Применение мультипотентных мезенхимных стромальных клеток для лечения острой реакции «трансплантат против хозяина»
DOI: 10.26442/00403660.2020.07.000757
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Kuzmina L.A., Petinati N.A., Vasilieva V.A., et al. Multipotent mesenchymal stromal cells application for acute graft versus host disease treatment. Therapeutic Archive. 2020; 92 (7): 23–30. DOI: 10.26442/00403660.2020.07.000757
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Материалы и методы. В исследование включены 35 больных, которым с целью терапии оРТПХ, резистентной к лечению, введены МСК, полученные из костного мозга здоровых доноров. Проанализированы клинические показатели пациентов, культуральные характеристики МСК, профиль экспрессии различных генов, в том числе участвующих в иммуномодуляции, экспрессия поверхностных маркеров, источник МСК, частота и количество введений МСК.
Результаты. Ответ на терапию достигнут в 74% случаев, полный ответ – у 13 (37%) пациентов, частичный ответ/клиническое улучшение также у 13 (37%). У 9 пациентов лечение оказалось неэффективным. Выявить группу пациентов, у которых можно прогнозировать хороший ответ на терапию с использованием МСК, не удалось. Обнаружены отличия в эффективных для лечения оРТПХ образцов МСК от неэффективных. В первых отмечены снижение суммарной клеточной продукции МСК, повышение экспрессии антигенов главного комплекса гистосовместимости и PDL-1.
Заключение. Эти данные позволяют выбирать необходимые образцы для лечения оРТПХ, что может улучшить клинические результаты. Терапия оРТПХ с помощью МСК показала сопоставимую эффективность по сравнению с другими подходами лечения. Учитывая низкий процент осложнений и отсутствие значимых негативных последствий, терапия МСК представляется одним из оптимальных подходов к лечению резистентных форм оРТПХ.
Ключевые слова: трансплантация аллогенных гемопоэтических стволовых клеток, реакция «трансплантат против хозяина», мультипотентные мезенхимные стромальные клетки.
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Aim. Analysis of the effectiveness of the MSCs aministration as the second- or third-line therapy of acute GVHD (aGVHD) resistant to glucocorticosteroid treatment.
Materials and methods. The study included 35 patients who received MSCs obtained from the bone marrow of healthy donors as a treatment of steroid-resistant aGVHD. The clinical parameters of patients, MSCs’ cultural characteristics, the MSC expression profile for various genes including those involved in immunomodulation, expression of cells’ surface markers, the source of MSCs, as well as the frequency and number of MSC administrations were analyzed.
Results. Response to therapy was achieved in 74% of cases, a complete response was reached in 13 (37%) patients, partial response/clinical improvement was demonstrated in 13 (37%). This treatment was ineffective in 9 patients. The prediction of a group of patients with good response to MSC therapy turned to be impossible. The differences between the effective and ineffective for the GVHD treatment MSCs samples were found. The effective ones were characterized with a decreased total MSCs production and an increase in the main histocompatibility complex and PDL-1 antigens expression.
Conclusion. These data allow to select optimal samples for aGVHD treatment that can improve clinical results. aGVHD treatment with MSCs has shown efficacy comparable to other treatment approaches. Given the low percentage of complications and the absence of significant adverse effects, MSC therapy seems to be one of the optimal approaches to the treatment of resistant forms of GVHD.
Keywords: allogeneic hematopoietic stem cell transplantation, graft versus host disease, multipotent mesenchymal stromal cells.
2. Choi SW, Levine JE, Ferrara JLM. Pathogenesis and management of graft-versus-host disease. Immunol Allergy Clin North Am. 2010;30:75-101 doi: 10.1016/j.iac.2009.10.001
3. Allen JL, Fore MS, Wooten J, et al. B cells from patients with chronic GVHD are activated and primed for survival via BAFF-mediated pathways. Blood. 2012;120:2529-36. doi: 10.1182/blood-2012-06-438911
4. Perkins J, Field T, Kim J, et al. A Randomized Phase II Trial Comparing Tacrolimus and Mycophenolate Mofetil to Tacrolimus and Methotrexate for Acute Graft-versus-Host Disease Prophylaxis. Biol. Blood Marrow Transplant. 2010;16:937-47.
