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Peripheral blood mononuclear cell (PBMC) proliferative responses to myelin immunodominant peptides before stem cell transplantation (pre-SCT) and at various times post-SCT in patients 3, 4, and 5. To amplify proliferative responses, interleukin-2 was added to PBMC cultures in the post-SCT assays. Assays shown in the first column (pre-SCT) were done on samples drawn before granulocyte colony-stimulating factor (G-CSF) administration. In patient 5, the second panel (pre-SCT, post-G-CSF) was an assay drawn after 4 days of G-CSF, just before the first stem cell collection. Myelin immunodominant peptides include myelin basic protein (MBP) 84-106, MBP 142-163, proteolipid protein (PLP) 104-117, PLP 142153, and myelin oligodendroglial glycoprotein (MOG) 42-53. PHA indicates phytohemagglutinin.
Source publication
Multiple sclerosis (MS) is an immune-mediated disease that may be amenable to high-dose immunosuppression with peripheral blood stem cell transplantation (SCT) in selected patients. Five MS patients (all women, ages 39-47 years) received granulocyte colony-stimulating factor (G-CSF) for stem cell mobilization, CD34 cell selection for T-cell depleti...
Context in source publication
Context 1
... responses were also suppressed post-SCT with a decrease from 22% to 78% (not shown). In patient 3, just after a 1-point EDSS progression 17 months post-SCT, a new proliferative response >2 times that of the control was demonstrated to the immunodominant PLP peptide 104-117 ( Figure 5), and a significant response to whole bovine myelin was also present (not shown). Earlier in patient 3, a new proliferative response to MBP 1-12 (Figure 4) was noted at 8 months after SCT, a time when there was no recognized change in clinical disease; and similar new responses without neurological worsening were noted in other MBP, MOG, and PLP peptides at 3 months after SCT in patients 4 and 5. ...
Citations
... An increase in regulatory populations was described following alemtuzumab treatment, both in the T and B cell Inebilizumab Depletion of putative disease-mediating CD19+ B cell clones (40,76) Reduced humoral immunity (40,76) AHSCT Ablation of disease-mediating T cells (77)(78)(79) Ablation of B cells contributing to disease pathogenesis (79) Transient reduction in cell mediated and innate immunity (increased risk of infections) (79-81). Transient reduction in myeloid-derived blood cells (79)(80)(81). ...
... Immune cell reconstitution promoted by thymic reactivation with regeneration of T cell receptor repertoire diversity (80, 82,83) Increase in regulatory function of B and T cells (79,(84)(85)(86) Reduced percentage and activation/ proliferation of pro-inflammatory T cell phenotypes (Th17, Th1, MAIT) (79,(86)(87)(88) Reduced production of pro-inflammatory cytokines, with shift towards antiinflammatory profile (77,84,86,87,89) Down-regulation of pro-inflammatory genes in adaptive and innate immunity cells (90)(91)(92) Secondary autoimmunity (93) *Most of the evidence on the effects of Ab-mediated cell depletion therapies were provided by studies on ocrelizumab and rituximab. ...
Development of disease-modifying therapies including monoclonal antibody (mAb)-based therapeutics for the treatment of multiple sclerosis (MS) has been extremely successful over the past decades. Most of the mAb-based therapies approved for MS deplete immune cell subsets and act through activation of cellular Fc-gamma receptors expressed by cytotoxic lymphocytes and phagocytes, resulting in antibody-dependent cellular cytotoxicity or by initiation of complement-mediated cytotoxicity. The therapeutic goal is to eliminate pathogenic immune cell components and to potentially foster the reconstitution of a new and healthy immune system. Ab-mediated immune cell depletion therapies include the CD52-targeting mAb alemtuzumab, CD20-specific therapeutics, and new Ab-based treatments which are currently being developed and tested in clinical trials. Here, we review recent developments in effector mechanisms and clinical applications of Ab-based cell depletion therapies, compare their immunological and clinical effects with the prototypic immune reconstitution treatment strategy, autologous hematopoietic stem cell transplantation, and discuss their potential to restore immunological tolerance and to achieve durable remission in people with MS.
... Studies on 15 patients were published in 1997 having secondary progressive MS. For MS both in primary and secondary progressive type several trials of ASCT were published and reported [3]. In 2009, the turning point and independent groups concluded that hematopoietic stem cell transplant could stop the disease in the majority of relapsing-remitting MS patients. ...
