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New autoimmune diseases after autologous hematopoietic stem cell transplantation for multiple sclerosis

Bone Marrow Transplantation volume 56, pages 1509–1517 (2021)Cite this article

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Abstract

Secondary autoimmune diseases (2ndADs), most frequently autoimmune cytopenias (AICs), were first described after allogeneic hematopoietic stem cell transplantation (HSCT) undertaken for malignant and hematological indications, occurred at a prevalence of ~5–6.5%, and were attributed to allogeneic immune imbalances in the context of graft versus host disease, viral infections, and chronic immunosuppression. Subsequently, 2ndADs were reported to complicate roughly 2–14% of autologous HSCTs performed for an autoimmune disease. Alemtuzumab in the conditioning regimen has been identified as a risk for development of 2ndADs after either allogeneic or autologous HSCT and is consistent with the high rates of 2ndADs when using alemtuzumab as monotherapy. Due to the significant consequences but variable incidence, depending on conditioning regimen, of 2ndADs and similarity in known immune reconstitution kinetics after autologous HSCT for autoimmune diseases and after alemtuzumab monotherapy, we propose that an imbalance between B and T lineage regeneration early after HSCT may underlie the pathogenesis of 2ndADs.

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Fig. 1: Schematic T and B cell immune reconstitution in months after autologous HSCT for autoimmune disease.

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References

  1. Sherer Y, Shoenfeld Y. Autoimmune diseases and autoimmunity post-bone marrow transplantation. Bone Marrow Transpl. 1998;22:873–81.

    Article  CAS  Google Scholar 

  2. Daikeler T, Tyndall A. Autoimmunity following haematopoietic stem-cell transplantation. Best Pract Res Clin Haematol. 2007;20:349e360.

    Article  CAS  Google Scholar 

  3. Kalwak K, Gorczyńska E, Wójcik D, Toporski J, Turkiewicz D, Slociak M, et al. Late-onset idiopathic thrombocytopenic purpura correlates with rapid B-cell recovery after allogeneic T-cell-depleted peripheral blood progenitor cell transplantation in children. Transpl Proc. 2002;34:3374–7.

    Article  CAS  Google Scholar 

  4. Kruizinga MD, van Tol MJD, Bekker V, Netelenbos T, Smiers FJ, Bresters D, et al. Risk factors, treatment and immune dysregulation in autoimmune cytopenia after allogeneic hematopoietic stem cell transplantation in pediatric patients. Biol Blood Marrow Transpl. 2018;24:772–8.

    Article  CAS  Google Scholar 

  5. Daikeler T, Labopin M, Ruggeri A, Crotta A, Abinun M, Hussein AA, et al. New autoimmune diseases after cord blood transplantation: a retrospective study of EUROCORD and the autoimmune disease working party of the European Group for Blood and Marrow Transplantation. Blood 2013;121:1059–64.

    Article  CAS  PubMed  Google Scholar 

  6. Lv W, Qu H, Wu M, Fan Z, Huang F, Xu N, et al. Autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation in adults: A southern China multicentre experience. Cancer Med. 2019;8:6549–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Miller PDE, Snowden JA, De Latour RP, Iacobelli S, Eikema DJ, Knol C, et al. Autoimmune cytopenias (AIC) following allogeneic haematopoietic stem cell transplant for acquired aplastic anaemia: a joint study of the Autoimmune Diseases and Severe Aplastic Anaemia Working Parties (ADWP/SAAWP) of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transpl. 2020;55:441–51.

    Article  CAS  Google Scholar 

  8. Loh Y, Oyama Y, Statkute L, Quigley K, Yaung K, Gonda E, et al. Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used. Blood. 2007;109:2643–2548.

    Article  CAS  PubMed  Google Scholar 

  9. Daikeler T, Labopin M, Di Gioia M, Abinun M, Alexander T, Miniati I, et al. Secondary autoimmune diseases occurring after HSCT for an autoimmune disease: a retrospective study of the EBMT Autoimmune Disease Working Party. Blood. 2011;118:1693–8.

    Article  CAS  PubMed  Google Scholar 

  10. Marrie RA, Cohen J, Stuve O, Trojano M, Sørensen PS, Reingold S, et al. A systematic review of the incidence and prevalence of comorbidity in multiple sclerosis: Overview. Mult Scler. 2015;21:263–81.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Alexander T, Greco R, Snowden JA. Hematopoietic stem cell transplantation for autoimmune disease. Ann Rev Med. 2021;72:215–28.

