 4923–33. 96. van Bergen CA, Kester MG, Jedema I et al. Multiple myeloma-reactive T cells recognize an activation-induced minor histocompatibility antigen encoded by the ATP-dependent interferon-responsive (ADIR) gene. Blood 2007: 109: 4089–96. 97. Wolfel C, Lennerz V, Lindemann E et al. Dissection and molecular analysis of alloreactive CD8+ T cell responses in allogeneic haematopoietic stem cell transplantation. Cancer Immunol Immunother 2008: 57: 849–57. 98. Oostvogels R, Minnema MC, van Elk M et al. Towards effective and safe immunotherapy after allogeneic stem cell

360

E. Spierings

transplantation: identification of hematopoietic-specific minor histocompatibility antigen UTA2-1. Leukemia 2013: 27: 642–9. 99. Maiers M, Gragert L, Klitz W. High-resolution HLA alleles and haplotypes in the United States population. Hum Immunol 2007: 68: 779–88. 100. Gonzalez-Galarza FF, Christmas S, Middleton D, Jones AR. Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations. Nucleic Acids Res 2011: 39: D913–9.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 347–360