The treatment of Multiple Sclerosis comprises two types of Regimens, those are Disease Modifying Drugs and Au-tologous Hematopoietic Stem Cell Transplantation (ASCT). ASCT has been studied in MS for more than two decades. It is a process in which normal/healthy blood stem cells of your own body replace your disease stem cells in bone marrow by using Granulocyte colony stimulating factors for stem cell mobilization, CD34 for stem cell depletion, and CY, Busulfan and Antithymocyte Globulins for ablation at the time of cell infusion. It has successfully treated over 1400 patients. The indication for treatment is age less than 45 years, short duration (less than 10 years), Expanded Disability Status Scale (EDSS) >5.5 not very disabled, highly active relapsing-remitting MS (RRMS), malignant and in progressive MS. Nonmyelo ablative ASCT for relapsing-remitting MS found improved neurologic disability and a 5-year disease-free remission of 80% and decreased the relapse in RRMS from 80-97%. It has proved to be the most effective treatment by showing no progression in disease after compared to Disease-Modifying Therapy (DMT), where relapsing and disability continue. The marked improvement in safety has shown its way from appropriate patient selection, the choice of conditioning regimen, increasing experience, and accreditation of transplant centers. In contrast to ASCT therapy, treatment with DMT's has low efficacy and due
... The rationale for delaying mobilization after an MS relapse is the concern that filgrastim, administered during stem cell mobilization, has been associated with flares of MS activity (Openshaw et al., 2000a(Openshaw et al., , 2000b. ...
Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly used to treat patients with highly active multiple sclerosis (MS) refractory to disease‐modifying therapy. Briefly, cyclophosphamide and filgrastim are used to mobilize autologous hematopoietic stem cells (HSC) into the circulation. HSC are harvested by leukapheresis, purified using a CD34 immunomagnetic selection process, and cryopreserved. Busulphan, cyclophosphamide, and rabbit anti‐thymocyte globulin are used to destroy the patient's autoreactive immune system, followed by infusion of the previously collected HSC, which reconstitute a naïve and self‐tolerant immune system. Many MS patients experience durable remissions with no evidence of new disease activity following aHSCT. Treatment‐related toxicity is rare, but potentially life‐threatening complications necessitate appropriate patient selection by MS neurologists and HSCT physicians. AHSCT must be performed with a highly trained multidisciplinary team expert to minimize morbidity and mortality. We present the current aHSCT procedure for an MS indication at The Ottawa Hospital, developed from our program's 20‐year experience. © 2022 Wiley Periodicals LLC.
Basic Protocol 1 : Candidate selection
Basic Protocol 2 : Autologous hematopoietic stem cell mobilization, collection, purification, and cryopreservation
Basic Protocol 3 : Autologous hematopoietic stem cell transplantation
Basic Protocol 4 : Supportive care following recovery from aHSCT (Beyond 100 days)
Basic Protocol 5 : Ongoing evaluation of multiple sclerosis
... Clinical trials of autologous hematopoietic stem cell transplantation (HSCT) were initiated in the 1990s [1]. Due to the unknown risks of this treatment and failure to appreciate that SPMS is predominately a neurodegenerative disease, early trials enrolled patients with SPMS, high EDSS disability scores, and in an attempt to completely destroy the pre-HSCT immune system, utilized intense myeloablative regimens originally developed for cancer [2][3][4][5][6][7][8][9][10][11][12][13][14][15]. Although myeloablative HSCT appeared effective in stopping acute attacks, new MRI lesion burden, and perhaps improving quality of life [16], patients with SPMS did not demonstrate post-HSCT neurological improvement, disease progression continued [2][3][4][5][6][7][8][9][10][11][12][13][14][15], and for at least 2 years after treatment, brain atrophy continued above normal age-related changes [17]. ...
... Due to the unknown risks of this treatment and failure to appreciate that SPMS is predominately a neurodegenerative disease, early trials enrolled patients with SPMS, high EDSS disability scores, and in an attempt to completely destroy the pre-HSCT immune system, utilized intense myeloablative regimens originally developed for cancer [2][3][4][5][6][7][8][9][10][11][12][13][14][15]. Although myeloablative HSCT appeared effective in stopping acute attacks, new MRI lesion burden, and perhaps improving quality of life [16], patients with SPMS did not demonstrate post-HSCT neurological improvement, disease progression continued [2][3][4][5][6][7][8][9][10][11][12][13][14][15], and for at least 2 years after treatment, brain atrophy continued above normal age-related changes [17]. ...