doi: 10.1016/j.bbmt.2010.01.010
5. Nakane T, Nakamae H, Yamaguchi T, et al. Use of mycophenolate mofetil and a calcineurin inhibitor in allogeneic hematopoietic stem-cell transplantation from HLA-matched siblings or unrelated volunteer donors: Japanese multicenter phase II trials. Int J Hematol. 2017;105:485-96. doi: 10.1007/s12185-016-2154-4
6. Zeiser R, Blazar BR. Acute graft-versus-host disease – Biologic process, prevention, and therapy. N Engl J Med. 2017;377:2167-79. doi: 10.1056/NEJMra1609337
7. Hill L, Alousi A, Kebriaei P, et al. New and emerging therapies for acute and chronic graft versus host disease. Ther Adv Hematol. 2018;9:21-46.
doi: 10.1177/2040620717741860
8. Ruutu T, Gratwohl A, De Witte T, et al. Niederwieser, Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Transplant. 2014;49:168-73. doi: 10.1038/bmt.2013.107
9. Bader P, Kuçi Z, Bakhtiar S, et al. Effective treatment of steroid and therapy-refractory acute graft-versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM). Bone Marrow Transplant. 2018;53:852-62. doi: 10.1038/s41409-018-0102-z
10. Deeg HJ. How I treat refractory acute GVHD. Blood. 2007;109:4119-26. doi: 10.1182/blood-2006-12-041889
11. Elgaz S, Kuçi Z, Kuçi S, et al. Clinical Use of Mesenchymal Stromal Cells in the Treatment of Acute Graft-versus-Host Disease. Transfus Med Hemotherapy. 2019;46:27-34. doi: 10.1159/000496809
12. Kitko CL, Levine JE. Extracorporeal photopheresis in prevention and treatment of acute GVHD. Transfus Apher Sci. 2015;52:151-6. doi: 10.1016/j.transci.2015.02.001
13. Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439-41. doi: 10.1016/S0140-6736(04)16104-7
14. Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107:367-72. doi: 10.1182/blood-2005-07-2657
15. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8:726-36. doi: 10.1038/nri2395
16. Dan YY, Riehle KJ, Lazaro C, et al. Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages. Proc Natl Acad Sci U S A. 2006;103:9912-7. doi: 10.1073/pnas.0603824103
17. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315-7. doi: 10.1080/14653240600855905
18. Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30:42-8.
19. Jones BJ, McTaggart SJ. Immunosuppression by mesenchymal stromal cells: from culture to clinic. Exp Hematol. 2008;36:733-41. doi: 10.1016/j.exphem.2008.03.006
20. Le Blanc K, Davies LC. MSCs-cells with many sides. Cytotherapy. 2018;20:273-8.
doi: 10.1016/j.jcyt.2018.01.009
21. Zhao L, Chen S, Yang P, et al. The role of mesenchymal stem cells in hematopoietic stem cell transplantation: prevention and treatment of graft-versus-host disease. Stem Cell Res Ther. 2019;10:182. doi: 10.1186/s13287-019-1287-9
22. Fisher SA, Cutler A, Doree C, et al. Mesenchymal stromal cells as treatment or prophylaxis for acute or chronic graft-versus-host disease in haematopoietic stem cell transplant (HSCT) recipients with a haematological condition. Cochrane Database Syst Rev. 2019;1:CD009768. doi: 10.1002/14651858.CD009768.pub2
23. Galleu A, Milojkovic D, Deplano S, et al. Mesenchymal stromal cells for acute graft-versus-host disease: response at 1 week predicts probability of survival. Br J Haematol. 2019;185:89-92. doi: 10.1111/bjh.15749
24. Von Dalowski F, Kramer M, Wermke M, et al. Mesenchymal Stromal Cells for Treatment of Acute Steroid-Refractory Graft Versus Host Disease: Clinical Responses and Long-Term Outcome. Stem Cells. 2016;34:357-66. doi: 10.1002/stem.2224
25. Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371:1579-86. doi: 10.1016/S0140-6736(08)60690-X
26. Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from hl-a-matched sibling donors1. Transplantation. 1974;18:295-304. doi: 10.1097/00007890-197410000-00001
27. Kuzmina LA, Petinati NA, Parovichnikova EN, et al. Multipotent Mesenchymal Stromal Cells for the Prophylaxis of Acute Graft-versus-Host Disease-A Phase II Study. Stem Cells Int. 2012;2012:968213. doi: 10.1155/2012/968213
28. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc. 2008;3:1101-8. doi: 10.1038/nprot.2008.73
