Autologous Hematopoietic Stem Cell Transplantation in Neuromyelitis Optica

Review Article

J Stem Cell Res Transplant. 2022; 9(1): 1042.

Autologous Hematopoietic Stem Cell Transplantation in Neuromyelitis Optica

Shao B* and Chu L

Department of Neurology, Affiliated Hospital of Guizhou Medical University, Guiyang, China

*Corresponding author: Lan Chu, Department of Neurology, Affiliated Hospital of Guizhou Medical University, Guiyang, China

Received: October 10, 2022; Accepted: November 08, 2022; Published: November 15, 2022


Neuromyelitis Optica Spectrum Disorders (NMOSD) is an autoimmune astrocyte disease characterized by high recurrence rate and disability rate, symptoms of neurologic deficit are aggravated with the increase of recurrence times, and treatment for remission phase is of great importance. However, immunosuppressant’s and targeted therapy used in remission phase have some disadvantages, such as off-label use, infection, need long time maintenance, patients with NMOSD may not response to those treatments and even relapse eventually. Highlighting the need for cell-based therapies bridge the gap of remission phase for refractory NMOSD, Hematopoietic Stem Cell Transplantation (HSCT) may precisely provide a potential approach as a promising therapy for refractory forms of NMOSD. Herein, we review clinical trials that implement HSCT on NMOSD in order to attract attention on this promising therapy that may induce long-term remission.

Keywords: Autologous hematopoietic stem cell transplantation; Immunotherapy; Neuromyelitis optica spectrum disorders; Longitudinal extended transverse myelitis; Optic neuritis


Neuromyelitis Optica (NMO) is an autoimmune astrocyte disease [1,2] characterized by Longitudinal Extended Transverse Myelitis (LETM) and Optic Neuritis (ON) [3], its pathogenic antibody is aquaporin-4-Immunoglobulin (AQP4-IgG) [4], one of most important aquaporin in CNS, where it is highly expressed on brain and lung tissue, also expressed on epithelial cells of the kidney ,stomach, airways, glands and skeleton muscle [5,6]. Since the milestone discovery of pathogenic antibody has been detected in patients of NMO made it distinct from Multiple Sclerosis (MS), disease definition has further broadened to NMO Spectrum Disorders (NMOSD) since 2007. While in year 2015 new criteria allow diagnosis with occurrence of one of six core characters with or without AQP4-IgG serologic status, but more restrict on clinical core characteristics and typical neuroimaging that includes ON, acute myelitis, area postrema syndrome, acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic lesions on Magnetic Resonance Imaging (MRI), symptomatic cerebral syndrome with NMOSDtypical brain lesions [7].

The clinical course of NMOSD is relapsing and the symptom of neurologic deficit is accumulated with the attack. The aim to treat NMO in remission period is to prevent recurrent attack, reduce relapse rate and reduce neurological disability and mortality. Although patient with NMOSD has largely benefit from numerous effective therapies includes immunosuppressants and monoclonal antibody. However, disease progression cannot be halted by these agents including Disease Modifying Treatment (DMTs) and immunosuppressants or monoclonal antibodies, especially some patients with refractory course they may relapse soon after initial treatment [8]. meantime immunosuppressants and monoclonal antibody treatment for NMO have some disadvantages, such as offlabel use [9], need life-long treatment , and patients may suffer serious side effects such as infection [10] and brings huge economic burden for patients. Even though NMO patient has benefited from these new immunotherapeutic approaches, disease cannot be cured to obtained a life-long remission. Therefore, making a room for explore profound and novel therapeutic approaches for NMO treatment. New evidence has demonstrated that Autologous Hematopoietic Stem Cell Transplantation (AHSCT) may play a promising and possibly curative strategies for NMO.

In this review, we will overview current knowledge on the potential mechanism of HSCT treatment, and then we will present up-to-date clinical analysis of the published evidence on the efficacy and adverse effect of hematopoietic stem cell transplantation on NMO. Then we will discuss outlook of Hematopoietic stem cell transplantation as a potential approach for patients with NMOSD, in order to provide an informative description of HSCT in NMO.

