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Front. Immunol. | doi: 10.3389/fimmu.2018.00410

Regenerating immunotolerance in Multiple Sclerosis with Autologous Haematopoietic Stem Cell Transplantation.

 Jennifer C. Massey1, 2, 3, 4*, Ian J. Sutton2, 4, David D. Ma1, 3, 4 and  John J. Moore1, 3, 4
  • 1Haematology and Bone Marrow Transplantation, St Vincent’s Hospital Sydney, Australia
  • 2Neurology, St Vincent’s Hospital Sydney, Australia
  • 3Centre for Applied Medical Research, St Vincent’s Hospital Sydney, Australia
  • 4St Vincent's Clinical School, University of New South Wales, Australia

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 haematopoietic 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 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 immune reconstitution 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 normalisation 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 immune reconstitution therapies, focusing on AHSCT, as a means of recalibrating the dysfunctional immune response observed in MS.

Keywords: Multiple Sclerosis, aHSCT, T cell receptor repertoire, Immune Tolerance, lymphopenia induced proliferation, alemtuzumab, Cladribine

Received: 06 Dec 2017; Accepted: 14 Feb 2018.

Edited by:

Maria Carolina Oliveira, University of São Paulo, Brazil

Reviewed by:

Michael Uhlin, Karolinska Institute (KI), Sweden
Sergio Querol, Banc de Sang i Teixits, Spain  

Copyright: © 2018 Massey, Sutton, Ma and Moore. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Jennifer C. Massey, St Vincent’s Hospital Sydney, Haematology and Bone Marrow Transplantation, Darlinghurst, Australia, jennifer.massey@svha.org.au