Objective
To investigate the results of real-world application of non-myeloablative autologous HSCT for multiple sclerosis (MS).
Methods
Between July 2003 and October 2019 at a single center (Northwestern University), 414 patients with relapsing remitting MS (RRMS) and 93 patients with newly diagnosed secondary progressive MS (SPMS) underwent non-myeloablative HSCT.
Results
There was one treatment-related death (0.19%) due to hospital-acquired legionella pneumonia, and one patient developed neutropenic bacteremia (Klebsiella pneumonia) without sepsis. Overall 5-year survival was 98.8%. Post HSCT secondary autoimmune diseases (2nd ADs) were idiopathic thrombocytopenia (ITP) and hypo or hyperthyroidism. ITP was highest with alemtuzumab (14%) and 0 to 2.8% for the non-alemtuzumab regimens. After HSCT, 16 patients developed hypothyroidism (3.5%) and 15 developed hyperthyroidism / Grave’s disease (3.3%). Relapse free survival (RFS) at 5 years for RRMS and SPMS was 80.1% and 98.1%, respectively, while progression free survival (PFS) at 4 years for RRMS and SPMS was 95% versus 66%, respectively. For patients with RRMS, the EDSS significantly improved (p < 0.0001) at each follow-up from a pre-HSCT mean of 3.87 to 2.51, 2.50, 2.41, 2.33, and 2.19 at 1, 2, 3, 4, and 5 years, respectively. For SPMS, the EDSS improved significantly only at 1 year but not thereafter. For SPMS, the mean baseline EDSS of 5.09 changed post-HSCT to 4.85 (p = 0.04), 4.88 (p = 0.2), 4.92 (p = .27), 4.72 (p = 0.07), and 4.2 (p = 0.21) at 1, 2, 3, 4, 5 years, respectively.
Conclusion
In patients with RRMS, autologous non-myeloablative HSCT is an effective one-time therapy, while HSCT appears of less benefit for newly diagnosed SPMS.
... Initially, patients considered suitable for the trials showed high disability, advanced progressing disease, unresponsiveness to conventional treatments, and, in some, disease activity in the year preceding the enrolment, evaluated by clinical deterioration or/and evidence of gadolinium (Gd)-enhanced disease lesions in magnetic resonance imaging (MRI). Results from these studies reported a remarkable reduction or complete abolition of disease activity established by a decreased number of Gd-positive lesions starting immediately after mobilization with cyclophosphamide (Cy) and further declining in the months after conditioning therapy (28)(29)(30)(31)(32)(33)(34). The effectiveness of HSCT in progressive MS was estimated by measuring the evolution of disability measured by the Expanded Disability Status Scale (EDSS) and showed a failure of 40% and 52% at 3 and 6 years, respectively, with a deterioration of neurological function (32,35), while disease progression-free survival at 15 years was 44% with active CNS disease pre-transplant and 10% for those without (36). ...
... In one study, CSF analysis of 4 patients pre and after HSCT revealed that OCBs reduced in the CSF at a rate consistent with reduced ongoing IgG synthesis rates (77). Other studies that reported OCBs remained largely unchanged (30,34,35,78). Persistence but reduction of OCBs in the CSF was observed at 2 years of the 4-year patient follow-up with a reduction of CSF IgG levels (41). ...
Multiple sclerosis (MS) is a central nervous system (CNS) disorder, which is mediated by an abnormal immune response coordinated by T and B cells resulting in areas of inflammation, demyelination, and axonal loss. Disease-modifying treatments (DMTs) are available to dampen the inflammatory aggression but are ineffective in many patients. Autologous hematopoietic stem cell transplantation (HSCT) has been used as treatment in patients with a highly active disease, achieving a long-term clinical remission in most. The rationale of the intervention is to eradicate inflammatory autoreactive cells with lympho-ablative regimens and restore immune tolerance. Immunological studies have demonstrated that autologous HSCT induces a renewal of TCR repertoires, resurgence of immune regulatory cells, and depletion of proinflammatory T cell subsets, suggesting a “resetting” of immunological memory. Although our understanding of the clinical and immunological effects of autologous HSCT has progressed, further work is required to characterize the mechanisms that underlie treatment efficacy. Considering that memory B cells are disease-promoting and stem-like T cells are multipotent progenitors involved in self-regeneration of central and effector memory cells, investigating the reconstitution of B cell compartment and stem and effector subsets of immunological memory following autologous HSCT could elucidate those mechanisms. Since all subjects need to be optimally protected from vaccine-preventable diseases (including COVID-19), there is a need to ensure that vaccination in subjects undergoing HSCT is effective and safe. Additionally, the study of vaccination in HSCT-treated subjects as a means of evaluating immune responses could further distinguish broad immunosuppression from immune resetting.