Biological and Historical Rationale of HSCT in NMOSD

Hematopoietic-stem-cells are self-renewing and ability of giving rise to all mature cell types that comprise the blood-forming system [11]. Hematopoietic stem cell transplantation is a complex procedure that reconstitute host hematopoietic system through chemotherapy followed by a reconstruction of a new immune system. According to the donor of Hematopoietic Stem Cells (HSCs), HSCT procedures can be divided into autologous (auHSCT) or allogeneic (alHSCT). In auHSCT, the patitent plays both donor and recipient. alHSCT include a healthy allogeneic donor and the recipient (patient), however alHSCT has a higher risk of Graft-Versus-Host Disease (GVHD) [12] and transplant related motality [13]. European Bone Marrow Transplantation (EBMT) Autoimmune Disease Working Party (ADWP) recommends the use of AHSCT in NMOSD as a clinical option, with grade II evidence, in therapy-refractory patients [14]. In the treatment of severe autoimmune disease auHSCT have been preferred to prevent further transplantation related morbidity and mortality.

Hematopoietic stem cell transplantation was initially been utilized to treat malignant disease [15], continually its role has emerged in the treatment of autoimmune disease including neurological ones [16]. In the early 1990s, the first report of HSCT for Experimental Autoimmune Encephalomyelitis (EAE) were conducted in rodent, which achieved effective response for both autologous and allogeneic HSCT [17]. And soon after a series of studies in SLJ mice or Lewis rats showed that HSCT could prevent symptom progression [18-22]. Based on the above studies from animal’s models, the first HSCT was exploited for MS patient in 1995 by Fassas [23]. Gradually, it has been through a hard time for exploration for HSCT in MS, including the evidence of failure in HSCT for MS patient [24]. Soon after, more studies demonstrated that HSCT as a therapeutic strategy in MS is curative and cost-effective [25-28].

While in 2010, AHSCT was firstly been adopted in NMO is from Chinese scholars [29], using autologous peripheral hematopoietic stem cell transplantation to treat one single NMO patient, a 23-yearold woman who has achieved clinical remission for more than 12 months after transplantation. The first report of applying alHSCT in NMO is from Greco, two NMO patients has achieved durable clinical remissions after alHSCT, both achieved AQP4-IgG negative status and stability on MRI [30].

The rationale of HSCT is to destroy auto reactive immune cells (particularly T and B cells) and reconfigured it by hematopoietic stem cell infusion allowing the reconstitution of a new, self-tolerant immune system(naive cells replaced the memory T cells), as a result of inducing long-term disease remission instead of long-term immunosuppression [30,31].

Clinical trials to date of HSCT in NMOSD

An overview of the latest studies in patients’ demographics, clinical characters, serology and treatment response are shown in Table 1.A total of twelve studies, 61 patients were included, nine studies were auto-HSCT, only three studies underwent allo-HSCT. Most (9/12) studies are case or case series, except Greco [30] and Burt [28] conduct retrospective and prospective cohort study respectively. Median age at transplantation was 34.5.years (3-58). (53) 87% patients were female, which showed a female predominance. (32)52% patients were seropositive for anti-AQP4 antibody. EDSS scores showed decrease after HSCT in ten studies. The first three complications post HSCT most frequently recorded were febrile neutropenia (5/12), CMV reactivation (3/12), diarrhea(3/12). Among 61 patients, (32)52% suffered relapse after HSCT, the median follow up were 44 months (6-108), at last follow up period most majority studies achieved clinical remission or progression free or relapse-free survival.


Immunotherapy for NMOSD has been evolving since immunosuppression to targeted therapy (Anti-CD20 monoclonal antibody, etc), current immune approaches could prevent disease relapse but still remains therapy-resistance and inefficient for progressive forms of NMO. Compared to MS, the development of HSCT for NMOSD is relatively young, HSCT has been utilized in MS more than 5000 patients for over 2 decades, while for NMOSD, HSCT has just been applied to 61 patients for 10 years. limited clinical trials to date has provide evidence for its efficacy and safety in NMOSD, evidence reviewed above showed that HSCT may be a most promising immunotherapy for NMOSD in the future, as long as cellbased therapy has emerged in order to start a new era in treatment of neurological immune disorders. But still, questions are worth thinking while carry on studies of HSCT on NMOSD patients:

When is the best time to carry HSCT? How much disease activity should be appropriate to underwent HSCT? Whether regimens such as rituximab works or the restoration of immune tolerance works in the mechanism of HSCT treatment? How young should patients be? Based on the questions above, more multicenter studies and randomized controlled trials are warranted to evaluate the efficacy and long-term outcomes of HSCT on NMOSD.

Declaration of Interest

No potential competing interest was reported by the authors.