29. Galipeau J, Sensébé L. Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities. Cell Stem Cell. 2018;22:824-33.
doi: 10.1016/j.stem.2018.05.004
30. Krasowska-Kwiecien A, Gozdzik J, Jarocha D, et al. Mesenchymal Stem Cells as a Salvage Treatment for Severe Refractory Graft-vs-Host Disease in Children After Bone Marrow Transplantation. Transplant Proc. 2019;51:880-9. doi: 10.1016/j.transproceed.2019.01.023
31. Kurtzberg J, Prockop S, Teira P, et al. Allogeneic human mesenchymal stem cell therapy (remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients. Biol Blood Marrow Transplant. 2014;20:229-35. doi: 10.1016/j.bbmt.2013.11.001
32. Lukomska B, Stanaszek L, Zuba-Surma E, et al. Challenges and Controversies in Human Mesenchymal Stem Cell Therapy. Stem Cells Int. 2019;2019:1-10. doi: 10.1155/2019/9628536
33. Resnick IB, Barkats C, Shapira MY, et al. Treatment of severe steroid resistant acute GVHD with mesenchymal stromal cells (MSC). Am J Blood Res. 2013;3:225-38.
34. Sánchez-Guijo F, Caballero-Velázquez T, López-Villar O, et al. Sequential third-party mesenchymal stromal cell therapy for refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20:1580-5. doi: 10.1016/j.bbmt.2014.06.015
35. Chen X, Wang C, Yin J, et al. Efficacy of mesenchymal stem cell therapy for steroid-refractory acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis. PLoS One. 2015;10.
doi: 10.1371/journal.pone.0136991
36. Ball LM, Bernardo ME, Roelofs H, et al. Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid-refractory, grade III–IV acute graft-versus-host disease. Br J Haematol. 2013;163:501-9. doi: 10.1111/bjh.12545
37. Le Blanc K, Tammik L, Sundberg B, et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol. 2003;57:11-20.
38. Deans RJ, Moseley АB. Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol. 2000;28:875-84.
39. Kapranov NM, Davydova YO, Galtseva IV, et al. Effect of priming of multipotent mesenchymal stromal cells with interferon γ on their immunomodulating properties. Biochem. 2017;82. doi: 10.1134/S000629791710008X.
40. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027-34. doi: 10.1084/jem.192.7.1027
41. Zhironkina OA, Shipounova IN, Bigildeev AE, et al. Proliferative potential of multipotent mesenchymal stromal cells from human bone marrow. Bull Exp Biol Med. 2012;152:543-7. doi: 10.1007/s10517-012-1571-5
42. Sotiropoulou PA, Perez SA, Salagianni M, et al. Characterization of the Optimal Culture Conditions for Clinical Scale Production of Human Mesenchymal Stem Cells. Stem Cells. 2006;24:462-71. doi: 10.1634/stemcells.2004-0331
43. Kapranov NM, Davydova YO, Gal’tseva IV, et al. Individual Differences of Multipotent Mesenchymal Stromal Cells Manifesting in during Interaction with Lymphocytes. Bull Exp Biol Med. 2018;165:584-8. doi: 10.1007/s10517-018-4218-3
________________________________________________
1. Zeiser R, Blazar BR, Acute Graft-versus-Host Disease – Biologic Process, Prevention, and Therapy. N Engl J Med. 2017;377:2167-79. doi: 10.1056/NEJMra1609337
2. Choi SW, Levine JE, Ferrara JLM. Pathogenesis and management of graft-versus-host disease. Immunol Allergy Clin North Am. 2010;30:75-101 doi: 10.1016/j.iac.2009.10.001
3. Allen JL, Fore MS, Wooten J, et al. B cells from patients with chronic GVHD are activated and primed for survival via BAFF-mediated pathways. Blood. 2012;120:2529-36. doi: 10.1182/blood-2012-06-438911
4. Perkins J, Field T, Kim J, et al. A Randomized Phase II Trial Comparing Tacrolimus and Mycophenolate Mofetil to Tacrolimus and Methotrexate for Acute Graft-versus-Host Disease Prophylaxis. Biol. Blood Marrow Transplant. 2010;16:937-47. doi: 10.1016/j.bbmt.2010.01.010
5. Nakane T, Nakamae H, Yamaguchi T, et al. Use of mycophenolate mofetil and a calcineurin inhibitor in allogeneic hematopoietic stem-cell transplantation from HLA-matched siblings or unrelated volunteer donors: Japanese multicenter phase II trials. Int J Hematol. 2017;105:485-96. doi: 10.1007/s12185-016-2154-4