... In early studies of AHSCT in MS, the qualitative and quantitative changes of oligoclonal IgG bands in the CSF and serum were analysed. The included samples were obtained after relatively short follow-up periods and these studies demonstrated the persistence of oligoclonal IgG in the CSF [177][178][179] . In one study, CSF oligoclonal bands persisted in the CSF of two patients at 4 and 6 years after transplantation, indicating that immunoglobulin-producing plasma cells persisted despite high-intensity conditioning and long-term disease remission 180 . ...
Increasing evidence indicates the involvement of B cells in the pathogenesis of multiple sclerosis (MS), but their precise roles are unclear. In this Review, we provide an overview of the development and physiological functions of B cells and the main mechanisms through which B cells are thought to contribute to CNS autoimmunity. In MS, abnormalities of B cell function include pro-inflammatory cytokine production, defective B cell regulatory function and the formation of tertiary lymphoid-like structures in the CNS, which are the likely source of abnormal immunoglobulin production detectable in the cerebrospinal fluid. We also consider the hypothesis that Epstein-Barr virus (EBV) is involved in the B cell overactivation that leads to inflammatory injury to the CNS in MS. We also review the immunological effects - with a focus on the effects on B cell subsets - of several successful therapeutic approaches in MS, including agents that selectively deplete B cells (rituximab, ocrelizumab and ofatumumab), agents that less specifically deplete lymphocytes (alemtuzumab and cladribine) and autologous haematopoietic stem cell transplantation, in which the immune system is unselectively ablated and reconstituted. We consider the insights that these effects on B cell populations provide and their potential to further our understanding and targeting of B cells in MS.
... Most transplant centers use 2-4 g/m 2 cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) for subsequent collection of hematopoietic progenitor cells. [2][3][4][5][6][7][8][9][10][11][12][13] The scheme allows for collection of more cells than the use of G-CSF as a single agent, and very few events of mobilization failure are described. Additionally, the administered cyclophosphamide promotes initial control of disease activity, contributing to the therapeutic effect of the transplant procedure. ...
... 6,9 The incorporation of less myeloablative regimens, center experience and center accreditation have contributed to the improved outcomes. 8,59,[65][66][67][68] Recently the American Society of Bone Marrow Transplantation 50 has conducted a comprehensive literature review, including many of the papers already discussed here, and recommended autologous HSCT as "standard of care, clinical evidence available" for treatment-refractory relapsing MS. ...
Autoimmune diseases are an important field for the development of bone marrow transplantation, or hematopoietic stem cell transplantation. In Europe alone, almost 3000 procedures have been registered so far. The Brazilian Society for Bone Marrow Transplantation (Sociedade Brasileira de Transplantes de Medula Óssea) organized consensus meetings for the Autoimmune Diseases Group, to review the available literature on hematopoietic stem cell transplantation for autoimmune diseases, aiming to gather data that support the procedure for these patients. Three autoimmune diseases for which there are evidence-based indications for hematopoietic stem cell transplantation are multiple sclerosis, systemic sclerosis and Crohn's disease. The professional stem cell transplant societies in America, Europe and Brazil (Sociedade Brasileira de Transplantes de Medula Óssea) currently consider hematopoietic stem cell transplantation as a therapeutic modality for these three autoimmune diseases. This article reviews the evidence available.
... This was probably due to the selection of patients, and that intermediate or high-intensity chemotherapeutic regimens were preferred. 7,20,[24][25][26] The reported mortality rates have consistently decreased over time, with most recent data from the EBMT registry describing less than 1% mortality. 12,27 Neutropenic fever and infections were the most common early adverse events, and 76% of the patients got fever and/or other signs of infection during hospitalization. ...
Background:
Hematopoietic stem cell treatment (HSCT) is a promising treatment option for multiple sclerosis (MS), but detailed safety and efficacy measures are still scarce.
Objective:
To evaluate the efficacy and safety of HSCT in MS.
Methods:
Retrospective single-center observational study of all MS patients that underwent HSCT in Norway during January 2015 to January 2018. The primary outcome was no evidence of disease activity (NEDA-3) status.