  1. Fujihara K, Misu T, Nakashima I, Takahashi T, Bradl M, et al. Neuromyelitis optica should be classified as an astrocytopathic disease rather than a demyelinating disease. Clin Exp Neuroimmunol. 2012; 3: 58–73.
  2. Lucchinetti CF, Guo Y, Popescu B, Fujihara K, Itoyama Y, et al. The Pathology of an Autoimmune Astrocytopathy: Lessons Learned from Neuromyelitis Optica. Brain Pathol. 2014; 24: 83-97.
  3. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG, et al. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006; 66: 1485–1489.
  4. Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. The Lancet. 2004; 364: 2106–2112.
  5. He D, Li Y, Dai Q, Zhang Y, Xu Z, et al. Myopathy associated with neuromyelitis optica spectrum disorders. Int J Neurosci. 2016; 126: 863–866.
  6. Saini H, Fernandez G, Kerr D, Levy M. Differential expression of aquaporin-4 isoforms localizes with neuromyelitis optica disease activity. J Neuroimmunol. 2010; 221: 68–72.
  7. Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015; 85: 177–189.
  8. Collongues N, de Seze J. Current and future treatment approaches for neuromyelitis optica. Ther Adv Neurol Disord. 2011; 4: 111–121.
  9. Kitley J, Waters P, Woodhall M, Leite MI, Murchison A, et al. Neuromyelitis Optica Spectrum Disorders With Aquaporin-4 and Myelin-Oligodendrocyte Glycoprotein Antibodies: A Comparative Study. JAMA Neurol. 2014; 71: 276- 83.
  10. Avouac A, Maarouf A, Stellmann J-P, Rico A, Boutiere C, et al. Rituximab- Induced Hypogammaglobulinemia and Infections in AQP4 and MOG Antibody-Associated Diseases. Neurol Neuroimmunol Neuroinflamm. 2021; 8: e977.
  11. HAWLEY RG, RAMEZANI A, HAWLEY TS. Hematopoietic Stem Cells. Methods Enzymol. 2006; 419: 149–179.
  12. Sykes M, Nikolic B. Treatment of severe autoimmune disease by stem-cell transplantation. Nature. 2005; 435: 620–627.
  13. Dominietto A, Lamparelli T, Raiola AM, et al. Transplant-related mortality and long-term graft function are significantly influenced by cell dose in patients undergoing allogeneic marrow transplantation. Blood 2002; 100: 3930–3934.
  14. Sharrack B, Saccardi R, Alexander T, Badogilo M, Burman J, et al. Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE). Bone Marrow Transplant. 2020; 55: 283–306.
  15. Thomas ED, Lochte HL, Cannon JH, Sahler OD, Ferebee JW, et al. Supralethal whole body irradiation and isologous marrow transplantation in man. J Clin Invest. 1959; 38: 1709–1716.
  16. Tyndall A, Gratwohl A. Blood and marrow stem cell transplants in autoimmune disease: a consensus report written on behalf of the European League against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 1997; 19: 643–645.
  17. Knaan-Shanzer S, Houben P, Kinwel-Bohré EP, van Bekkum DW. Remission induction of adjuvant arthritis in rats by total body irradiation and autologous bone marrow transplantation. Bone Marrow Transplant. 1991; 8: 333–338.
  18. Karussis DM, Slavin S, Lehmann D, Mizrachi-Koll R, Abramsky O, Ben-Nun A, et al. Prevention of experimental autoimmune encephalomyelitis and induction of tolerance with acute immunosuppression followed by syngeneic bone marrow transplantation. J Immunol. 1992; 148: 1693–1698.
  19. Karussis DM, Vourka-Karussis U, Lehmann D, et al. Prevention and reversal of adoptively transferred, chronic relapsing experimental autoimmune encephalomyelitis with a single high dose cytoreductive treatment followed by syngeneic bone marrow transplantation. J Clin Invest. 1993; 92: 765–772.
  20. van Gelder M, Kinwel-Bohré EP, van Bekkum DW. Treatment of experimental allergic encephalomyelitis in rats with total body irradiation and syngeneic BMT. Bone Marrow Transplant. 1993; 11: 233–241.
  21. Burt RK, Burns W, Ruvolo P, Fishcer A, Shiao C, et al. Syngeneic bone marrow transplantation eliminates V beta 8.2 T lymphocytes from the spinal cord of Lewis rats with experimental allergic encephalomyelitis. J Neurosci Res. 1995; 41: 526–531.
