The T Cell Receptor Repertoire Diversity Following Hematopoietic Stem Cell Transplantation
-
Fahimeh Zamani
,
Reza Mirfakhraie
,
Sayyed Reza Safaee Nodehi
,
Yaghoub Mollaei-Kandelous
,
Hossein Jafari
,
Mohammad Farahmand
,
Farhad Rezaei
,
Majid Teymoori-Rad
,
Abolfazl Movafagh
Abstract
Immune reconstitution after hematopoietic stem cell transplantation (HSCT) with a conditioning regimen has appeared to be a promising treatment for autoimmune diseases and hematologic malignancies. This study aimed to assess the T cell receptor (TCR) repertoire diversity in CD4+ cells of patients with hematological malignancies who received allogeneic or autologous HSCT.
The diversity of the TCR repertoire was evaluated in 13 patients with hematologic malignancies before and four months after HSCT. Amino acid changes in the 25 Vβ families were evaluated using Spectratyping and data were presented as Hamming distance (HD). HD more than 20% was considered a change in TCR repertoire after HSCT.
The mean HD was significantly changed after transplantation in all Vβ gene families, with most amino acid changes in p4 and p22 families. There was a strong negative correlation between the HD as the index of TCR repertoire and age (r = −0.62,). The results revealed no association between HD mean and parameters such as sex, disease, conditioning regimen, and type of transplantation.
Our data revealed that commonly used conditioning regimens in Iran could successfully cause TCR repertoire diversity in patients with hematologic malignancies in the short term. The amount of change in TCR repertoire was inversely correlated with the increasing age of patients.
1. Epah J, Schafer R. Implications of hematopoietic stem cells heterogeneity for gene therapies. Gene Ther. 2021;28(9):528-41.
2. Li Y, Xu L. Evaluation of TCR repertoire diversity in patients after hematopoietic stem cell transplantation. Stem Cell Investig. 2015;2:17.
3. Swart JF, Delemarre EM, van Wijk F, Boelens JJ, Kuball J, van Laar JM, et al. Haematopoietic stem cell transplantation for autoimmune diseases. Nat Rev Rheumatol. 2017;13(4):244-56.
4. Abrahamsson S, Muraro PA. Immune re-education following autologous hematopoietic stem cell transplantation. Autoimmunity. 2008;41(8):577-84.
5. Arruda LCM, Malmegrim KCR, Lima-Junior JR, Clave E, Dias JBE, Moraes DA, et al. Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients. Blood Adv. 2018;2(2):126-41.
6. Delemarre EM, van den Broek T, Mijnheer G, Meerding J, Wehrens EJ, Olek S, et al. Autologous stem cell transplantation aids autoimmune patients by functional renewal and TCR diversification of regulatory T cells. Blood. 2016;127(1):91-101.
7. Muraro PA, Douek DC, Packer A, Chung K, Guenaga FJ, Cassiani-Ingoni R, et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J Exp Med. 2005;201(5):805-16.
8. Kalincik T, Brown JWL, Robertson N, Willis M, Scolding N, Rice CM, et al. Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study. Lancet Neurol. 2017;16(4):271-81.
9. Mancardi G, Sormani MP, Muraro PA, Boffa G, Saccardi R. Intense immunosuppression followed by autologous haematopoietic stem cell transplantation as a therapeutic strategy in aggressive forms of multiple sclerosis. Mult Scler. 2018;24(3):245-55.
10. de Koning C, Nierkens S, Boelens JJ. Strategies before, during, and after hematopoietic cell transplantation to improve T-cell immune reconstitution. Blood. 2016;128(23):2607-15.
11. Park H, Byun JM, Koh Y, Yoon SS, Park H, Lee J, et al. Comparison of Different Conditioning Regimens in Allogeneic Hematopoietic Stem-Cell Transplantation Shows Superiority of Total Body Irradiation-Based Regimen for Younger Patients With Acute Leukemia: A Nationwide Study. Clin Lymphoma Myeloma Leuk. 2019;19(11):e605-e15.
12. Storb R. History of pediatric stem cell transplantation. Pediatr Transplant. 2004;8 Suppl 5:5-11.
13. Jethava YS, Sica S, Savani B, Socola F, Jagasia M, Mohty M, et al. Conditioning regimens for allogeneic hematopoietic stem cell transplants in acute myeloid leukemia. Bone Marrow Transplant. 2017;52(11):1504-11.
14. Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood. 2014;124(3):344-53.
15. Hunger SP, Loh KM, Baker KS, Schultz KR. Controversies of and unique issues in hematopoietic cell transplantation for infant leukemia. Biol Blood Marrow Transplant. 2009;15(1 Suppl):79-83.
16. Atkins HL, Bowman M, Allan D, Anstee G, Arnold DL, Bar-Or A, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016;388(10044):576-85.
17. Passweg JR, Baldomero H, Bader P, Basak GW, Bonini C, Duarte R, et al. Is the use of unrelated donor transplantation leveling off in Europe? The 2016 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2018;53(9):1139-48.
18. Snowden JA, Badoglio M, Labopin M, Giebel S, McGrath E, Marjanovic Z, et al. Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases. Blood Adv. 2017;1(27):2742-55.
19. Seif F, Khoshmirsafa M, Mousavi M, Beshkar P, Rafeian-Kopaei M, Bagheri N, et al. Interleukin-21 receptor might be a novel therapeutic target for the treatment of rheumatoid arthritis. Journal of Experimental & Clinical Medicine. 2014;6(2):57-61.
20. Currier JR, Deulofeut H, Barren KS, Kehn PJ, Robinson MA. Mitogens, superantigens, and nominal antigens elicit distinctive patterns of TCRB CDR3 diversity. Human immunology. 1996;48(1-2):39-51.
21. Currier JR, Robinson MA. Spectratype/immunoscope analysis of the expressed TCR repertoire. Current protocols in immunology. 2000;38(1):10.28. 1-10.28. 4.
22. Toubai T, Hirate D, Shono Y, Ota S, Ibata M, Mashiko S, et al. Chimerism and T-cell receptor repertoire analysis after unrelated cord blood transplantation with a reduced-intensity conditioning regimen following autologous stem cell transplantation for multiple myeloma. Int J Lab Hematol. 2008;30(1):75-81.
23. Yew PY, Alachkar H, Yamaguchi R, Kiyotani K, Fang H, Yap KL, et al. Quantitative characterization of T-cell repertoire in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2015;50(9):1227-34.
24. Fozza C, Barraqueddu F, Corda G, Contini S, Virdis P, Dore F, et al. Study of the T-cell receptor repertoire by CDR3 spectratyping. J Immunol Methods. 2017;440:1-11.
25. Gaballa A, Clave E, Uhlin M, Toubert A, Arruda LC. Evaluating thymic function after human hematopoietic stem cell transplantation in the personalized medicine era. Frontiers in Immunology. 2020;11:1341.
26. Danby R, Rocha V. Improving engraftment and immune reconstitution in umbilical cord blood transplantation. Front Immunol. 2014;5:68.
27. Seggewiss R, Einsele H. Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update. Blood. 2010;115(19):3861-8.
28. van Den Brink M, Leen AM, Baird K, Merchant M, Mackall C, Bollard CM. Enhancing immune reconstitution: from bench to bedside. Biol Blood Marrow Transplant. 2013;19(1 Suppl):S79-83.
29. Wiegering V, Eyrich M, Winkler B, Schlegel PG. Comparison of immune reconstitution after allogeneic vs. autologous stem cell transplantation in 182 pediatric recipients. Pediatric Hematology Oncology Journal. 2017;2(1):2-6.
30. Farge D, Arruda LCM, Brigant F, Clave E, Douay C, Marjanovic Z, et al. Long-term immune reconstitution and T cell repertoire analysis after autologous hematopoietic stem cell transplantation in systemic sclerosis patients. Journal of Hematology & Oncology. 2017;10(1):21.
31. Farge D, Henegar C, Carmagnat M, Daneshpouy M, Marjanovic Z, Rabian C, et al. Analysis of immune reconstitution after autologous bone marrow transplantation in systemic sclerosis. Arthritis Rheum. 2005;52(5):1555-63.
32. Pockley AG, Lindsay JO, Foulds GA, Rutella S, Gribben JG, Alexander T, et al. Immune Reconstitution After Autologous Hematopoietic Stem Cell Transplantation in Crohn's Disease: Current Status and Future Directions. A Review on Behalf of the EBMT Autoimmune Diseases Working Party and the Autologous Stem Cell Transplantation In Refractory CD-Low Intensity Therapy Evaluation Study Investigators. Front Immunol. 2018;9:646.