    Article  CAS  PubMed  Google Scholar 

  12. Openshaw H, Lund BT, Kashyap A, Atkinson R, Sniecinski I, Weiner LP, et al. Peripheral blood stem cell transplantation in multiple sclerosis with busulfan and cyclophosphamide conditioning: report of toxicity and immunological monitoring. Biol Blood Marrow Transpl. 2000;6:563–75.

    Article  CAS  Google Scholar 

  13. 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 multicenter single-group phase 2 trial. Lancet. 2016;388:576–85.

    Article  PubMed  Google Scholar 

  14. Fassas A, Kimiskidis VK, Sakellari I, Kapinas K, Anagnostopoulos A, Tsimourtou V, et al. Long-term results of stem cell transplantation for MS: a single-center experience. Neurology. 2011;76:1066–70.

    Article  CAS  PubMed  Google Scholar 

  15. Burt RK, Cohen BA, Russell E, Spero K, Joshi A, Oyama Y, et al. Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores. Blood. 2003;102:2373–8.

    Article  CAS  PubMed  Google Scholar 

  16. Nash RA, Bowen JD, McSweeney PA, Pavletic SZ, Maravilla KR, Park MS, et al. High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Blood. 2003;102:2364–72.

    Article  CAS  PubMed  Google Scholar 

  17. Bowen JD, Kraft GH, Wundes A, Guan Q, Maravilla KR, Gooley TA, et al. Autologous hematopoietic cell transplantation following high-dose immunosuppressive therapy for advanced multiple sclerosis: long-term results. Bone Marrow Transpl. 2012;47:946–51.

    Article  CAS  Google Scholar 

  18. Samijn JP, te Boekhorst PA, Mondria T, van Doorn PA, Flach HZ, van der Meché FG, et al. Intense T cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis. J Neurol Neurosurg Psychiatry. 2006;77:46–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ni XS, Ouyang J, Zhu WH, Wang C, Chen B. Autologous hematopoietic stem cell transplantation for progressive multiple sclerosis: report of efficacy and safety at three yr of follow up in 21 patients. Clin Transpl. 2006;20:485–9.

    Article  Google Scholar 

  20. Xu J, Ji BX, Su L, Dong HQ, Sun XJ, Liu CY. Clinical outcomes after autologous hematopoietic stem cell transplantation in patients with progressive multiple sclerosis. Chin Med J. 2006;119:1851–5.

    Article  PubMed  Google Scholar 

  21. Saccardi R, Mancardi GL, Solari A, Bosi A, Bruzzi P, Di Bartolomeo P, et al. Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life. Blood. 2005;105:2601–7.

    Article  CAS  PubMed  Google Scholar 

  22. Saiz A, Blanco Y, Carreras E, Berenguer J, Rovira M, Pujol T, et al. Clinical and MRI outcome after autologous hematopoietic stem cell transplantation in MS. Neurology. 2004;62:282–4.

    Article  CAS  PubMed  Google Scholar 

  23. Shevchenko YL, Novik AA, Kuznetsov AN, Afanasiev BV, Lisukov IA, Kozlov VA, et al. High dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Exp Hematol. 2008;36:922–8.

    Article  CAS  PubMed  Google Scholar 

  24. Mancardi GL, Sormani MP, Di Gioia M, Vuolo L, Gualandi F, Amato MP, et al. Autologous haematopoietic stem cell transplantation with an intermediate intensity conditioning regimen in multiple sclerosis: the Italian multicentre experience. Mult Scler. 2012;18:835–42.

    Article  CAS  PubMed  Google Scholar 

  25. Fagius J, Lundgren J, Oberg G. Early highly aggressive MS successfully treated by haematopoietic stem cell transplantation. Mult Scler. 2009;15:229–37.

    Article  CAS  PubMed  Google Scholar 

  26. Shevchenko JL, Kuznetsov AN, Ionova TI, Melnichenko VY, Fedorenko DA, Kurbatova KA, et al. Long-term outcomes of autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis: physician’s and patient’s perspectives. Ann Hematol. 2015;94:1149–57.