  22. van Gelder M, van Bekkum DW. Effective treatment of relapsing experimental autoimmune encephalomyelitis with pseudoautologous bone marrow transplantation. Bone Marrow Transplant. 1996; 18: 1029–1034.
  23. Fassas A, Anagnostopoulos A, Kazis A, Kapinas K, Sakellari I, et al. Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study. Bone Marrow Transplant. 1997; 20: 631–638.
  24. Burt RK, Cohen BA, Russell E, Spero K, Joshi A, 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: 2373–2378.
  25. Saccardi R, Kozak T, Bocelli-Tyndall C, Fassas A, Kazis A, et al. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database. Mult. Scler. Houndmills Basingstoke Engl. 2006; 12: 814–823.
  26. Chen B, Zhou M, Ouyang J, Zhou R, Xu J, et al. Long-term efficacy of autologous haematopoietic stem cell transplantation in multiple sclerosis at a single institution in China. Neurol. Sci. Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol. 2012; 33: 881–886.
  27. Xu J, Ji B-X, Su L, Donh HQ, Sun WL, et al. Clinical outcome of autologous peripheral blood stem cell transplantation in opticospinal and conventional forms of secondary progressive multiple sclerosis in a Chinese population. Ann Hematol. 2011; 90: 343–348.
  28. Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, 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: 165–174.
  29. Peng F, Qiu W, Li J, Hu X, Huang R, et al. A Preliminary Result of Treatment of Neuromyelitis Optica With Autologous Peripheral Hematopoietic Stem Cell Transplantation. The Neurologist. 2010; 16: 375–378.
  30. Greco R, Bondanza A, Vago L, Moiola L, Rossi P, et al. Allogeneic hematopoietic stem cell transplantation for neuromyelitis optica: Allogeneic HSCT for NMO. Ann Neurol. 2014; 75: 447–453.
  31. Burman J, Tolf A, Hägglund H, Askmark H. Autologous haematopoietic stem cell transplantation for neurological diseases. J. Neurol. Neurosurg. Psychiatry. 2018; 89: 147–155.
  32. Matiello M. Failure of Autologous Hematopoietic Stem Cell Transplantation to Prevent Relapse of Neuromyelitis Optica. Arch Neurol. 2011; 68: 953-5.
  33. Aouad P, Li J, Arthur C, Burt R, Fernando S, et al. Resolution of aquaporin-4 antibodies in a woman with neuromyelitis optica treated with human autologous stem cell transplant. J Clin Neurosci. 2015; 22: 1215–1217.
  34. Greco R, Bondanza A, Oliveira MC, Badogilo M, Burman J, et al. Autologous hematopoietic stem cell transplantation in neuromyelitis optica: A registry study of the EBMT Autoimmune Diseases Working Party. Mult Scler J. 2015; 21: 189–197.
  35. Hoay KY, Ratnagopal P. Autologous Hematopoietic Stem Cell Transplantation for the Treatment of Neuromyelitis Optica in Singapore. Acta Neurol. Taiwanica. 2018; 27: 26–32.
  36. Burt RK, Balabanov R, Han X, Burns C, Gastala J, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation for neuromyelitis optica. Neurology 2019; 93: e1732–e1741.
  37. Khan TR, Zimmern V, Aquino V, Wang C. Autologous hematopoietic stem cell transplantation in a pediatric patient with aquaporin-4 neuromyelitis optica spectrum disorder. Mult Scler Relat Disord. 2021; 50: 102852.
  38. Burton JM, Duggan P, Costello F, Metz L, Storek J, et al. A pilot trial of autologous hematopoietic stem cell transplant in neuromyelitis optic spectrum disorder. Mult Scler Relat Disord. 2021; 53: 102990.
  39. Ceglie G, Papetti L, Figà Talamanca L, Lucarelli B, Algeri M, et al. T-cell depleted HLA-haploidentical HSCT in a child with neuromyelitis optica. Ann Clin Transl Neurol. 2019; 6: 2110–2113.
  40. Hau L, Kállay K, Kertész G, Goda V, Kassa C, et al. Allogeneic haematopoietic stem cell transplantation in a refractory case of neuromyelitis optica spectrum disorder. Mult Scler Relat Disord. 2020; 42: 102110.

Download PDF

Citation: Shao B and Chu L. Autologous Hematopoietic Stem Cell Transplantation in Neuromyelitis Optica. J Stem Cell Res Transplant. 2022; 9(1): 1042.

Journal Scope
Editorial Board
Instruction for Authors
Submit Your Article
Contact Us