Dataset Information

Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS.

ABSTRACT: Autologous stem cell transplantation (ASCT) for progressive multiple sclerosis (MS) may reset the immune repertoire.The objective of this paper is to analyse lymphocyte recovery in patients with progressive MS treated with ASCT.Patients with progressive MS not responding to conventional treatment underwent ASCT following conditioning with high-dose cyclophosphamide and antithymocyte globulin. Lymphocyte subset analysis was performed before ASCT and for two years following ASCT. Neurological function was assessed by the EDSS before ASCT and for three years post-ASCT.CD4+ T-cells fell significantly post-transplant and did not return to baseline levels. Recent thymic emigrants and naïve T-cells fell sharply post-transplant but returned to baseline by nine months and twelve months, respectively. T-regulatory cells declined post-transplant and did not return to baseline levels. Th1 and Th2 cells did not change significantly while Th17 cells fell post-transplant but recovered to baseline by six months. Neurological function remained stable in the majority of patients. Progression-free survival was 69% at three years.This study demonstrates major changes in the composition of lymphocyte subsets following ASCT for progressive MS. In particular, ablation and subsequent recovery of thymic output is consistent with the concept that ASCT can reset the immune repertoire in MS patients.

SUBMITTER: Cull G

PROVIDER: S-EPMC5415040 | biostudies-literature | 2017 Jan-Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS.

Cull G G Hall D D Fabis-Pedrini M J MJ Carroll W M WM Forster L L Robins F F Ghassemifar R R Crosbie C C Walters S S James I I Augustson B B Kermode A K AK

Multiple sclerosis journal - experimental, translational and clinical 20170101 1

<h4>Background</h4>Autologous stem cell transplantation (ASCT) for progressive multiple sclerosis (MS) may reset the immune repertoire.<h4>Objective</h4>The objective of this paper is to analyse lymphocyte recovery in patients with progressive MS treated with ASCT.<h4>Methods</h4>Patients with progressive MS not responding to conventional treatment underwent ASCT following conditioning with high-dose cyclophosphamide and antithymocyte globulin. Lymphocyte subset analysis was performed before ASC ...[more]

PMID: 28607754

Similar Datasets

Project description:Background and objectivesAutologous hematopoietic stem cell transplantation (aHSCT) is increasingly used to treat aggressive forms of multiple sclerosis (MS). This procedure is believed to result in an immune reset and restoration of a self-tolerant immune system. Immune reconstitution has been extensively studied for T cells, but only to a limited extent for B cells. As increasing evidence suggests an important role of B cells in MS pathogenesis, we sought here to better understand reconstitution and the extent of renewal of the B-cell system after aHSCT in MS.MethodsUsing longitudinal multidimensional flow cytometry and immunoglobulin heavy chain (IgH) repertoire sequencing following aHSCT with BCNU + Etoposide + Ara-C + Melphalan anti-thymocyte globulin, we analyzed the B-cell compartment in a cohort of 20 patients with MS in defined intervals before and up to 1 year after aHSCT and compared these findings with data from healthy controls.ResultsTotal B-cell numbers recovered within 3 months and increased above normal levels 1 year after transplantation, successively shifting from a predominantly transitional to a naive immune phenotype. Memory subpopulations recovered slowly and remained below normal levels with reduced repertoire diversity 1 year after transplantation. Isotype subclass analysis revealed a proportional shift toward IgG1-expressing cells and a reduction in IgG2 cells. Mutation analysis of IgH sequences showed that highly mutated memory B cells and plasma cells may transiently survive conditioning while the analysis of sequence cluster overlap, variable (IGHV) and joining (IGHJ) gene usage and repertoire diversity suggested a renewal of the late posttransplant repertoire. In patients with early cytomegalovirus reactivation, reconstitution of naive and memory B cells was delayed.DiscussionOur detailed characterization of B-cell reconstitution after aHSCT in MS indicates a reduced reactivation potential of memory B cells up to 1 year after transplantation, which may leave patients susceptible to infection, but may also be an important aspect of its mechanism of action.