    Article  CAS  PubMed  Google Scholar 

  27. Nash RA, Huttggon GJ, Racke MK, Popat U, Devine SM, Griffith LM, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report. JAMA Neurol. 2015;72:159–69.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Nash RA, Hutton GJ, Racke MK, Popat U, Devine SM, Steinmiller KC, et al. High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS. Neurology. 2017;88:842–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fassas A, Anagnostopoulos A, Kazis A, Kapinas K, Sakellari I, Kimiskidis V, et al. Autologous stem cell transplantation in progressive multiple sclerosis—an interim analysis of efficacy. J Clin Immunol. 2000;20:24–30.

    Article  CAS  PubMed  Google Scholar 

  30. Burt RK, Loh Y, Cohen B, Stefoski D, Balabanov R, Katsamakis G, et al. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol. 2009;8:244–53.

    Article  CAS  PubMed  Google Scholar 

  31. Burt RK, Balabanov R, Han X, Sharrack B, Morgan A, Quigley K, et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2015;313:275–84.

    Article  PubMed  Google Scholar 

  32. Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC, et al. Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: a randomized clinical trial. JAMA. 2019;321:165–74.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ruiz-Argüelles GJ, Olivares-Gazca JC, Olivares-Gazca M, Leon-Peña AA, Murrieta-Alvarez I, Cantero-Fortiz Y, et al. Self-reported changes in the expanded disability status scale score in patients with multiple sclerosis after autologous stem cell transplants: real-world data from a single center. Clin Exp Immunol. 2019;198(Dec):351–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Burt RK, Han X, Quigley K, Arnautovic I, Shah SJ, Lee DC, et al. Cardiac safe hematopoietic stem cell transplantation for systemic sclerosis with poor cardiac function: a pilot safety study that decreases neutropenic interval to 5 days. Bone Marrow Transpl. 2021;56:50–59.

    Article  CAS  Google Scholar 

  35. Burman J, Jacobaeus E, Svenningsson A, Lycke J, Gunnarsson M, Nilsson P, et al. Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry. 2014;85:1116–21.

    Article  PubMed  Google Scholar 

  36. Arruda LCM, de Azevedo JTC, de Oliveira GLV, Scortegagna GT, Rodrigues ES, Palma PVB, et al. Immunological correlates of favorable long-term clinical outcome in multiple sclerosis patients after autologous hematopoietic stem cell transplantation. Clin Immunol. 2016;169:47–57.

    Article  CAS  PubMed  Google Scholar 

  37. Karnell FG, Lin D, Motley S, Duhen T, Lim N, Campbell DJ, et al. Reconstitution of immune cell populations in multiple sclerosis patients after autologous stem cell transplantation. Clin Exp Immunol. 2017;189(3):268–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sallusto F, Lenig D, Förster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999;401:708–12.

    Article  CAS  PubMed  Google Scholar 

  39. 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;201:805–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Abrahamsson SV, Angelini DF, Dubinsky AN, Morel E, Oh U, Jones JL, et al. Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis. Brain: a J Neurol. 2013;136:2888–903.

    Article  Google Scholar 

  41. Booth NJ, McQuaid AJ, Sobande T, Kissane S, Agius E, Jackson SE, et al. Different proliferative potential and migratory characteristics of human CD4+ regulatory T cells that express either CD45RA or CD45RO. J Immunol. 2010;184:4317–26.

    Article  CAS  PubMed  Google Scholar 

  42. Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, et al. A human memory T-cell subset with stem cell-like properties. Nat Med. 2011;17:1290–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cieri N, Oliveira G, Greco R, Forcato M, Taccioli C, Cianciotti B, et al. Generation of human memory stem T cells after haploidentical T-replete hematopoietic stem cell transplantation. Blood 2015;125:2865–74.

    Article  CAS  PubMed  Google Scholar 

  44. Cianciotti BC, Ruggiero E, Campochiaro C, Oliveira G, Magnani ZI, Baldini M, et al. CD4+ memory stem T cells recognizing citrullinated epitopes are expanded in patients with rheumatoid arthritis and sensitive to tumor necrosis factor blockade. Arthritis Rheumatol. 2020;72:565–75.

    Article  CAS  PubMed  Google Scholar 

  45. Thibult ML, Mamessier E, Gertner-Dardenne J, Pastor S, Just-Landi S, Xerri L, et al. PD-1 is a novel regulator of human B-cell activation. Int Immunol. 2013;25:129–37.