33. Ruder J, Rex J, Obahor S, Docampo MJ, Muller AMS, Schanz U, et al. NK Cells and Innate-Like T Cells After Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis. Front Immunol. 2021;12:794077.
34. Szodoray P, Varoczy L, Papp G, Barath S, Nakken B, Szegedi G, et al. Immunological reconstitution after autologous stem cell transplantation in patients with refractory systemic autoimmune diseases. Scand J Rheumatol. 2012;41(2):110-5.
35. Arruda LC, Clave E, Moins-Teisserenc H, Douay C, Farge D, Toubert A. Resetting the immune response after autologous hematopoietic stem cell transplantation for autoimmune diseases. Curr Res Transl Med. 2016;64(2):107-13.
36. Lutter L, Spierings J, van Rhijn-Brouwer FCC, van Laar JM, van Wijk F. Resetting the T Cell Compartment in Autoimmune Diseases With Autologous Hematopoietic Stem Cell Transplantation: An Update. Front Immunol. 2018;9:767.
37. Hamidieh AA, Behfar M, Babaki AE, Jalali A, Hosseini AS, Jahani M, et al. Hematopoietic SCT in Iranian children 1991-2012. Bone Marrow Transplant. 2015;50(4):517-22.
38. Chen X, Hale GA, Barfield R, Benaim E, Leung WH, Knowles J, et al. Rapid immune reconstitution after a reduced-intensity conditioning regimen and a CD3-depleted haploidentical stem cell graft for paediatric refractory haematological malignancies. Br J Haematol. 2006;135(4):524-32.
39. Hakim FT, Memon SA, Cepeda R, Jones EC, Chow CK, Kasten-Sportes C, et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest. 2005;115(4):930-9.
40. Lin RJ, Elias HK, van den Brink MRM. Immune Reconstitution in the Aging Host: Opportunities for Mechanism-Based Therapy in Allogeneic Hematopoietic Cell Transplantation. Front Immunol. 2021;12:674093.
41. Britanova OV, Putintseva EV, Shugay M, Merzlyak EM, Turchaninova MA, Staroverov DB, et al. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J Immunol. 2014;192(6):2689-98.
42. Gkazi AS, Margetts BK, Attenborough T, Mhaldien L, Standing JF, Oakes T, et al. Clinical T Cell Receptor Repertoire Deep Sequencing and Analysis: An Application to Monitor Immune Reconstitution Following Cord Blood Transplantation. Front Immunol. 2018;9:2547.
2. Li Y, Xu L. Evaluation of TCR repertoire diversity in patients after hematopoietic stem cell transplantation. Stem Cell Investig. 2015;2:17.
3. Swart JF, Delemarre EM, van Wijk F, Boelens JJ, Kuball J, van Laar JM, et al. Haematopoietic stem cell transplantation for autoimmune diseases. Nat Rev Rheumatol. 2017;13(4):244-56.
4. Abrahamsson S, Muraro PA. Immune re-education following autologous hematopoietic stem cell transplantation. Autoimmunity. 2008;41(8):577-84.
5. Arruda LCM, Malmegrim KCR, Lima-Junior JR, Clave E, Dias JBE, Moraes DA, et al. Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients. Blood Adv. 2018;2(2):126-41.
6. Delemarre EM, van den Broek T, Mijnheer G, Meerding J, Wehrens EJ, Olek S, et al. Autologous stem cell transplantation aids autoimmune patients by functional renewal and TCR diversification of regulatory T cells. Blood. 2016;127(1):91-101.
7. Muraro PA, Douek DC, Packer A, Chung K, Guenaga FJ, Cassiani-Ingoni R, et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J Exp Med. 2005;201(5):805-16.
8. Kalincik T, Brown JWL, Robertson N, Willis M, Scolding N, Rice CM, et al. Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study. Lancet Neurol. 2017;16(4):271-81.
9. Mancardi G, Sormani MP, Muraro PA, Boffa G, Saccardi R. Intense immunosuppression followed by autologous haematopoietic stem cell transplantation as a therapeutic strategy in aggressive forms of multiple sclerosis. Mult Scler. 2018;24(3):245-55.
10. de Koning C, Nierkens S, Boelens JJ. Strategies before, during, and after hematopoietic cell transplantation to improve T-cell immune reconstitution. Blood. 2016;128(23):2607-15.
11. Park H, Byun JM, Koh Y, Yoon SS, Park H, Lee J, et al. Comparison of Different Conditioning Regimens in Allogeneic Hematopoietic Stem-Cell Transplantation Shows Superiority of Total Body Irradiation-Based Regimen for Younger Patients With Acute Leukemia: A Nationwide Study. Clin Lymphoma Myeloma Leuk. 2019;19(11):e605-e15.
12. Storb R. History of pediatric stem cell transplantation. Pediatr Transplant. 2004;8 Suppl 5:5-11.
13. Jethava YS, Sica S, Savani B, Socola F, Jagasia M, Mohty M, et al. Conditioning regimens for allogeneic hematopoietic stem cell transplants in acute myeloid leukemia. Bone Marrow Transplant. 2017;52(11):1504-11.
14. Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood. 2014;124(3):344-53.
15. Hunger SP, Loh KM, Baker KS, Schultz KR. Controversies of and unique issues in hematopoietic cell transplantation for infant leukemia. Biol Blood Marrow Transplant. 2009;15(1 Suppl):79-83.
16. Atkins HL, Bowman M, Allan D, Anstee G, Arnold DL, Bar-Or A, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016;388(10044):576-85.
17. Passweg JR, Baldomero H, Bader P, Basak GW, Bonini C, Duarte R, et al. Is the use of unrelated donor transplantation leveling off in Europe? The 2016 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2018;53(9):1139-48.
18. Snowden JA, Badoglio M, Labopin M, Giebel S, McGrath E, Marjanovic Z, et al. Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases. Blood Adv. 2017;1(27):2742-55.
19. Seif F, Khoshmirsafa M, Mousavi M, Beshkar P, Rafeian-Kopaei M, Bagheri N, et al. Interleukin-21 receptor might be a novel therapeutic target for the treatment of rheumatoid arthritis. Journal of Experimental & Clinical Medicine. 2014;6(2):57-61.
20. Currier JR, Deulofeut H, Barren KS, Kehn PJ, Robinson MA. Mitogens, superantigens, and nominal antigens elicit distinctive patterns of TCRB CDR3 diversity. Human immunology. 1996;48(1-2):39-51.
21. Currier JR, Robinson MA. Spectratype/immunoscope analysis of the expressed TCR repertoire. Current protocols in immunology. 2000;38(1):10.28. 1-10.28. 4.
22. Toubai T, Hirate D, Shono Y, Ota S, Ibata M, Mashiko S, et al. Chimerism and T-cell receptor repertoire analysis after unrelated cord blood transplantation with a reduced-intensity conditioning regimen following autologous stem cell transplantation for multiple myeloma. Int J Lab Hematol. 2008;30(1):75-81.
23. Yew PY, Alachkar H, Yamaguchi R, Kiyotani K, Fang H, Yap KL, et al. Quantitative characterization of T-cell repertoire in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2015;50(9):1227-34.
24. Fozza C, Barraqueddu F, Corda G, Contini S, Virdis P, Dore F, et al. Study of the T-cell receptor repertoire by CDR3 spectratyping. J Immunol Methods. 2017;440:1-11.
25. Gaballa A, Clave E, Uhlin M, Toubert A, Arruda LC. Evaluating thymic function after human hematopoietic stem cell transplantation in the personalized medicine era. Frontiers in Immunology. 2020;11:1341.
26. Danby R, Rocha V. Improving engraftment and immune reconstitution in umbilical cord blood transplantation. Front Immunol. 2014;5:68.
27. Seggewiss R, Einsele H. Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update. Blood. 2010;115(19):3861-8.
28. van Den Brink M, Leen AM, Baird K, Merchant M, Mackall C, Bollard CM. Enhancing immune reconstitution: from bench to bedside. Biol Blood Marrow Transplant. 2013;19(1 Suppl):S79-83.
