mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2019-5-847-860mimmun-1660Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESКЛИНИЧЕСКИ ЗНАЧИМЫЕ МИНОРНЫЕ АНТИГЕНЫ ГИСТОСОВМЕСТИМОСТИ ДЛЯ РОССИЙСКИХ ПАЦИЕНТОВ, ПОЛУЧАЮЩИХ ТРАНСПЛАНТАЦИЮ СТВОЛОВЫХ КЛЕТОК КРОВИCLINICALLY RELEVANT MINOR HISTOCOMPATIBILITY ANTIGENS FOR RUSSIAN PATIENTS UNDERGOING HEMATOPOIETIC STEM CELL TRANSPLANTATIONhttps://orcid.org/0000-0002-9423-1269РоманюкД. С.RomaniukD. S.

магистр биологии, научный сотрудник лаборатории трансплантационной иммунологии

Москва

MSc (Biology), Research Associate, Laboratory of Transplantation Immunology

Moscow

dimrnk@gmail.comХмелевскаяА. А.KhmelevskayaA. A.

бакалавр биологии, стажер-исследователь лаборатории трансплантационной иммунологии

Москва

BSc (Biology), Research Intern, Laboratory of Transplantation Immunology

Moscow

humbiomy@gmail.comПостовскаяА. М.PostovskayaA. M.

магистр биологии, стажер лаборатории трансплантационной иммунологии

Москва

MSc (Biology), Research Intern, Laboratory of Transplantation Immunology

Moscow

postovskaya.ann@gmail.comМалькоД. Б.MalkoD. B.

к.техн.н., научный сотрудник лаборатории трансплантационной иммунологии

Москва

PhD (Technics), Research Associate, Laboratory of Transplantation Immunology

Moscow

malko.d@blood.ruКузьминоваЕ. П.KuzminovaE. P.

к.б.н., старший научный сотрудник лаборатории тканевого типирования

Москва

PhD (Biology), Senior Research Associate, Laboratory of Tissue Typing

Moscow

kuzminova.e@blood.ruХамагановаЕ. Г.KhamaganovaE. G.

д.б.н., заведующий лабораторией тканевого типирования

Москва

PhD, MD (Biology), Head, Laboratory of Tissue Typing

Moscow

khamaganova.e@blood.ruЕфимовГ. А.EfimovG. A.

Ефимов Григорий Александрович, к.б.н., заведующий лабораторией трансплантационной иммунологии 

125167, Россия, Москва, Новый Зыковский проезд, 4.

Тел.: 8 (495) 612-44-43.

Efimov Grigory A., PhD (Biology), Head, Laboratory of Transplantation Immunology

125167, Russian Federation, Moscow, Novy Zykovsky pass., 4.

Phone: 7 (495) 612-44-43.

efimov.g@blood.ruФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения РФРоссияNational Research Center for HematologyRussian Federation201912032019215847860Copyright © Романюк Д.С., Хмелевская А.А., Постовская А.М., Малько Д.Б., Кузьминова Е.П., Хамаганова Е.Г., Ефимов Г.А., 20192019Романюк Д.С., Хмелевская А.А., Постовская А.М., Малько Д.Б., Кузьминова Е.П., Хамаганова Е.Г., Ефимов Г.А.Romaniuk D.S., Khmelevskaya A.A., Postovskaya A.M., Malko D.B., Kuzminova E.P., Khamaganova E.G., Efimov G.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/2019-21-5-9

Трансплантация гемопоэтических стволовых клеток (ТГСК) от здорового донора применяется при лечении неопластических заболеваний кроветворной системы. Одним из осложнений трансплантации является развитие аллоиммунной реакции «трансплантат против хозяина» (РТПХ), которая в случае полной совместимости по аллелям генов главного комплекса гистосовместимости (HLA) обусловлена различиями в пептидах, представляемых молекулами HLA на поверхности клеток. Такие полиморфные пептиды – минорные антигены гистосовместимости (МАГ) – могут происходить из любых генов, в том числе специфично экспрессированных в клетках кроветворной системы. В этом случае развивается реакция «трансплантат против лейкоза» (РТПЛ), которая препятствует развитию рецидива. Одним из самых частых аллелей HLA для европейской части России является аллель A*02:01. Нами были оценены частоты 20 полиморфизмов, приводящих к появлению МАГ, представляемых в контексте молекул A*02:01, для потенциальных доноров костного мозга или стволовых клеток крови (СКК) регистра ФГБУ «НМИЦ гематологии» МЗ РФ, также мы определили встречаемость иммуногенных несоответствий в реальных парах донор – реципиент. Всего было генотипировано 608 потенциальных доноров, 90 доноров и 92 пациента. При сравнении с публичными базами данных частот полиморфизмов было показано, что частоты аллелей МАГ в российской популяции наиболее близки к частотам европейской популяции. На основании этих данных была рассчитана вероятность возникновения после ТГСК аллоиммунного ответа, направленного против МАГ: в 33 и 75% случаев родственной и неродственной ТГСК, соответственно, ожидается три и более генетических иммуногенных несоответствия (ИН). Подсчет реального числа ИН в 20 родственных и 20 неродственных парах донор – реципиент согласуется с теоретическим расчетом. Исходя из определенных частот, самыми перспективными для российской популяции мишенями для разработки направленной клеточной терапии злокачественных заболеваний кроветворной системы являются МАГ LB-NDC80-1P/A, LB-CCL4-1T и HA-1. Полученные данные можно использовать при планировании алло-ТГСК для российских пациентов.

Hematopoietic stem cell transplantation (HSCT) from healthy donors is used for blood cancer treatment. Alloreactive graft-versus-host disease (GvHD) is one of the post-transplant detrimental side effects, and the main reason for GVHD after HSCT fully matched for human leukocyte peptide antigens (HLA) presented by HLA molecules on cell surface. These polymorphic peptides, minor histocompatibility antigens (MiHA), arise from any genes, including those expressed at hematopoietic tissues. The latter may lead to the s.c. graft-versus-leukemia effect (GvL), thus preventing relapse of a malignancy. A*02:01 is one of the most frequent HLA alleles for European part of Russia. We assessed frequencies for 20 MiHA-encoded genetic polymorphisms, presented via A*02:01 allele, for plausible bone marrow donors, or hematopoietic stem cells (HSC) from the Donor Registry at Russian National Research Center for Hematology, we have also determined a number of immunogenic mismatches for these 20 MiHA in real donor – recipient pairs. A total of 608 potential donors, 90 donors and 92 recipients were genotyped. Using public data, we have shown that frequencies for MiHA coding genes are most close to appropriate frequencies among the European population. We have calculated probability of MiHA-specific alloimmune response after HSCT: there are chances of 33 and 75% for three or more immunogenic mismatches (IM) for related and unrelated HSCTs, respectively. Real frequencies for immune mismatch in 20 related and 20 unrelated donor – recipient pairs are in accordance with estimated theoretical probabilities. As based on the calculated frequencies, we suggest the LB-NDC80- 1P/A, LB-CCL4- 1T, and HA-1 MiHA to be the most promising minor antigens for targeted cell therapies of hematopoietic tissue malignancies. The data obtained could be used for planning allo-HSCTs in Russian patients.

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The authors declare that there are no conflicts of interest present.