    Article  CAS  PubMed  Google Scholar 

  46. Gernert M, Tony HP, Schwaneck EC, Gadeholt O, Schmalzing M. Autologous hematopoietic stem cell transplantation in systemic sclerosis induces long-lasting changes in B cell homeostasis toward an anti-inflammatory B cell cytokine pattern. Arthritis Res Ther. 2019;21:106.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Arruda LCM, Malmegrim KCR, Lima-Júnior 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;2:126–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Peng B, Ming Y, Yang C. Regulatory B cells: the cutting edge of immune tolerance in kidney transplantation. Cell Death Dis. 2018;9:1–13.

    Article  CAS  Google Scholar 

  49. Tuohy O, Costelloe L, Hill-Cawthorne G, Bjornson I, Harding K, Robertson N, et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry. 2015;86:208–15.

    Article  PubMed  Google Scholar 

  50. Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K. Interpreting lymphocyte reconstitution data from the pivotal phase 3 trials of alemtuzumab. JAMA Neurol. 2017;74:961–9.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Le Lann L, Jouve PE, Alarcón-Riquelme M, Jamin C, Pers JO.PRECISESADS Flow Cytometry Study Group; PRECISESADS Clinical Consortium. Standardization procedure for flow cytometry data harmonization in prospective multicenter studies.Sci Rep.2020;10:11567.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Alexander T, Bondanza A, Muraro PA, Greco R, Saccardi R, Daikeler T, et al. SCT for severe autoimmune diseases: consensus guidelines of the European Society for Blood and Marrow Transplantation for immune monitoring and biobanking. Bone Marrow Transpl. 2015;50:173–80.

    Article  CAS  Google Scholar 

  53. Kreuzaler M, Rauch M, Salzer U, Birmelin J, Rizzi M, Grimbacher B, et al. Soluble BAFF levels inversely correlate with peripheral B cell numbers and the expression of BAFF receptors. J Immunol Jan. 2012;188:497–503.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Richard K. Burt, Xiaoqiang Han & Kathleen Quigley

  2. Neuroimmunology and Immunotherapy, Department of Brain Sciences, Imperial College London, London, UK

    Paolo A. Muraro

  3. Unité de Médecine Interne: Maladies Auto-immunes et Pathologie Vasculaire (UF 04), IRSL, EA-3518, Université de Paris, MATHEC, Centre de Référence des Maladies auto-immunes systémiques Rares d’Ile-de-France, Filière FAI2R, Hôpital St-Louis, AP-HP, Paris, France

    Dominique Farge

  4. Divisão de Imunologia Clínica, Departamento de Clínica Médica, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil

    Maria Carolina Oliveira

  5. Department of Haematology, Sheffield Teaching Hospitals, NHS Foundation Trust and the University of Sheffield, Sheffield, UK

    John A. Snowden

  6. Department of Hematology, Careggi University Hospital, Florence, Italy

    Riccardo Saccardi

  7. Department of Microbiology, Immunology and Parasitology DMIP Federal University of São Paulo UNIFESP, São Paulo, Brasil

    Valquiria Bueno

  8. Department of Microbiology and Immunology, and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    Daniela Frasca

  9. The A.A. Maximov Department of Hematology and Cellular Therapy, National Pirogov Medical Surgical Center, Moscow, Russian Federation

    Denis Fedorenko

  10. Department of Neurology, Uppsala University, Uppsala, Sweden

    Joachim Burman

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  1. Richard K. Burt
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Correspondence to Richard K. Burt.

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Conflict of interest

Professor John A Snowden declares honoraria for an advisory board from MEDAC, and as an IDMC member for a trial supported by Kiadis Pharma, all outside the submitted work. Professor Paolo A. Muraro reports no conflict of interest. He discloses travel support and speaker honoraria from unrestricted educational activities organized by Novartis, Bayer HealthCare, Bayer Pharma, Biogen Idec, Merck-Serono and Sanofi Aventis. He also discloses consulting to Magenta Therapeutics and Jasper Therapeutics. All the other authors have nothing to declare.

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Burt, R.K., Muraro, P.A., Farge, D. et al. New autoimmune diseases after autologous hematopoietic stem cell transplantation for multiple sclerosis. Bone Marrow Transplant 56, 1509–1517 (2021). https://doi.org/10.1038/s41409-021-01277-y

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