29. Wiegering V, Eyrich M, Winkler B, Schlegel PG. Comparison of immune reconstitution after allogeneic vs. autologous stem cell transplantation in 182 pediatric recipients. Pediatric Hematology Oncology Journal. 2017;2(1):2-6.
30. Farge D, Arruda LCM, Brigant F, Clave E, Douay C, Marjanovic Z, et al. Long-term immune reconstitution and T cell repertoire analysis after autologous hematopoietic stem cell transplantation in systemic sclerosis patients. Journal of Hematology & Oncology. 2017;10(1):21.
31. Farge D, Henegar C, Carmagnat M, Daneshpouy M, Marjanovic Z, Rabian C, et al. Analysis of immune reconstitution after autologous bone marrow transplantation in systemic sclerosis. Arthritis Rheum. 2005;52(5):1555-63.
32. Pockley AG, Lindsay JO, Foulds GA, Rutella S, Gribben JG, Alexander T, et al. Immune Reconstitution After Autologous Hematopoietic Stem Cell Transplantation in Crohn's Disease: Current Status and Future Directions. A Review on Behalf of the EBMT Autoimmune Diseases Working Party and the Autologous Stem Cell Transplantation In Refractory CD-Low Intensity Therapy Evaluation Study Investigators. Front Immunol. 2018;9:646.
33. Ruder J, Rex J, Obahor S, Docampo MJ, Muller AMS, Schanz U, et al. NK Cells and Innate-Like T Cells After Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis. Front Immunol. 2021;12:794077.
34. Szodoray P, Varoczy L, Papp G, Barath S, Nakken B, Szegedi G, et al. Immunological reconstitution after autologous stem cell transplantation in patients with refractory systemic autoimmune diseases. Scand J Rheumatol. 2012;41(2):110-5.
35. Arruda LC, Clave E, Moins-Teisserenc H, Douay C, Farge D, Toubert A. Resetting the immune response after autologous hematopoietic stem cell transplantation for autoimmune diseases. Curr Res Transl Med. 2016;64(2):107-13.
36. Lutter L, Spierings J, van Rhijn-Brouwer FCC, van Laar JM, van Wijk F. Resetting the T Cell Compartment in Autoimmune Diseases With Autologous Hematopoietic Stem Cell Transplantation: An Update. Front Immunol. 2018;9:767.
37. Hamidieh AA, Behfar M, Babaki AE, Jalali A, Hosseini AS, Jahani M, et al. Hematopoietic SCT in Iranian children 1991-2012. Bone Marrow Transplant. 2015;50(4):517-22.
38. Chen X, Hale GA, Barfield R, Benaim E, Leung WH, Knowles J, et al. Rapid immune reconstitution after a reduced-intensity conditioning regimen and a CD3-depleted haploidentical stem cell graft for paediatric refractory haematological malignancies. Br J Haematol. 2006;135(4):524-32.
39. Hakim FT, Memon SA, Cepeda R, Jones EC, Chow CK, Kasten-Sportes C, et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest. 2005;115(4):930-9.
40. Lin RJ, Elias HK, van den Brink MRM. Immune Reconstitution in the Aging Host: Opportunities for Mechanism-Based Therapy in Allogeneic Hematopoietic Cell Transplantation. Front Immunol. 2021;12:674093.
41. Britanova OV, Putintseva EV, Shugay M, Merzlyak EM, Turchaninova MA, Staroverov DB, et al. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J Immunol. 2014;192(6):2689-98.
42. Gkazi AS, Margetts BK, Attenborough T, Mhaldien L, Standing JF, Oakes T, et al. Clinical T Cell Receptor Repertoire Deep Sequencing and Analysis: An Application to Monitor Immune Reconstitution Following Cord Blood Transplantation. Front Immunol. 2018;9:2547.
| Files | ||
| Issue | Vol 21 No 5 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i5.11045 | |
| Keywords | ||
| Hamming distance Hematopoietic stem cell transplantation Spectratyping T cell receptor | ||
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How to Cite
1.
Zamani F, Mirfakhraie R, Safaee Nodehi SR, Mollaei-Kandelous Y, Jafari H, Farahmand M, Rezaei F, Teymoori-Rad M, Movafagh A. The T Cell Receptor Repertoire Diversity Following Hematopoietic Stem Cell Transplantation. Iran J Allergy Asthma Immunol. 2022;21(5):584-593.