Project description:ObjectiveTo study the evolution of the neuropathy and long-term disability in a large cohort of patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome following autologous stem cell transplantation (ASCT).MethodsRetrospective chart review documenting the clinical, electrophysiologic, and laboratory characteristics of patients with POEMS syndrome undergoing ASCT at Mayo Clinic, Rochester.ResultsSixty patients with a median follow-up time of 61 months were studied. All patients had peripheral polyneuropathy and demonstrated neurologic improvement after ASCT (apart from one patient who died early). Before ASCT, 27 patients (45%) required a wheelchair and 17 (29%) required a walker or foot brace. At the end of the follow-up period, no patient was using a wheelchair and 23 patients (38%) were using a foot brace. The median Neuropathy Impairment Score improved from 66 to 48 points at 12 months and to 30 points at most recent follow-up (p < 0.0001). Median Rankin Scale score improved from 3 to 1.5 (p < 0.0001). Vascular endothelial growth factor levels decreased from a median of 452 to 63.5 pg/mL (p < 0.0001). The ulnar compound motor action potential amplitude (median) improved from 4.3 to 7.6 mV (p < 0.0001) and ulnar compound motor action potential conduction velocity (median) improved from 34 to 51 m/s (p < 0.0001). Predicted forced vital capacity improved from 81% to 88% (p < 0.0001). Periengraftment syndrome occurred in 24 patients. Fourteen patients required additional chemotherapy and/or radiation following ASCT, but there was no clinical deterioration in the neuropathy in any of these patients. Six patients died: 1 due to POEMS, 1 due to failed engraftment, and 4 due to other malignancies (2 myelodysplastic syndrome, 1 lymphoma, 1 metastatic lung cancer).ConclusionPatients with POEMS syndrome who undergo ASCT have a significant and meaningful improvement of their neuropathy by multiple measurements during both short and long-term follow-up, which corresponds to reduction in morbidity and disability (none are in wheelchair long-term). Periengraftment syndrome was common but manageable. Fatal complications, although rare, did occur, usually in association with other malignancies.Classification of evidenceThis study provides Class IV evidence that for patients with POEMS syndrome, ASCT improves neuropathy-related function.

Project description:Autologous stem cell transplantation (ASCT) is a standard of care for patients with chemosensitive, relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and diffuse large B cell lymphoma (DLBCL). Whereas the clinical benefit of ASCT has traditionally been attributed solely to cytoreduction from intensive chemotherapy, ASCT has important immunogenic effects that may contribute to its antitumor efficacy and could provide a favorable immune environment for post-ASCT immune-based maintenance treatments. We previously reported clinical results of a phase II trial (ClinicalTrials.gov identifier NCT02362997) testing 8 doses of pembrolizumab maintenance therapy after ASCT for patients with R/R cHL or DLBCL. To clarify the impact of pembrolizumab on immune reconstitution, we compared the kinetics of peripheral blood immune cell recovery after ASCT for trial patients receiving pembrolizumab maintenance to those of a contemporaneous control cohort of similar patients undergoing ASCT without pembrolizumab maintenance. This study was conducted to characterize the impact of post-ASCT pembrolizumab maintenance therapy on immune reconstitution for patients with R/R DLBCL and cHL and to identify candidate biomarkers of efficacy and immune-related adverse events (irAEs). Peripheral blood (PB) mononuclear cell samples were prospectively collected at 1 to 18 months after ASCT and analyzed by flow cytometry using a panel of fluorophore-conjugated monoclonal antibodies to identify B cells, natural killer (NK) cells, and various dendritic cell (DC) and T cell subsets. A median of 5 (range, 1 to 8) post-ASCT PB samples were collected from 144 patients (59 in the pembrolizumab group and 85 in the control group). Clinical characteristics of the 2 cohorts were similar. Compared with cHL patients, DLBCL patients (all of whom received anti-CD20 monoclonal antibody therapy before ASCT) had delayed CD19+ cell reconstitution that persisted for at least 18 months after ASCT. No other differences in immune reconstitution based on lymphoma subtype were observed. Post-ASCT pembrolizumab maintenance therapy was associated with an elevation in circulating DCs (driven by higher levels of plasmacytoid and immature DCs) that persisted for the duration of pembrolizumab treatment, along with a significant reduction in PD-1+ T cells that persisted for 6 to 12 months after completion of pembrolizumab therapy. Despite the key role of T cells in mediating the effects of PD-1 blockade, pembrolizumab maintenance did not affect recovery of any T cell subsets. In an exploratory analysis, a higher baseline CD4+ terminal effector memory cell count (defined as CD3+CD4+CD45RA+CD62L-) was associated with inferior progression-free survival (PFS), but only among patients who received pembrolizumab maintenance (P = .003). As continuous variables, lower absolute levels of NK cells (P = .009), PD-1+ CD4+ T cells (P = .005), and PD-1+ CD8+ T cells (P = .005) before pembrolizumab initiation were each associated with a higher risk of grade 2+ irAEs. Our findings indicate that post-ACST pembrolizumab maintenance therapy is associated with a persistent elevation of circulating DCs, but its impact on the reconstitution of other immune cells in peripheral blood appears limited. Our study suggests that early features of post-ASCT immune reconstitution could be associated with PFS and the risk of irAE and warrant additional investigation. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Dataset Information

Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS.

Publications

Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets