OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press84310.17650/1818-8346-2023-18-3-115-124BASIC RESEARCHФУНДАМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯ В ПРАКТИЧЕСКОЙ МЕДИЦИНЕ НА СОВРЕМЕННОМ ЭТАПЕMinor histocompatibility antigens represented in HLA-A*02:01 and their search strategiesМинорные антигены гистосовместимости, представляемые в HLA-А*02:01, и стратегии их поискаhttps://orcid.org/0000-0002-9423-1269RomanyukD. S.РоманюкД. С.
Russian Federation

125167

4 Novyy Zykovskiy Proezd

Moscow

125167

Новый Зыковский пр-д, 4

Москва

https://orcid.org/0000-0001-5917-7554PilunovA. M.ПилуновА. М.
Russian Federation

125167

4 Novyy Zykovskiy Proezd

Moscow

125167

Новый Зыковский пр-д, 4

Москва

https://orcid.org/0000-0001-7129-6062EfimovG. A.ЕфимовГ. А.
Germany

51429

Friedrich-Ebert-Straße 68

Bergisch Gladbach

51429

ул. Фридрих-Элберт, 68

Бергиш-Гладбах

https://orcid.org/0000-0002-8664-6341BogolyubovaA. V.БоголюбоваА. В.
Russian Federation

Apollinariya Vasil’evna Bogolyubova

125167

4 Novyy Zykovskiy Proezd

Moscow

Аполлинария Васильевна Боголюбова 

125167

Новый Зыковский пр-д, 4

Москва

apollinariya.bogolyubova@gmail.comhttps://orcid.org/0000-0001-6177-3566ParovichnikovaE. N.ПаровичниковаЕ. Н.
Russian Federation

125167

4 Novyy Zykovskiy Proezd

Moscow

125167

Новый Зыковский пр-д, 4

Москва

National Medical Research Center for Hematology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава РоссииMiltenyi Biotec B. V. & Co. KGМилтени Биотек ГмбХ130920231831151241309202313092023https://oncohematology.abvpress.ru/ongm/article/view/843

   Minor histocompatibility antigens (MiHAs) are polymorphic peptides on the cell surface derived from self-proteins that are capable to induce an immune response during allogeneic hematopoietic stem cells transplantation. Their presentation occurs in the context of the certain major histocompatibility complex (HLA – human leucocyte antigen) alleles. One of the most common HLA alleles is HLA-A*02:01. Accordingly, for a significant number of donors and recipients pairs, it is possible to use the MiHAs presented in the HLA-A*02:01 as a target for relapsed leukemia therapy. This review discusses the main known MiHAs presented in the context of HLA-A*02:01, their characteristics and approaches used for identification. The described approaches may be used to search for new MiHAs for immunotherapy.

   Минорные антигены гистосовместимости (МАГ) – полиморфные пептиды на поверхности клеток, представляющие собой фрагменты собственных белков организма, которые способны вызывать иммунный ответ при аллогенной трансплантации гемопоэтических стволовых клеток. Их презентация на поверхности клетки обусловлена присутствием определенных аллелей главного комплекса гистосовместимости (HLA – human leucocyte antigen). Одним из самых распространенных аллелей HLA является HLA-A*02:01. Соответственно, для значительного количества пар доноров и реципиентов возможно использование МАГ, представляемых в HLA-A*02:01, в качестве мишени при направленной терапии рецидивов лейкозов. В обзоре обсуждаются основные из известных МАГ, презентируемых в контексте HLA-A*02:01, их характеристики и подходы, использованные для идентификации. Описанные подходы могут применяться для поиска новых МАГ в контексте мишеней для иммунотерапии.

immunotherapyminor histocompatibility antigenallogenic hematopoietic stem cell transplantationиммунотерапияминорный антиген гистосовместимостиаллогенная трансплантация гемопоэтических стволовых клетокThe work was supported by the State Foundation of the Ministry of Health of RussiaРабота выполнена при поддержке Государственного задания Минздрава РоссииDausset J. Iso-leuco-anticorps. Acta Haematol 1958;20(1–4): 156–66. DOI: 10.1159/000205478Efimov G.A., Vdovin A.S., Grigoryev A.A. et al. Immunobiology of acute graft-versus-host disease. Meditsinskaya immunologiya = Medical Immunology 2016;17(6):499–516. (In Russ.). DOI: 10.15789/1563-0625-2015-6-499-516Ефимов Г.А., Вдовин А.С., Григорьев А.А. и др. Иммунобиология острой реакции «трансплантат против хозяина». Медицинская иммунология 2015;17(6):499–516. DOI: 10.15789/1563-0625-2015-6-499-516Rötzschke O., Falk K., Wallny H. et al. Characterization of naturally occurring minor histocompatibility peptides including H-4 and H-Y. Science 1990;249(4966):283–7. DOI: 10.1126/science.1695760Townsend A.R.M., Rothbard J., Gotch F.M. et al. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell 1986;44(6): 959–68. DOI: 10.1016/0092-8674(86)90019-xSnell G. Methods for the study of histocompatibility genes. J Genet 1948;49(2):87–108. DOI: 10.1007/BF02986826Counce S., Smith P., Barth R., Snell G.D. Strong and weak histocompatibility gene differences in mice and their role in the rejection of homografts of tumors and skin. Ann Surg 1956;144(2):198–204. DOI: 10.1097/00000658-195608000-00009Goulmy E. Minor histocompatibility antigens in man and their role in transplantation. Transplant Rev 1988;2:29–53. DOI: 10.1016/s0955-470x(88)80005-3Bjorkman P., Saper M., Samraoui B. et al. Structure of the human class I histocompatibility antigen, HLA-A2. Nature 1987;329(6139):506–12. DOI: 10.1038/329506a0Bjorkman P., Saper M., Samraoui B. et al. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 1987;329(6139):512–8. DOI: 10.1038/329512a0Bassani-Sternberg M., Chong C., Guillaume P. et al. Deciphering HLA-I motifs across HLA peptidomes improves neo-antigen predictions and identifies allostery regulating HLA specificity. PLoS Comput Biol 2017;13(8):e1005725. DOI: 10.1371/journal.pcbi.1005725González-Galarza F.F., Takeshita L., Santos E. et al. Allele frequency net 2015 update: new features for HLA epitopes, KIR and disease and HLA adverse drug reaction associations. Nucleic Acids Res 2015;43:D784–8. DOI: 10.1093/nar/gku1166Griffioen M., van Bergen C.A.M., Falkenburg J.H.F. Autosomal minor histocompatibility antigens: how genetic variants create diversity in immune targets. Front Immunol 2016;7:100. DOI: 10.3389/fimmu.2016.00100Oostvogels R., Kneppers E., Minnema M. et al. Efficacy of hostdendritic cell vaccinations with or without minor histocompatibility antigen loading, combined with donor lymphocyte infusion in multiple myeloma patients. Bone Marrow Transplant 2016;52(2):228–37. DOI: 10.1038/bmt.2016.250Meij P., Jedema I., van der Hoorn M. et al. Generation and administration of HA-1-specific T-cell lines for the treatment of patients with relapsed leukemia after allogeneic stem cell transplantation: a pilot study. Haematologica 2012;97(8):1205–8. DOI: 10.3324/haematol.2011.053371De Rijke B., van Horssen-Zoetbrood A., Beekman J.M. et al. A frameshift polymorphism in P2X5 elicits an allogeneic cytotoxic T lymphocyte response associated with remission of chronic myeloid leukemia. J Clin Invest 2005;115(12):3506–16. DOI: 10.1172/jci24832Spierings E., Brickner A.G., Caldwell J.A. et al. The minor histocompatibility antigen HA-3 arises from differential proteasomemediated cleavage of the lymphoid blast crisis (Lbc) oncoprotein. Blood 2003;102(2):621–9. DOI: 10.1182/blood-2003-01-0260Brickner A.G., Warren E.H., Caldwell J.A. et al. The immunogenicity of a new human minor histocompatibility antigen results from differential antigen processing. J Exp Medicine 2001;193(2):195–206. DOI: 10.1084/jem.193.2.195Den Haan J.M.M., Meadows L.M., Wang W. et al. The minor histocompatibility antigen HA-1: a diallelic gene with a single amino acid polymorphism. Science 1998;279(5353):1054–7. DOI: 10.1126/science.279.5353.1054Pierce R.A., Field E.D., Mutis T. et al. The HA-2 minor histocompatibility antigen is derived from a diallelic gene encoding a novel human class I myosin protein. J Immunol 2001;167(6): 3223–30. DOI: 10.4049/jimmunol.167.6.3223Bijen H.M., Hassan C., Kester M.G.D. et al. Specific T cell responses against minor histocompatibility antigens cannot generally be explained by absence of their allelic counterparts on the cell surface. Proteomics 2017;18(12):1700250. DOI: 10.1002/pmic.201700250Granados D., Rodenbrock A., Laverdure J.P. et al. Proteogenomicbased discovery of minor histocompatibility antigens with suitable features for immunotherapy of hematologic cancers. Leukemia 2016;30(6):1344–54. DOI: 10.1038/leu.2016.22Goulmy E., Termijtelen A., Bradley B.A. et al. HLA restriction of non-HLA-A, -B, -C and -D cell mediated lympholysis (CML). Tissue Antigens 1976;8(5):317–26. DOI: 10.1111/j.1399-0039.1976.tb00583.xPilunov A.M., Romaniuk D.S., Efimov G.A., Savchenko V.G. Minor histocompatibility antigens as targets for T-cell immunotherapy. Gematologiya i transfuziologiya = Russian Journal of Hematology and Transfusiology 2021;66(3):322–45. (In Russ.). DOI: 10.35754/0234-5730-2021-66-3-322-345Пилунов А.М., Романюк Д.С., Ефимов Г.А., Савченко В.Г. Минорные антигены гистосовместимости как мишени Т-клеточной иммунотерапии. Гематология и трансфузиология 2021;66(3):322–45. DOI: 10.35754/0234-5730-2021-66-3-322-345Romaniuk D.S., Khmelevskaya A.A., Postovskaya A.M. et al. Clinically relevant minor histocompatibility antigens for russian patients undergoing hematopoietic stem cell transplantation. Meditsinskaya immunologiya = Medical Immunology 2019;21(5):847–60. (In Russ.). DOI: 10.15789/1563-0625-2019-5-847-860Романюк Д.С., Хмелевская А.А., Постовская А.М. и др. Клинически значимые минорные антигены гистосовместимости для российских пациентов, получающих трансплантацию стволовых клеток крови. Медицинская иммунология 2019;21(5):847–60. DOI: 10.15789/1563-0625-2019-5-847-860Wenandy L., Kollgaard T., Letsch A. et al. The 1170 A–P singlenucleotide polymorphism (SNP) in the Her-2/neu protein (HER2) as a minor histocompatibility antigen (mHag). Leukemia 2009;23(10):1926–9. DOI: 10.1038/leu.2009.112Den Haan J.M., Sherman N.E., Blokland E. et al. Identification of a graft versus host disease-associated human minor histocompatibility antigen. Science 1995;268(5216):1476–80. DOI: 10.1126/science.7539551Oostvogels R., Minnema M.C., van Elk M. et al. Towards effective and safe immunotherapy after allogeneic stem cell transplantation: identification of hematopoietic-specific minor histocompatibility antigen UTA2-1. Leukemia 2013;27(3):642–9. DOI: 10.1038/leu.2012.277Van Bergen C.A.M., Kester M.G.D., 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(9):4089–96. DOI: 10.1182/blood-2006-08-043935Hombrink P., Hassan C., Kester M.G. et al. Identification of biological relevant minor histocompatibility