Regenerating Immunotolerance in Multiple Sclerosis with Autologous Hematopoietic Stem Cell Transplant

Abstract

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system where evidence implicates an aberrant adaptive immune response in the accrual of neurological disability. The inflammatory phase of the disease responds to immunomodulation to varying degrees of efficacy; however, no therapy has been proven to arrest progression of disability. Recently, more intensive therapies, including immunoablation with autologous hematopoietic stem cell transplantation (AHSCT), have been offered as a treatment option to retard inflammatory disease, prior to patients becoming irreversibly disabled. Empirical clinical observations support the notion that the immune reconstitution (IR) that occurs following AHSCT is associated with a sustained therapeutic benefit; however, neither the pathogenesis of MS nor the mechanism by which AHSCT results in a therapeutic benefit has been clearly delineated. Although the antigenic target of the aberrant immune response in MS is not defined, accumulated data suggest that IR following AHSCT results in an immunotolerant state through deletion of pathogenic clones by a combination of direct ablation and induction of a lymphopenic state driving replicative senescence and clonal attrition. Restoration of immunoregulation is evidenced by changes in regulatory T cell populations following AHSCT and normalization of genetic signatures of immune homeostasis. Furthermore, some evidence exists that AHSCT may induce a rebooting of thymic function and regeneration of a diversified naïve T cell repertoire equipped to appropriately modulate the immune system in response to future antigenic challenge. In this review, we discuss the immunological mechanisms of IR therapies, focusing on AHSCT, as a means of recalibrating the dysfunctional immune response observed in MS.

Immune Reconstitution Therapy or Continuous Immunosuppression for the Management of Active Relapsing–Remitting Multiple Sclerosis Patients? A Narrative Review

“…Overall, the short course of treatment and extended period of efficacy beyond the period of reduction in lymphocyte counts observed in many patients is consistent with an IRT-like mechanism (Fig. 1) [17]. Treatment with Cladribine Tablets 3.5 mg/kg also reduced the rate of conversion to clinically definite MS over 2 years in patients with a first demyelinating event [51].…”

“…Briefly, in aHSCT HCSs are mobilized from the bone marrow and harvested, following which the patient's pathological immune system is ablated entirely using strong immunosuppressive drugs; subsequent reinfusion of the HSCs allows the immune system to rebuild, without further autoimmunity if the treatment is successful [16,17]. Clinical studies suggest that aHSCT is an effective treatment, with progression-free survival in 70-91% of patients, MRI event-free survival in 85-100% and ''no evidence of disease activity'' (NEDA) in 68-70%, at 4-5 years post-treatment [16].…”

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)

“…aHSCT is performed with the premise to reconstitute, and ideally re-condition, the immune system towards a selftolerant state by depleting the autoreactive immunologic memory with high-dose chemotherapy followed by a profound regeneration of a renewed and diverse immune system, i.e. 'immune reset' [120][121][122][123].…”

The TCR Repertoire Reconstitution in Multiple Sclerosis: Comparing One-Shot and Continuous Immunosuppressive Therapies

“…Two successful RRMS disease-modifying therapies are natalizumab (NTZ), a humanized monoclonal antibody directed against the integrin α4β1 (or Very Late Antigen-4, VLA-4) that prevents the migration of pathogenic T cells into the CNS (4), and AHSCT that resets the immune system and restores immune tolerance by depleting pathogenic adaptive immune cells (5). Both treatments are particularly effective in those patients who have failed previous conventional therapies (6,7).…”