6. Zeiser R, Blazar BR. Acute graft-versus-host disease – Biologic process, prevention, and therapy. N Engl J Med. 2017;377:2167-79. doi: 10.1056/NEJMra1609337
7. Hill L, Alousi A, Kebriaei P, et al. New and emerging therapies for acute and chronic graft versus host disease. Ther Adv Hematol. 2018;9:21-46. doi: 10.1177/2040620717741860
8. Ruutu T, Gratwohl A, De Witte T, et al. Niederwieser, Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Transplant. 2014;49:168-73. doi: 10.1038/bmt.2013.107
9. Bader P, Kuçi Z, Bakhtiar S, et al. Effective treatment of steroid and therapy-refractory acute graft-versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM). Bone Marrow Transplant. 2018;53:852-62. doi: 10.1038/s41409-018-0102-z
10. Deeg HJ. How I treat refractory acute GVHD. Blood. 2007;109:4119-26. doi: 10.1182/blood-2006-12-041889
11. Elgaz S, Kuçi Z, Kuçi S, et al. Clinical Use of Mesenchymal Stromal Cells in the Treatment of Acute Graft-versus-Host Disease. Transfus Med Hemotherapy. 2019;46:27-34. doi: 10.1159/000496809
12. Kitko CL, Levine JE. Extracorporeal photopheresis in prevention and treatment of acute GVHD. Transfus Apher Sci. 2015;52:151-6. doi: 10.1016/j.transci.2015.02.001
13. Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439-41. doi: 10.1016/S0140-6736(04)16104-7
14. Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107:367-72. doi: 10.1182/blood-2005-07-2657
15. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8:726-36. doi: 10.1038/nri2395
16. Dan YY, Riehle KJ, Lazaro C, et al. Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages. Proc Natl Acad Sci U S A. 2006;103:9912-7. doi: 10.1073/pnas.0603824103
17. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315-7. doi: 10.1080/14653240600855905
18. Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30:42-8.
19. Jones BJ, McTaggart SJ. Immunosuppression by mesenchymal stromal cells: from culture to clinic. Exp Hematol. 2008;36:733-41. doi: 10.1016/j.exphem.2008.03.006
20. Le Blanc K, Davies LC. MSCs-cells with many sides. Cytotherapy. 2018;20:273-8. doi: 10.1016/j.jcyt.2018.01.009
21. Zhao L, Chen S, Yang P, et al. The role of mesenchymal stem cells in hematopoietic stem cell transplantation: prevention and treatment of graft-versus-host disease. Stem Cell Res Ther. 2019;10:182. doi: 10.1186/s13287-019-1287-9
22. Fisher SA, Cutler A, Doree C, et al. Mesenchymal stromal cells as treatment or prophylaxis for acute or chronic graft-versus-host disease in haematopoietic stem cell transplant (HSCT) recipients with a haematological condition. Cochrane Database Syst Rev. 2019;1:CD009768. doi: 10.1002/14651858.CD009768.pub2
23. Galleu A, Milojkovic D, Deplano S, et al. Mesenchymal stromal cells for acute graft-versus-host disease: response at 1 week predicts probability of survival. Br J Haematol. 2019;185:89-92. doi: 10.1111/bjh.15749
24. Von Dalowski F, Kramer M, Wermke M, et al. Mesenchymal Stromal Cells for Treatment of Acute Steroid-Refractory Graft Versus Host Disease: Clinical Responses and Long-Term Outcome. Stem Cells. 2016;34:357-66. doi: 10.1002/stem.2224
25. Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371:1579-86. doi: 10.1016/S0140-6736(08)60690-X
26. Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from hl-a-matched sibling donors1. Transplantation. 1974;18:295-304. doi: 10.1097/00007890-197410000-00001
27. Kuzmina LA, Petinati NA, Parovichnikova EN, et al. Multipotent Mesenchymal Stromal Cells for the Prophylaxis of Acute Graft-versus-Host Disease-A Phase II Study. Stem Cells Int. 2012;2012:968213. doi: 10.1155/2012/968213
28. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc. 2008;3:1101-8. doi: 10.1038/nprot.2008.73
29. Galipeau J, Sensébé L. Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities. Cell Stem Cell. 2018;22:824-33. doi: 10.1016/j.stem.2018.05.004
30. Krasowska-Kwiecien A, Gozdzik J, Jarocha D, et al. Mesenchymal Stem Cells as a Salvage Treatment for Severe Refractory Graft-vs-Host Disease in Children After Bone Marrow Transplantation. Transplant Proc. 2019;51:880-9. doi: 10.1016/j.transproceed.