Results:
A total of 30 patients with a median follow-up time of 26 months (range: 11-48) were evaluated. In total, 25 (83%) achieved NEDA-3 status, and none received disease-modifying treatment after HSCT. For 13 (43%) of the patients, there were sustained improvement in Expanded Disability Status Scale (EDSS) score, and 10 (33%) were working full time after the treatment, compared to only 1 (3%) before treatment. There were no serious treatment-related complications and was no mortality. Five patients (17%) were diagnosed with an autoimmune thyroid disease after the procedure, and 10 (43%) of the women had amenorrhea lasting >12 months and symptoms of ovarian failure.
Conclusion:
HSCT in MS is an effective and relatively safe treatment option, with few serious complications and no mortality in Norway, so far. However, long-term adverse event with amenorrhea is a common problem.
... Moreover, treatment with G-CSF prior to the onset of EAE and during remission aggravates the disease (Verda et al., 2006). In agreement with these data, the symptoms of MS are also aggravated in human patients treated with G-CSF (Openshaw et al., 2000;Burt et al., 2001). The massive infiltration of neutrophils into CNS lesions occurs following the induction of EAE by the passive transfer of myelin-specific Th2 and Th17 cells, which secrete GM-CSF and IL-17, respectively (Woodberry et al., 2018;Lafaille et al., 1997;Herges et al., 2012). ...
... During relapses, the plasma of MS patients contains higher levels of CXCL1, CXCL5, neutrophil elastase and CD11b/CD18 compared to patients in remission, healthy controls and patients with noninflammatory neurological diseases (Aoki et al., 1984;Ziaber et al., 1998). The pathogenicity of human neutrophils in autoimmune demyelinating diseases is also suggested by the exacerbation of symptoms in patients with optico-spinal MS and neuromyelitis optica when treated with recombinant G-CSF, which is known to mobilize neutrophils from the bone marrow (Openshaw et al., 2000;Jacob et al., 2012). As described above for EAE, circulating neutrophils with a suppressive phenotype have also been detected during MS. ...
Neutrophils are the first line of defense in the innate immune system, helping to maintain tissue homeostasis as well as eliminating pathogens and self-components. The traditional view of neutrophils as simple phagocytes has been revised over the last decade as new research reveals their unappreciated complexity. Neutrophils are phenotypically and functionally heterogeneous, allowing them to act as modulators of both inflammation and immune responses. During acute inflammation, neutrophils perform a variety of beneficial effector functions, but when inflammation is induced by injury (sterile inflammation) the benefits of neutrophils in tissue repair are more controversial. In several pathological conditions, including cancer and autoimmune diseases, neutrophils can trigger harmful tissue damage. Interestingly, neutrophils are also key players in neuroinflammatory disorders, during which they transmigrate in the central nervous system, acquire a toxic phenotype, home in on neurons, and release harmful molecules that compromise neuronal functions. In this review, we discuss recent data that redefine the cell biology and phenotype of neutrophils, focusing on the role of these cells in multiple sclerosis and Alzheimer's disease, both of which feature strong neuroinflammatory components.
... Although the removal of malignant cells is assumed to be a key aspect in the treatment of lymphomas and myelomas, less is known about the mechanisms behind the improvements seen in patients with inflammatory diseases. To minimize the mortality and morbidity related to the conditioning regimens [4][5][6], nonmyeloablative conditioning regimens are now preferred for MS [7]. AHSCT is thought to reset the immune system and induce a new and more tolerant system, rather than merely reducing the number of autoreactive immune cells [8]. ...
Little is known about the inflammatory milieu in the blood during autologous hematopoietic stem cell transplantation (AHSCT) and how it is affected by the stem cell mobilization, collection, and reinfusion and conditioning regimen. In this study, we analyzed 92 proteins connected to inflammation at 10 time points during and after AHSCT in 16 patients with multiple sclerosis (MS). Serum from 29 patients with newly diagnosed MS and 15 healthy controls were included for comparative analysis. There were no significant differences in inflammatory serum protein levels between patients with newly diagnosed MS and healthy controls, but 29 out of 73 detectable proteins were significantly altered between at least 2 adjacent sampling time points during AHSCT. The predominant changes occurred after the conditioning regimen had been administered, whereas stem cell mobilization, collection, and reinfusion appeared to have less impact. Two distinct response patterns could be discerned, likely representing loss of basal cytokine production and homeostasis. The analyzed serum proteins gradually returned to baseline levels after treatment, with no remaining differences at 3 months after AHSCT. We conclude that treatment with AHSCT has a major but transient impact on the inflammatory milieu of peripheral blood.