antigens within the B-lymphocyte-derived HLA-ligandome using a reverse immunology approach. Clin Cancer Res 2015;21(9):2177–86. DOI: 10.1158/1078-0432.CCR-14-2188Tykodi S.S., 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(16):5260–9. DOI: 10.1158/1078-0432.ccr-08-0028Wölfel 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 2007;57(6):849–57. DOI: 10.1007/s00262-007-0421-1Van Bergen C.A.M., Rutten C.E., van der Meijden E.D. et al. Highthroughput characterization of 10 new minor histocompatibility antigens by whole genome association scanning. Cancer Res 2010;70(22):9073–83. DOI: 10.1158/0008-5472.can-10-1832Armistead P.M., Liang S., Li H. et al. Common minor histocompatibility antigen discovery based upon patient clinical outcomes and genomic data. PLoS One 2010;6(8):e23217. DOI: 10.1371/journal.pone.0023217Hombrink P., Hassan C., Kester M.G.D. et al. Discovery of T cell epitopes implementing HLA-peptidomics into a reverse immunology approach. J Immunol 2013;190(8):3869–77. DOI: 10.4049/jimmunol.1202351Kamei M., Nannya Y., Torikai H. et al. HapMap scanning of novel human minor histocompatibility antigens. Blood 2009;113(21):5041–8. DOI: 10.1182/blood-2008-07-171678Van Bergen C.A., van Luxemburg-Heijs S.A., de Wreede L.C. et al. Selective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell response. J Clin Invest 2017;127(2):517–29. DOI: 10.1172/JCI86175Sherry S.T., Ward M.H., Kholodov M. et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 2001;29(1):308–11. DOI: 10.1093/nar/29.1.308Cunningham F., Allen J.E., Allen J. et al. Ensembl 2022. Nucleic Acids Res 2021;50(D1):D988–95. DOI: 10.1093/nar/gkab1049Goulmy E., van Leeuwen A., Blokland E. et al. Major histocompatibility complex-restricted H-Y-specific antibodies and cytotoxic T lymphocytes may recognize different self determinants. J Exp Medicine 1982;155(5):1567–72. DOI: 10.1084/jem.155.5.1567Goulmy E., Termijtelen A., Bradley B.A., van Rood J.J. Y-antigen killing by T cells of women is restricted by HLA. Nature 1977;266(5602):544–5. DOI: 10.1038/266544a0Goulmy E., Gratama J.W., Blokland E. et al. A minor transplantation antigen detected by MHC-restricted cytotoxic T lymphocytes during graft-versus-host disease. Nature 1983;302(5904):159–61. DOI: 10.1038/302159a0Goulmy E., van der Poel J., Giphart M., van Rood J.J. Analysis of the functional epitopes on different HLA-A2 molecules. Immunogenetics 1984;20(1):13–21. DOI: 10.1007/bf00373443Goulmy E., Gratama J.W., Blokland E. et al. Recognition of an – as yet unknown – minor transplantation antigen by post-transplantation lymphocytes from an AML patient. Exp Hematol 1982.Van Els C.A., D’Amaro J., Pool J. et al. Immunogenetics of human minor histocompatibility antigens: their polymorphism and immunodominance. Immunogenetics 1992;35(3):161–5. DOI: 10.1007/bf00185109Goulmy 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(5):281–5. DOI: 10.1056/nejm199602013340501De Bueger M., Bakker A., Rood J.J.V. et al. 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(5):1788–94.Mutis T., Goulmy E. Hematopoietic system-specific antigens as targets for cellular immunotherapy of hematological malignancies. Semin Hematol 2002;39(1):23–31. DOI: 10.1053/shem.2002.29248Meadows L., Wang W., den Haan J.M. et al. The HLA-A*02:01-restricted H-Y antigen contains a posttranslationally modified cysteine that significantly affects T cell recognition. Immunity 1997;6(3):273–81. DOI: 10.1016/s1074-7613(00)80330-1Chen 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(6):2874–81.Suh W.K., Cohen-Doyle M.F., Fruh K. et al. Interaction of MHC class I molecules with the transporter associated with antigen processing. Science 1994;264(5163):1322–6. DOI: 10.1126/science.8191286Murata M., Warren E.H., Riddell S.R. A human minor histocompatibility antigen resulting from differential expression due to a gene deletion. J Exp Med 2003;197(10):1279–89. DOI: 10.1084/jem.20030044Consortium I.H., Frazer K.A., Ballinger D.G. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 2007;449(7164):851–61. DOI: 10.1038/nature06258Sudo T., Kamikawaji N., Kimura A. et al. Differences in MHC class I self peptide repertoires among HLA-A2 subtypes. J Immunol 1995;155(10):4749–56.Andreatta M., Nielsen M. Gapped sequence alignment using artificial neural networks: application to the MHC class I system. Bioinformatics 2016;32(4):511–7. DOI: 10.1093/bioinformatics/btv639Sudmant P.H., Rausch T., Gardner E.J. et al. An integrated map of structural variation in 2,504 human genomes. Nature 2015;526(7571):75–81. DOI: 10.1038/nature15394Rongcun Y., Salazar-Onfray F., Charo J. et al. Identification of new HER2/neu-derived peptide epitopes that can elicit specific CTL against autologous and allogeneic carcinomas and melanomas. J Immunol 1999;163(2):1037–44.Olayioye M.A., Neve R.M., Lane H.A., Hynes N.E. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 2000;19(13):3159–67. DOI: 10.1093/emboj/19.13.3159Ayoub N.M., Al-Shami K.M., Yaghan R.J. Immunotherapy for HER2-positive breast cancer: recent advances and combination therapeutic approaches. Breast Cancer (Dove Medical Press) 2019;11:53–69. DOI: 10.2147/bctt.s175360Tobias J., Garner-Spitzer E., Drinić M. et al. Vaccination against Her-2/neu, with focus on peptide-based vaccines. Esmo Open 2022;7(1):100361. DOI: 10.1016/j.esmoop.2021.100361Szöőr Á., Tóth G., Zsebik B. et al. Trastuzumab derived HER2-specific CARs for the treatment of trastuzumab-resistant breast cancer: CAR T cells penetrate and eradicate tumors that are not accessible to antibodies. Cancer Lett 2020;484:1–8. DOI: 10.1016/j.canlet.2020.04.008Xu J., Meng Q., Sun H. et al. HER2-specific chimeric antigen receptor-T cells for targeted therapy of metastatic colorectal cancer. Cell Death Dis 2021;12(12):1109. DOI: 10.1038/s41419-021-04100-0Abrahao-Machado L.F., Scapulatempo-Neto C. HER2 testing in gastric cancer: An update. World J Gastroenterol 2016;22(19):4619–25. DOI: 10.3748/wjg.v22.i19.4619Joshi S.K., Keck J.M., Eide C.A. et al. ERBB2/HER2 mutations are transforming and therapeutically targetable in leukemia. Leukemia 2020;34(10):2798–804. DOI: 10.1038/s41375-020-0844-7Schuler M.M., Dönnes P., Nastke M.D. et al. SNEP: SNP-derived Epitope Prediction program for minor H antigens. Immunogenetics 2005;57(11):816–20. DOI: 10.1007/s00251-005-0054-5Spaapen R.M., Lokhorst H.M., 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(12):2863–72. DOI: 10.1084/jem.20080713Holloway P.A., Kaldenhoven N., Kok-Schoemaker H.M. et al. A class II-restricted cytotoxic T-cell clone recognizes a human minor histocompatibility antigen with a restricted tissue distribution. Br J Haematol 2004;128(1):73–81. DOI: 10.1111/j.1365-2141.2004.05283.xWarren E.H., Otterud B.E., Linterman R.W. et al. Feasibility of using genetic linkage analysis to identify the genes encoding T cell-defined minor histocompatibility antigens. Tissue Antigens 2002;59(4):293–303. DOI: 10.1034/j.1399-0039.2002.590407.xMarijt W.A.E., Heemskerk M.H.M., Kloosterboer F.M. 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 USA 2003;100:2742–7. DOI: 10.1073/pnas.0530192100