2019.01.023
31. Kurtzberg J, Prockop S, Teira P, et al. Allogeneic human mesenchymal stem cell therapy (remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients. Biol Blood Marrow Transplant. 2014;20:229-35. doi: 10.1016/j.bbmt.2013.11.001
32. Lukomska B, Stanaszek L, Zuba-Surma E, et al. Challenges and Controversies in Human Mesenchymal Stem Cell Therapy. Stem Cells Int. 2019;2019:1-10. doi: 10.1155/2019/9628536
33. Resnick IB, Barkats C, Shapira MY, et al. Treatment of severe steroid resistant acute GVHD with mesenchymal stromal cells (MSC). Am J Blood Res. 2013;3:225-38.
34. Sánchez-Guijo F, Caballero-Velázquez T, López-Villar O, et al. Sequential third-party mesenchymal stromal cell therapy for refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20:1580-5. doi: 10.1016/j.bbmt.2014.06.015
35. Chen X, Wang C, Yin J, et al. Efficacy of mesenchymal stem cell therapy for steroid-refractory acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis. PLoS One. 2015;10. doi: 10.1371/journal.pone.0136991
36. Ball LM, Bernardo ME, Roelofs H, et al. Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid-refractory, grade III–IV acute graft-versus-host disease. Br J Haematol. 2013;163:501-9. doi: 10.1111/bjh.12545
37. Le Blanc K, Tammik L, Sundberg B, et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol. 2003;57:11-20.
38. Deans RJ, Moseley АB. Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol. 2000;28:875-84.
39. Kapranov NM, Davydova YO, Galtseva IV, et al. Effect of priming of multipotent mesenchymal stromal cells with interferon γ on their immunomodulating properties. Biochem. 2017;82. doi: 10.1134/S000629791710008X.
40. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027-34. doi: 10.1084/jem.192.7.1027
41. Zhironkina OA, Shipounova IN, Bigildeev AE, et al. Proliferative potential of multipotent mesenchymal stromal cells from human bone marrow. Bull Exp Biol Med. 2012;152:543-7. doi: 10.1007/s10517-012-1571-5
42. Sotiropoulou PA, Perez SA, Salagianni M, et al. Characterization of the Optimal Culture Conditions for Clinical Scale Production of Human Mesenchymal Stem Cells. Stem Cells. 2006;24:462-71. doi: 10.1634/stemcells.2004-0331
43. Kapranov NM, Davydova YO, Gal’tseva IV, et al. Individual Differences of Multipotent Mesenchymal Stromal Cells Manifesting in during Interaction with Lymphocytes. Bull Exp Biol Med. 2018;165:584-8. doi: 10.1007/s10517-018-4218-3
ФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава России, Москва, Россия
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L.A. Kuzmina, N.A. Petinati, V.A. Vasilieva, M.V. Dovydenko, M.Yu. Drokov, Yu.O. Davydova, N.M. Kapranov, N.V. Sats, Yu.A. Chabaeva, S.M. Kulikov, T.V. Gaponova, N.I. Drize, E.N. Parovichnikova, V.G. Savchenko
National Research Center for Hematology, Moscow, Russia